Skaaby, T., Kilpeläinen, T. O., Taylor, A. E., Mahendran, Y., Wong, A.,Ahluwalia, T. S., Paternoster, L., Trompet, S., Stott, D. J., Flexeder,C., Zhou, A., Brusselle, G., Sajjad, A., Lahousse, L., Tiemeier, H.,Have, C. T., Thuesen, B. H., Kårhus, L. L., Møllehave, L. T., ...Linneberg, A. (2019). Association of alcohol consumption with allergicdisease and asthma: a multi-centre Mendelian randomizationanalysis. Addiction, 114(2), 216-225.https://doi.org/10.1111/add.14438
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1
Supplementary Material
CONTENTS
STUDY DESCRIPTIONS ...................................................................................................................................... 3
The Allergy98 Cohort ........................................................................................................................................ 3
British 1958 Birth Cohort .................................................................................................................................. 4
The Dan-Monica10 study .................................................................................................................................. 5
GOYA Males ..................................................................................................................................................... 6
Health2006 ......................................................................................................................................................... 7
Inter99 ................................................................................................................................................................ 8
DanFunD............................................................................................................................................................ 9
KORA .............................................................................................................................................................. 11
NSHD .............................................................................................................................................................. 12
The 1936 Cohort .............................................................................................................................................. 13
Prosper ............................................................................................................................................................. 14
The Rotterdam Study ....................................................................................................................................... 14
SHIP ................................................................................................................................................................. 15
SHIP TREND .................................................................................................................................................. 16
The Copenhagen City Heart Study .................................................................................................................. 17
The NEO study ................................................................................................................................................ 18
UK Biobank ..................................................................................................................................................... 19
SUPPLEMENTARY TABLES ............................................................................................................................ 22
Table S1 ........................................................................................................................................................... 22
Table S2 ........................................................................................................................................................... 25
Table S4 ........................................................................................................................................................... 27
MAIN SUPPLEMENTARY FIGURES ............................................................................................................... 29
Figure S1 .......................................................................................................................................................... 29
Figure S2 .......................................................................................................................................................... 30
Figure S3 .......................................................................................................................................................... 31
Figure S4 .......................................................................................................................................................... 33
Figure S5 .......................................................................................................................................................... 34
Figure S6 .......................................................................................................................................................... 35
Figure S7 .......................................................................................................................................................... 36
Figure S8 .......................................................................................................................................................... 37
Figure S9 .......................................................................................................................................................... 38
Figure S10 ........................................................................................................................................................ 39
2
Figure S11 ........................................................................................................................................................ 40
Figure S12 ........................................................................................................................................................ 41
Figure S13 ........................................................................................................................................................ 42
REFERENCES ..................................................................................................................................................... 43
3
Study descriptions
The Allergy98 Cohort
The Copenhagen Allergy study began in 1990 that included two groups of persons living in
the Western part of the Copenhagen Region (1). The first group was randomly selected from
the general population, and the other group included persons with allergic respiratory
symptoms that were chosen by a screening questionnaire from a random sample of the
general population. In the present study, we used data from the follow-up study in 1997–1998
(referred to as ‘Allergy98’). In the Allergy98 study, 1,966 persons aged 15–77 years with
Danish nationality were invited, and 1,216 (participation rate 61.9%) participated. The study
included comprehensive questionnaire, interview, clinical, and biochemical data.
Genotyping
Genotyping of the rs1229984 SNP was performed by TaqMan Chemistry (Applied
Biosystems, Foster City, CA) or PCR amplification followed by restriction cleavage
analysis(2).
Hay fever, asthma, allergic sensitization and total IgE
Hay fever was defined as a positive answer to the question: “Have you had hay fever in the
last 12 months?” Asthma was defined as a positive answer to the question: “Have you had
asthma in the last 12 months?” We used the ADVIA Centaur sIgE assay (Bayer Corporation,
New York, NY) to test serum specific IgE to mite (Dermatophagoides pteronyssinus), grass,
cat, and birch, dog and mugwort(3). The specific IgE analysis was positive if the
measurement was ≥0.35 kU/l. Specific IgE positivity, atopy, was defined as one or more
positive tests for specific IgE against the tested allergens. Serum total IgE was measured with
Immulite (Siemens, Erlangen, Germany).
Alcohol status and intake
Participants were classified as non-drinkers and ever-drinkers, respectively, depending on
their answers to the following questions: “On average, how much of the following have you
drunk each week in the last 12 months? Number of beers/glasses of wine/glasses of liquor?”
Alcohol intake per week was calculated as the sum of the number of each alcoholic beverage
consumed according to the question above.
Ethics
The Allergy98 Cohort was approved by the Ethics Committee of Copenhagen and the Danish
Data Protection Agency. We followed the recommendations of the Declaration of Helsinki,
and each participant gave informed written consent.
Funding and acknowledgements
We thank the staff at the Centre for Preventive Medicine for their assistance. The
Copenhagen Allergy Study is supported by grants from the Danish Medical Research
Council, the Danish Health Insurance Fund, the Danish Ministry of Health (the National
Health Fund for Research and Development), the Danish Medical Research Council and the
Danish Ministry of Health (Research Centre for Environmental Health: Environmental Health
Research Programme 1997), and ALK Abelló A/S, Denmark.
Additional information
The analyses are not adjusted for principal component. The alcohol and rs1229984 SNP data
was previously published by Linneberg et al(4) and Husemoen et al(2).
4
British 1958 Birth Cohort
The British 1958 birth cohort (1958BC) is a longitudinal population based study and includes
all births during one week in March in 1958 in England, Scotland and Wales (5).
Approximately 17,000 participants were recruited at birth and were subsequently followed up
at ages 7, 11, 16, 23, 33, 42 and 45 years. At each follow-up, information on socioeconomic
status, health and development, and familial and education factors were obtained. Information
on asthma and hay fever is based on information collected at the age of 42. At 45 years of
age, 11,971 participants currently living in Britain were invited to take part in a biomedical
survey, of whom 9,377 (78%) filled in a questionnaire, in which information on alcohol
intake were obtained and 8,302 (89%) also provided a blood sample, in which serum IgE
concentration were measured and DNA were extracted for genotyping.
Genotyping
Genetic information was obtained from 3000 randomly selected blood samples collected at
45 years, through the Wellcome Trust Case Control Consortium(6) in which the 1958BC was
used as a source for population controls. The samples were genotyped on the Affymetrix 6.0
platform. The SNP rs1229984 was directly genotyped with a call rate of 96%.
Hay fever, asthma, allergic sensitization and total IgE
At age 42, participants were asked whether they had ever had asthma. 3.25% missing data
(percentage of participants with missing information on the outcome among those with
genetic data). Allergic sensitization was defined as specific IgE ≥0.30 kU/l in blood serum for
any of the following 3 inhalant allergens including dust, cat and grass. Note: specific IgE
were only measured if total IgE was greater than 30 kU/l. 2.98% missing data (percentage of
participants with missing information on the outcome among those with genetic data). Total
IgE was assayed using the HYTEC-automated enzyme immunoassay (7).
2.86% missing data (percentage of participants with missing information on the outcome
among those with genetic data). Serum total IgE were measured at the age of 45. Information
on hayfever and asthma were collected at the age of 42.
Alcohol status and intake
The information on alcohol intake was obtained at the age of 45. The alcohol intake data in
1958BC are intervals and we take the median value of each interval (1-7 units/week = 4
units/week; 7-14 units/week = 10.5 units/week; 14-21 units/week = 17.5 units/week; >21
units/week = 21 units/week).
Ethics
Written consent was obtained from participants for the use of information in medical studies.
The 45-year biomedical survey and genetic studies were approved by the South-East Multi-
Centre Research Ethics Committee (ref: 01/1/44) and the joint UCL/UCLH Committees on
the Ethics of Human Research (Ref: 08/H0714/40).
Funding and acknowledgements
This work made use of data and samples generated by the 1958 Birth Cohort (NCDS) , which
is managed by the Centre for Longitudinal Studies at the UCL Institute of Education, The
authors are deeply grateful to the 1958 birth cohort participants for their longstanding
commitment and support, and to all staff for cohort coordination and data collection.
5
The management of the 1958 Birth Cohort is funded by the Economic and
Social Research Council (grant number ES/M001660/1). Access to these resources was
enabled via the 58READIE Project funded by Wellcome Trust and Medical Research Council
(grant numbers WT095219MA and G1001799). DNA collection was funded by MRC grant
G0000934 and cell-line creation by Wellcome Trust grant 068545/Z/02. This study makes
use of data generated by the Wellcome Trust Case-Control Consortium. A full list of
investigators who contributed to generation of the data is available from the Wellcome Trust
Case-Control Consortium website. Funding for the project was provided by the Wellcome
Trust under the award 076113. This research used resources provided by the Type 1 Diabetes
Genetics Consortium, a collaborative clinical study sponsored by the National Institute of
Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and
Infectious Diseases, National Human Genome Research Institute, National Institute of Child
Health and Human Development, and Juvenile Diabetes Research Foundation International
(JDRF) and supported by U01 DK062418. Great Ormond Street Hospital/University College
London, Institute of Child Health receives a proportion of funding from the Department of
Health's National Institute for Health Research (NIHR) ('Biomedical Research Centres'
funding).
Additional information
The analyses are adjusted for principal component. The observational or genetic data have
previously been published.
The Dan-Monica10 study
In 1982–1984, a random sample of 4807 persons from the referral area of Glostrup County
Hospital, Copenhagen, was invited to participate in the Danish MONICA I health survey (8).
The study was a part of an international World Health Organization (WHO) co-ordinated
study, MONItoring of trends and determinants in CArdiovascular Diseases (MONICA). The
sample was selected to represent an equal number of men and women born in 1922, 1932,
1942 or 1952 (age 30, 40, 50 and 60 years). A total of 226 Individuals, who were not of
Danish nationality, were excluded. Of the remaining 4581 Danes, 3608 participated (79%).
We used data from a follow-up examination performed in 1993-1994, called Dan-
MONICA10. Since the first examination, 428 subjects had died and 23 had moved and could
not be reached. The remaining 4130 Danes were invited to a new examination, when the
participants were aged 41, 51, 61, or 71 years old. A total of 2656 (64%) participated in the
Dan-MONICA10 follow-up study. The health examinations took place a Research Centre for
Prevention and Health, Glostrup. Participants completed a self-administered questionnaire on
cardiovascular risk factors, medical history and lifestyle habits, including smoking and
physical activity. A physical examination was performed by trained staff.
Hay fever, asthma, allergic sensitization and total IgE
Hay fever was defined as a positive answer to the question: “Has a doctor ever told you that
you had allergic hay fever?” Asthma was defined as a positive answer to the question: “Has a
doctor ever told you that you had asthma?”Allergic sensitisation, atopy, was defined by
determination of serum specific IgE as described in previous studies (9-12). In the Monica1
study, serum specific IgE positivity was tested using the ADVIA Centaur Allergy Screen
assay (Bayer HealthCare Diagnostics division, Tarrytown, N.Y., USA) (13) that is a multi-
allergen assay to detect specific serum IgE antibodies to 19 common inhalant allergens.
6
Atopy was defined as one or more positive results according to the manufacturer’s
instructions. Total IgE was not measured.
Alcohol status and intake
Participants were classified as non-drinkers and ever-drinkers, respectively, depending on
their answers to the following questions: “On average, how much of the following have you
drunk each week in the last 12 months? Number of beers/glasses of wine/glasses of liquor?”
Alcohol intake per week was calculated as the sum of the number of each alcoholic beverage
consumed according to the question above.
Genotyping
Genotyping of the rs1229984 SNP was performed using KBiosciences allele-specific PCR
(KASPar) (KBioscience, Hoddesdon, UK).
Ethics
Ethics approval was given by the local research ethics committee. All participants in the Dan-
Monica10 study gave written consent and the study was conducted in accordance with the
Second Helsinki Declaration.
Funding and acknowledgements
The Dan-MONICA10 was sponsored by The Danish Heart Foundation; the Danish Medical
Research Council; The Danish Hospital Foundation of Medical Research, region of
Copenhagen, the Faroe Islands and Greenland; The Danish Health Insurance Foundation; The
Foundation of E. & M. Wedel-Wedellsborg; Landsforeningen til Bekæmpelse af
Kredsløbssygdomme; The Augustinus Foundation; The Becket Foundation; and The
Foundation of senior registrar J. & L. Boserup.
Additional information
The analyses are not adjusted for principal component. The associations assessed in this study
have not previously been published.
GOYA Males
Genomics of Overweight Young Adults (GOYA) males is a longitudinal case-cohort (obese,
non-obese) study comprising a randomly (1%) selected control group and all extremely
overweight men identified among 362,200 Caucasian men examined at the mean age of 20
years at the draft boards in Copenhagen and its surrounding areas during 1943–1977. Obesity
was defined as 35% overweight relative to a local standard in use at the time (mid 1970’s),
corresponding to a BMI ≥31.0 kg/m2, which proved to be above the 99th percentile. All of
the obese and 50% of the random sampled controls, who were still living in the region, were
invited to a follow-up survey in 1992–94 at the mean age of 46 years, at which time the blood
samples were taken and genotyping were performed for a total of 673 extremely overweight
and 792 controls. With a sampling fraction of 0.5% (50% of 1%), the controls represent about
158,000 men among whom the case group was the most obese. In the current study,
information from cohort part comprising 790 individuals with non-missing data was utilized.
Genotype
Genome-wide genotyping on the Illumina 610 k quad chip was carried out at the Centre
National de Ge´notypage (CNG), Evry, France. We excluded SNPs with minor allele
7
frequency, 1%, 0.5% missing genotypes or which failed an exact test of Hardy-Weinberg
equilibrium (HWE) in the controls. We also excluded any individual who did not cluster with
the CEU individuals (Utah residents with ancestry from northern and western Europe) in a
multidimensional scaling analysis seeded with individuals from the International HapMap
release 22.
Alcohol status and intake
Participants were classified as non-drinkers if they reported to drink alcohol “never/almost
never” and ever-drinkers if they reported to drink alcohol “Monthly”, “Weekly” or “Daily”.
Alcohol intake per week was calculated as the sum of the number of self-reported
consumption of beers, glasses of wine, and glasses of liquor per week.
Hay fever, asthma, allergic sensitization and total IgE
Asthma was evaluated by questionnaire with the question: ”Do you suffer from Asthma?”
Hay fever was evaluated by the question: “Does food, medicine or grass give you hay fever?”
Allergic sensitization and serum total IgE were not determined.
Ethics
The study was approved by the regional scientific ethics committee and the Danish Data
Protection Board with consent from the participants.
Funding and acknowledgements
The GOYA study was conducted as part of the activities of the Danish Obesity Research
Centre (DanORC, www.danorc.dk) and The MRC centre for Causal Analyses in
Translational Epidemiology (MRC CAiTE). The genotyping for GOYA was funded by the
Wellcome Trust (WT 084762). GOYA is a nested study within The Danish National Birth
Cohort which was established with major funding from the Danish National Research
Foundation. Additional support for this cohort has been obtained from the Pharmacy
Foundation, the Egmont Foundation, The March of Dimes Birth Defects Foundation, the
Augustinus Foundation, and the Health Foundation. TSA was supported by the Gene Diet
Interactions in Obesity (GENDINOB, www.gendinob.dk ) postdoctoral fellowship grant. LP
is funded by an MRC Population Health Scientist Fellowship (MR/J012165/1).
Additional information
The analyses are not adjusted for principal components, but ethnic outliers and related
individuals were already excluded during post genotyping quality control. Some data were
previously published (14).
Health2006
The Health2006 study took place from 2006 to 2008 and consisted of a random sample of
7,931 Danish (Danish nationality and born in Denmark) men and women aged 18-69 years
invited to participate in a health examination(15). A total of 3,471 (43.8%) persons
participated. Potential participants living in the Copenhagen area were identified in the
central Danish Civil Registration System, and then recruited by invitation. The aim was to
investigate the prevalence and risk factors of chronic diseases such as asthma, allergies,
cardiovascular disease, and diabetes.
Genotyping
8
Blood samples were taken from all participants as part of their health examination. The buffy
coat was frozen for DNA extraction, and later genomic DNA was extracted using a Qiagen
AutoPure LS system. Genotyping was performed using KBiosciences allele-specific PCR
(KASPar) (KBiosciences, Hoddesdon, UK).
Hay fever, asthma, allergic sensitization and total IgE
We used the ADVIA Centaur sIgE assay (Bayer Corporation, New York, NY) to test serum
specific IgE to mite (Dermatophagoides [D.] pteronyssinus), grass, cat, and birch (3). The
specific IgE analysis was positive if the measurement was ≥0.35 kU/l. Allergic sensitization,
atopy, was defined as one or more positive tests for specific IgE against the allergens.
Classification of hay fever and asthma was done by the questions: ”Has a doctor ever told
you that you had/have hay fever?” and ”Has a doctor ever told you that you had/have
asthma”. Serum total IgE was not determined.
Alcohol status and intake
Participants were classified as non-drinkers and ever-drinkers, respectively, depending on
their answers to the following questions: “On average, how much of the following have you
drunk each week in the last 12 months? Number of beers/number of strong beers/glasses of
wine/ glasses of fortified wine/glasses of liquor. Alcohol intake per week was calculated as
the sum of the number of each alcoholic beverage consumed (strong beers count for 1.5 units
of alcohol) according to the question above.
Ethics
The Health2006 study was approved by the Ethical Committee of Copenhagen (KA-
20060011) and the Danish Data Protection Agency. Informed written consent was obtained
from all participants.
Funding and acknowledgements
The Health2006 study was financially supported by grants from the Velux Foundation; the
Danish Medical Research Council, Danish Agency for Science, Technology and Innovation;
the Aase and Ejner Danielsens Foundation; ALK-Abello´ A/S (Hørsholm, Denmark), Timber
Merchant Vilhelm Bangs Foundation, MEKOS Laboratories (Denmark) and Research Centre
for Prevention and Health, the Capital Region of Denmark.
Additional information
The analyses are not adjusted for principal component. The data concerning the alcohol-
associated SNP and allergy have not been published previously.
Inter99
The Inter99 study is a randomised controlled trial (CT00289237, ClinicalTrials.gov)
investigating the effects of lifestyle intervention on CVD (N=61,301) (16). We used baseline
data from a random subsample of 12,934 men and women aged approximately 30, 35, 40, 45,
50, 55, or 65 years invited to participate in a health examination during 1999-2001.
Participants were living in the Copenhagen area and were identified in the central Danish
Civil Registration System, and recruited by invitation. Only participants with a Northern
European origin (Denmark, Norway, Sweden, Iceland, and Faeroe Islands) were included in
the present study.
9
Genotyping
DNA was extracted from blood samples taken from all participants as part of their health
examination. Genotyping was performed using KBiosciences allele-specific PCR (KASPar)
(KBiosciences, Hoddesdon, UK).
Hay fever, asthma, allergic sensitization and total IgE
Asthma was defined as a positive answer to the question: “Has a doctor ever told you that
you had asthma?” Serum samples were analyzed for specific IgE to mite (D. pteronyssinus),
grass, cat, and birch by the IMMULITE 2000 Allergy Immunoassay System (17). The
specific IgE analysis was positive if the measurement was ≥0.35 kU/l. Allergic sensitization
was defined as a positive test for specific IgE against any of the allergens. Serum total IgE
was measured with IMMULITE_ 2000 Allergy Immunoassay System in 2008(17). Hay fever
was not determined.
Alcohol status and intake
Alcohol intake was defined as the number of self-reported units of alcohol consumed each
week. Strong beers contributed 1.5 units of alcohol. Participants were classified as non-
drinkers and ever-drinkers, respectively, depending on their reported consumption of alcohol.
Ethics
Informed written consent was obtained from all participants. The study was approved by the
Ethical Committee of Copenhagen.
Funding and acknowledgements
Data collection in the Inter99 study was supported economically by The Danish Medical
Research Council, The Danish Centre for Evaluation and Health Technology Assessment,
Novo Nordisk, Copenhagen County, The Danish Heart Foundation, The Danish
Pharmaceutical Association, Augustinus foundation, Ib Henriksen foundation and Becket
foundation. LLNH was supported by the Health Insurance Foundation (grant No. 2010 B
131).
Additional information
The analyses are not adjusted for principal component. The data concerning the alcohol-
associated SNP (rs1229984) and allergy have not been published previously.
DanFunD
The DanFunD study (18) was initiated at the Research Centre for Prevention and Health,
Glostrup, Denmark, as a random sample of the general adult population. The cohort
comprises a total of 9,656 individuals aged 18–76 years, born in Denmark and living in the
Western part of the greater Copenhagen. The cohort consist of DanFunD part one and
DanFunD part two. In the current study, we use the DanFunD part two data. The DanFunD
part two was carried out from 2012 to 2015. A total of 7,493 individuals aged 18–72 years
participated.
Genotyping
Genotyping was conducted applying Human OmniExpress Bead array on human leukocyte
DNA, covering ~800,000 single nucleotides. The genotyping data was imputed from national
and international genotype panels.
10
Hay fever, asthma, allergic sensitization and total IgE
Classification of hay fever and asthma was done by the questions: ”Has a doctor ever told
you that you had/have hay fever?” and ”Has a doctor ever told you that you had/have
asthma”. Serum samples were analyzed for IgE sensitization to inhalant allergens on a Phadia
250 system at Thermo Scientific ImmunoDiagnostics, Allerød, Denmark. Measurements
were performed in March-July 2016. Samples were screened for specific IgE to the most
common inhalant allergens by using the Phadiatop. Phadiatop-positive (>0.35 kUA/L)
samples were further analyzed for specific IgE to the four most clinical relevant inhalant
allergens in Denmark: grass, birch, Dermatophagoides pteronyssinus, and cat. The specific
IgE analysis was positive if the measurement was ≥0.35 kU/l. Allergic sensitization was
defined as a positive test for specific IgE against any of the allergens. Total IgE was not
measured.
Lung function
Forced expiratory volume in 1-second (FEV1) and forced vital capacity (FVC) were
measures at baseline by spirometry and expressed in litres.
Alcohol status and intake
Participants were classified as non-drinkers and ever-drinkers, respectively, depending on
their answers to the following questions: “Did you drink alcohol in the last 12 months?
Alcohol intake per week was calculated as the sum of the number of each alcoholic beverage
consumed.
Ethics
Written informed consent was obtained from all participants, and the study was approved by
the Ethical Committee of Copenhagen County (Ethics Committee: KA-2006-0011, H-3-
2011-081, and H-3-2012- 0015) and the Danish Data Protection Agency.
Funding and acknowledgements
This study was supported by TrygFonden (7-11-0213), the Lundbeck Foundation (R155-
2013-14070), and Novo Nordisk Foundation (NNF15OC0015896). The measurements of
serum specific IgE were funded by the Lundbeck Foundation (Grant number R165-2013-
15410), the A.P. Møller Foundation for the Advancement of Medical Science (Grant number
15-363), and Aase and Einar Danielson’s Foundation (Grant number 10-001490). The Novo
Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center
at the University of Copenhagen partially funded by an unrestricted donation from the Novo
Nordisk Foundation (www.metabol.ku.dk).
Additional information
The principal investigator of the DanFunD, Torben Jørgensen, from RCPH leads the
coordination of projects and activities and is responsible for the operation of DanFunD,
including scientific, administrative, financial, ethics, and communication tasks. The steering
committee consists of Professor Torben Jørgensen, Professor Per Fink, senior scientist Sine
Skovbjerg, chief physician Jesper Mehlsen, and chief physician Lene Falgaard Eplov. The
steering committee reviews the scientific progress and oversees the direction and progress of
the scientific objectives. For more information, please contact DanFunD administrative and
scientific officer Thomas Dantoft or visit our webpage at http://www.danfund.org.
11
KORA
The Cooperative Health Research in the Region of Augsburg (KORA) study is a population
based study. The study participants were recruited from the third MONICA survey (S3)
which was conducted in 1994–1995 in Augsburg, Germany. The objective and protocols of
the MONICA surveys have been previously described (19). Briefly, four cross-sectional
health surveys (MONICA S1 to S4) were performed in the population aged 25-74 years of
the city of Augsburg and two surrounding counties. In total, 4856 participants were recruited
in the S3 survey in 1994/1995. The study used for these analyses is a nested case-control
study comprising 1537 participants, which was performed between September 1997 and
December 1998 and in which cases were defined by sensitization status (SPT/RAST). Details
of the sampling frame and study design have been published earlier (20).
Genotyping
The study participants underwent a standardized medical examination including blood draw.
Genotyping was performed on the Illumina Omni 2.5 and the Illumina Omni Express
platform. Genotypes were called with Genome Studio and annotated to NCBI build 37.
(Before imputation, SNPs with call rates <98% were excluded. Imputation was performed
with IMPUTE v2.3.0 using the 1000G phase 1 (v3) reference panel.) (21).
Hay fever, asthma, allergic sensitization and total IgE
Information on hay fever was requested using a self-administered questionnaire. The
participants were asked whether hay fever was ever diagnosed by a doctor. Information on
asthma was requested using a self-administered questionnaire. The participants were asked
whether asthma was ever diagnosed by a doctor. Allergen specific IgE antibodies to common
aeroallergens (grass and birch pollen, housedust mite, cat and Cladosporium) were
determined by the fluorescence enzyme immunoassay technique (CAP-FEIA, Pharmacia,
Uppsala, Sweden). Allergic sensitization was defined as serum specific IgE sensitivity (≥
0.35 kU/l) against at least one inhalant allergen.
Alcohol status and intake
Information on self-reported alcohol status and alcohol intake was not available.
Ethics
The study was approved by the ethics committee of the Bavarian Medical Association, and
written informed consent was obtained from each participant.
Funding
The KORA research platform (KORA, Cooperative Research in the Region of Augsburg) and
the MONICA Augsburg studies were initiated and financed by the Helmholtz Zentrum
München – German Research Center for Environmental Health, which is funded by the
German Federal Ministry of Education and Research and by the State of Bavaria.
Furthermore, KORA research was supported within the Munich Center of Health Sciences
(MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ.
Additional information
The analyses were not adjusted for principal components. The current associations have not
been previously published.
12
NSHD
The Medical Research Council National Survey of Health and Development (NSHD) is an
on-going prospective population based birth cohort study consisting of all births in England,
Scotland and Wales in one week in March 1946 (22). The sample includes single, legitimate
births whose fathers were in non-manual or agricultural occupations and a randomly selected
one in four of all others, whose fathers were in manual labor. The original cohort comprising
2,547 women and 2,815 men have been followed-up over 24 times since their birth. The data
collected to date include repeat cognitive function, physical, lifestyle and anthropomorphic
measures, as well as blood analytes and other measures. The cohort recently completed a
particularly intensive phase of clinical assessment and biological sampling with blood and
urine sampling and analysis, and cardiac and vascular imaging (23).
Genotyping
DNA was extracted from blood samples collected in 1999 (24). Genotyping was carried out
by LGC Genomics (Hoddesdon, UK; www.lgcgenomics.com) using fluorescence-based
competitive allele-specific PCR (KASPar).
Hay fever, asthma, allergic sensitization and total IgE
The study has data on self-reported hay fever and self-reported asthma. The outcome hay
fever variable was derived from responses to questions about hay fever asked by the research
nurses at home visits in 1989 and 1999. In 1989, cohort members were asked whether they
had ever had hay fever, and in 1999 they were asked whether they had had it in the last 10
years. The asthma variable was derived from responses to questions about asthma asked by
the research nurses at home visits in 1989 and 1999. In 1989, cohort members were asked
whether they had ever had asthma, and in 1999 they were asked whether they had had it in
the last 10 years. Allergic sensitization and serum total IgE were not determined.
Alcohol status and intake
Alcohol status and intake were derived from responses to questions about drinking asked by
research nurses at home visits in 1999. The alcohol status variable was derived from
responses to whether cohort members had drunk alcohol in the last year. The alcohol intake
variable was derived from responses to questions asked about number of alcoholic drinks in
the last 7 days.
Additional information
The analyses are not adjusted for principal component. Some of the observational or genetic
data have previously been published in CARTA papers or elsewhere (25).
Ethics
Ethical approval was given by the Central Manchester Research Ethics Committee, and the
participants gave informed written consent.
Funding and acknowledgements
We are very grateful to the members of this birth cohort for their continuing interest and
participation in the study. We would like to acknowledge the Swallow group at University
College London, who performed the DNA extractions. This work was funded by the Medical
Research Council [MC_UU_12019/1].
13
The 1936 Cohort
The 1936 Cohort is a longitudinal population-based study based on a sample of 1,200
randomly selected persons living in 1976 (aged 40 years at the time of the study) in 4
municipalities (Broendby, Glostrup, Herlev, and Ledoeje-Smoerum) of Copenhagen drawn
from the Danish Civil Registration. They were invited by letter for a health examination that
focused on cardiovascular risk factors. The letter contained a questionnaire regarding medical
history, health and lifestyle that they were asked to complete in advance. Between 1976 and
1977, a total of 1,052 persons were examined (participation rate=87.7%). In 1995–1996 all
participants (now aged 60 years) were invited for a re-examination where a total of 695 were
examined (participation rate=66%). We use the re-examination data in the current study.
Genotyping
DNA was extracted and purified from leukocytes (LGC Genomics, Hoddlesdon, UK). All
participants were genotyped with the Illumina Infinium HumanCoreExome-12 BeadChip
(CoreExomeChip) using HiScan system (Illumina) at the Novo Nordisk Foundation Centre
for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark. The
standard pipeline in Illumina Genome Studio software was used for the genotype calling.
A total of 538,448 markers on 684 individuals entered the Quality Control (QC) pipeline,
where 9886 markers were removed due to a call-rate below 95% before QC on individuals
could begin. 28 individuals were excluded due to: 1) a call-rate below 95%, 2) extreme
positive or negative inbreeding coefficients 3) ethnic outliers using Principal Component
Analysis (PCA) on ancestral markers, 4) unknown pedigree relation found by Identical By
Descent (IBD) analysis, where the individual with the lowest call rate for each pedigree-pair
was removed, 5) sample duplicates, and finally 6) sex discrepancy.
We used a combination of scripts written in Python (v2.7.3) and R (v3.0.1)
together with the PLINK (v1.07) software in our QC pipeline. After QC, 656 individuals with
528,562 markers were ready for imputation.
Additional genotypes were imputed with 1,000 Genomes haplotypes Phase I
integrated variant set release (SHAPE2) in NCBI build 37 (hg19) coordinates, using
IMPUTE2 (26) on all markers that passed a Hardy-Weinberg Equilibrium (HWE) filter
(pHWE<0.005), into the 1000 genomes phase 1 panel(27).
Hay fever, asthma, allergic sensitization and total IgE
The questionnaire used in 1995–1996 (at 60 years of age) included the following questions on
atopic diseases: “Has a doctor ever told you that you had hay fever?” (self-reported hay fever
if they answered “yes”)” and “Has a doctor ever told you that you had asthma?” (self-
reported asthma if they answered “yes”).
Measurements of aeroallergen sensitization were performed using the ADVIA
Centaur® Allergy Screen assay (Bayer HealthCare Diagnostics division, Tarrytown, N.Y.,
USA) that is a multi-allergen assay for the qualitative detection of specific serum IgE
antibodies specific to serum levels of common inhalant allergens. The test includes a total of
19 common inhalant allergens. Allergic sensitization was defined as a positive result of the
binary assay output. Serum total IgE was not determined.
Alcohol status and intake
Participants were classified as non-drinkers and ever-drinkers, respectively, depending on
their self-reported consumption of beers, glasses of wine, and glasses of liquor each week.
Alcohol intake per week was calculated as the sum of the number of each alcoholic beverage
consumed according to the question above.
14
Ethics
The study was conducted according to the principles of the Declaration of Helsinki. It was
approved by the Local Ethics Committee, and participants gave written informed consent.
Additional information
The current analyses are not adjusted for principal component. The current associations have
not been previously published.
Prosper
All data come from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER)
that is a population-based randomized controlled trial. A detailed description of the study has
been published elsewhere (28). PROSPER was a prospective multicenter randomized
placebo-controlled trial to assess whether treatment with pravastatin diminishes the risk of
major vascular events in elderly. Between December 1997 and May 1999, we screened and
enrolled subjects in Scotland (Glasgow), Ireland (Cork), and the Netherlands (Leiden). Men
and women aged 70-82 years were recruited if they had pre-existing vascular disease or
increased risk of such disease because of smoking, hypertension, or diabetes. A total number
of 5,804 subjects were randomly assigned to pravastatin or placebo. A large number of
prospective tests were performed including Biobank tests and cognitive function
measurements.
Genotyping
A total of 5,763 subjects’ DNA was available for genotyping. Genotyping was performed
with a Taqman assay.
Hay fever, asthma, allergic sensitization and total IgE
Asthma was defined as a self-reported diagnosis of asthma in the adverse events database.
Hay fever, allergic sensitization and total IgE were not assessed.
Alcohol status and intake
Alcohol status was self-reported and requested as units per week during the last month at
baseline of the study (mean age 75.3yr).
Ethics
Local hospital ethics committees in Scotland, Ireland, and the Netherlands approved the
PROSPER study, and all participants provided informed consent.
Additional information
The current associations have not been previously published.
The Rotterdam Study
This study was embedded in the Rotterdam Study, a prospective population-based cohort that
started in 1990 among inhabitants aged ≥55 years residing in a suburb of Rotterdam, the
Netherlands (29). Initially 7983 persons living in the well-defined Ommoord district in the
15
city of Rotterdam in The Netherlands (78 % of 10,215 invitees) participated in the study.
From January 1990 onwards, participants were recruited for the Rotterdam Study. In 2000,
3011 participants (out of 4472 invitees) who had become 55 years of age or moved into the
study district since the start of the study were added to the cohort. In 2006 a further extension
of the cohort was initiated in which 3932 subjects were included, aged 45–54 years, out of
6057 invited, living in the Ommoord district. For the present study, after exclusion of
participants with missing data on one of the exposures and outcome (alcohol status (n=2608);
alcohol quantity (n=2321); rs1229984 genotype (n=1511); and asthma (n=509) information
on each determinant was available from 7977 participants for analyses.
Genotyping
All persons attending the baseline examination in 1990-1993 consented to genotyping, and
had DNA extracted from blood leucocytes. Genotyping of autosomal SNPs was performed in
persons with high-quality extracted DNA using the Illumina Infinium II HumanHap550chip
v3.0® array according to the manufacturer’s protocols. In the second cohort (baseline
examination in 2000), the majority of the DNA samples were genotyped using the
HumanHap 550 Duo Arrays; 5% were genotyped using the Human 610 Quad Arrays
(Illumina). In the third cohort (baseline examination in 2006), all DNA samples were
genotyped using the Illumina Infinium II HumanHap550chip v3.0®array. Regarding
imputation, the set of genotyped input SNPs used for imputation in each study was selected
based on highest quality GWA data. The call rate was set at >98% in Rotterdam Study; the
minor allele frequency at >0.01; and the Hardy-Weinberg P >10-6.
Alcohol status and intake
The study has information of both alcohol status and alcohol quantity.
Hay fever, asthma, allergic sensitization and total IgE
Asthma was defined as a physician-diagnosed asthma at cohort entry (or within 1 year after
cohort entry). The number of missing data relative to asthma was 6% (n=509). Hay fever,
allergic sensitization and serum total IgE were not measured at baseline.
Ethics
A written informed consent was obtained from all participants. The Rotterdam Study has
been approved by the medical ethics committee according to the Population Study Act
Rotterdam Study, executed by the Ministry of Health, Welfare and Sports of the Netherlands.
SHIP
The Study of Health in Pomerania (SHIP) is a population-based epidemiological study in the
region of Western Pomerania. SHIP was at first planned as a cross-sectional study (30).
Examinations were held in centers stationed at Stralsund and Greifswald between the 16th of
October 1997 and the 19th of May 2001. SHIP-0 concluded with a participant proportion of
68,8%. The participation proportion of women was slightly higher (69.4%) than the men’s
(68.2%). Participation in the different age groups for women ranged from 76.6% (participants
aged between 50 and 60) to 49.5% (participants aged between 70 and 80) and for men from
74.3% (participants aged between 50 and 60) to 63.2% (participants aged between 70 and
80). More information incl. the above can be found at: http://www.medizin.uni-
greifswald.de/cm/fv/ship/stud_desc_en.html
16
Genotyping
Genotyping was performed using the Human SNP 6.0 Array (Affymetrix, Santa Clara, CA,
USA). Hybridization of genomic DNA was genotyped according to the manufacturer’s
standard recommendations. Genotypes were determined using the Birdseed2 clustering
algorithm. All remaining arrays had a sample call rate > 92 %.
Hay fever, asthma, allergic sensitization and total IgE
Participants were classified as having hay fever if they answered confirmatory to the
question: “Do you sometimes or all the time suffer from hay fever?” The participants were
defined as having allergic asthma or not according to self-reported questionnaire information.
Serum total IgE levels were measured by the Latex IgE test on the BN II Nephelometer
(Dade Behring Marburg GmbH, Marburg, Germany) and expressed in IU/ml (31). Serum
specific IgE was not measured.
Alcohol status and intake
Alcohol intake was defined as the amount of self-reported alcohol consumption last week.
Participants were classified as non-drinkers and ever-drinkers, respectively, depending on
their reported consumption of alcohol.
Additional information
The analyses are not adjusted for principal components.
Ethics
SHIP was planned and accompanied with support and advice from an external Data Safety
and Monitoring Committee (DSMC). Each participant gave written informed consent. The
study conformed to the principles of the Declaration of Helsinki and was approved by the
Ethics Committee of the University of Greifswald.
Funding and acknowledgements
SHIP is part of the Community Medicine Research Network of the University Medicine
Greifswald, which is supported by the German Federal State of Mecklenburg – West
Pomerania.
SHIP TREND
The Study of Health in Pomerania (SHIP) is a population-based epidemiological study in the
region of Western Pomerania. In SHIP TREND baseline, a new sample has been drawn for a
new cohort, to be examined from September 2008. More information can be found at:
http://www.medizin.uni-greifswald.de/cm/fv/ship/stud_desc_en.html
Genotyping
Genotyping was performed using the Illumina Human Omni 2.5 array. Hybridisation of
genomic DNA was done in accordance with the manufacturer’s standard recommendations at
the Helmholtz Zentrum München. The genetic data analysis workflow was created using the
Software InforSense. Genetic data were stored using the database Caché (InterSystems).
Genotypes were determined using the GenomeStudio Genotyping Module v1.0 (GenCall
algorithm). All arrays included had a genotyping rate of at least 94%. The overall genotyping
efficiency of the GWA was 99.67 %.
17
Hay fever, asthma, allergic sensitization and total IgE
In interview, participants were asked whether a doctor had ever diagnosed them with allergy,
and if so, which type of allergy. Participants who answered “allergy to house dust mite” or
“pollen allergy” were defined as having hay fever in the current study. A diagnosis of lung
asthma was defined as the participants that reported to have bronchial asthma. Allergic
sensitization and serum total IgE were not measured.
Alcohol status and intake
Alcohol intake per week was defined according to the amount of self-reported alcohol
consumption in the last 30 days. Participants were classified as non-drinkers and ever-
drinkers, respectively, depending on their reported consumption of alcohol.
Additional information
The analyses are not adjusted for principal components.
Ethics
SHIP was planned and accompanied with support and advice from an external Data safety
and Monitoring Committee (DSMC). Each participant gave written informed consent. The
study conformed to the principles of the Declaration of Helsinki and was approved by the
Ethics Committee of the University of Greifswald.
Funding and acknowledgements
SHIP-Trend is part of the Community Medicine Research Network of the University
Medicine Greifswald, which is supported by the German Federal State of Mecklenburg –
West Pomerania.
The Copenhagen City Heart Study
Data originates from The Copenhagen City Heart Study which consists of four consecutive
studies conducted in Denmark in 1976-78, 1981-83, 1991-94, and in 2001-03. Participants
were randomly chosen from the general population above 20 years living in the Copenhagen
area. Before visiting the study clinic, participants completed a questionnaire including
questions on alcohol intake and other lifestyle factors. At the clinic visit, physical
examinations were performed and questionnaires were checked for missing information and
any uncertainties were clarified. Also, blood samples were obtained for the purpose of
measurement of different biochemical and DNA markers at the 1991-94 examination. Hence,
participants attending this examination were included in the present study. Of 10,135
individuals who participated in this examination (response rate=61%), 91% gave blood for
biochemical and DNA analyses. Participants of Asian or Black descent (n=142) or with
missing questionnaire data (n=14) were excluded from further study. In all, 9080 Whites of
Danish ethnicity were eligible for this study, some of whom also participated in the
examinations in 1976-78 (n=6408), 1981-83 (n=6615), and in 2001-03 (n=4684). All
participants gave informed consent and the ethics committee for Copenhagen and
Frederiksberg approved the study (#100.2039/91). Enrolment and examination procedures
have been described in more detail elsewhere (32;33).
18
Genotyping
The ADH1B·2 allele (rs1229984, Arg47His in exon 3) and ADH1C·2 allele (rs698,
Ile349Val in exon 8) were identified by means of duplex polymerase chain reaction (PCR)
followed by Nanogen microelectronic chip technology (Nanogen NMW 1000 NanochipTM
Molecular Biology Workstation (34) using standard conditions (details available from
authors). In a validation study, the accuracy of the Nanogen method was found to be
comparable to restriction fragment length polymorphism (35).
Hay fever, asthma, allergic sensitization and total IgE
A diagnosis of hay fever was defined as a positive answer to the question: “Does food,
medicine, grass animals etc. give you, hay fever?” A diagnosis of asthma was defined as a
positive answer to the question: “Do you have asthma?" Allergic sensitization and serum total
IgE were not measured.
Alcohol status and intake
Amount of usual alcohol intake was reported as weekly consumption of beer (in bottles),
wine (in glasses), and spirits (in units). Assuming one drink to be equal to 12 grams of pure
alcohol, a measure of total weekly alcohol intake was calculated. Participants were classified
as non-drinkers or ever-drinkers, respectively, if they had answered 0 or >0 drinks/week.
Additional information
The analyses are not adjusted for principal components. The analyses have not been
published previously.
Ethics
Each participant gave written informed consent. The study conformed to the principles of the
Declaration of Helsinki and was approved by the Ethics Committee.
The NEO study
The NEO study is a population-based cohort with oversampling of individuals with BMI > 27
kg/m2. It was designed for extensive phenotyping to investigate pathways that lead to obesity-
related diseases. The NEO study is a population-based, prospective cohort study that includes
6,671 individuals aged 45–65 years, with an oversampling of individuals with overweight or
obesity. At baseline, information on demography, lifestyle, and medical history have been
collected by questionnaires. In addition, samples of 24-h urine, fasting and postprandial blood
plasma and serum, and DNA were collected. Participants underwent an extensive physical
examination, including anthropometry, electrocardiography, spirometry, and measurement of
the carotid artery intima-media thickness by ultrasonography. In random subsamples of
participants, magnetic resonance imaging of abdominal fat, pulse wave velocity of the aorta,
heart, and brain, magnetic resonance spectroscopy of the liver, indirect calorimetry, dual
energy X-ray absorptiometry, or accelerometry measurements were performed. The
collection of data started in September 2008 and completed at the end of September 2012.
Participants are currently being followed for the incidence of obesity-related diseases and
mortality. More information: http://www.ncbi.nlm.nih.gov/pubmed/23576214
Genotyping
19
Genotyping was performed using the Illumina HumanCoreExome chip, which was
subsequently imputed to the 1000 genome reference panel. Genotyping calling algorithm is
GenCall. Genotyping and SNP call rates >98%.
Hay fever, asthma, allergic sensitization and total IgE
Participants were defined as having asthma if they had the general practitioner record code
R96 (asthma) according to the International Classification of Primary Care. Hay fever,
allergic sensitization and serum total IgE were not assessed.
Alcohol status and intake
Alcohol intake was calculated from total dietary intake. Dietary intake was assessed using a
semi-quantitative food frequency questionnaire (FFQ), originally validated in the Dutch
general population. For calibration purposes in our study population, two 24-h dietary recalls
have been performed by telephone in a random subsample of 110 men and 119 women.
Ethics
The Medical Ethical Committee of the Leiden University Medical Center (LUMC) approved
the design of the study. All participants gave their written informed consent.
Funding and acknowledgements
The authors of the NEO study thank all individuals who participated in the Netherlands
Epidemiology in Obesity study, all participating general practitioners for inviting eligible
participants and all research nurses for collection of the data. We thank the NEO study group,
Pat van Beelen, Petra Noordijk and Ingeborg de Jonge for the coordination, lab and data
management of the NEO study. The genotyping in the NEO study was supported by the
Centre National de Génotypage (Paris, France), headed by Jean-Francois Deleuze. The NEO
study is supported by the participating Departments, the Division and the Board of Directors
of the Leiden University Medical Center, and by the Leiden University, Research Profile
Area Vascular and Regenerative Medicine. Dennis Mook-Kanamori is supported by Dutch
Science Organization (ZonMW-VENI Grant 916.14.023).
Additional information
The analyses are adjusted for principal components (4). The data has not been published
previously.
UK Biobank
The UK Biobank is a large prospective study with over 500,000 participants from across the
United Kingdom and aged 40–69 years at recruitment in 2006–2010 (36). The study has both
data from questionnaires, physical measures, sample assays, accelerometry, multimodal
imaging, genome-wide genotyping and longitudinal follow-up for a large number of health-
related outcomes. We included participants of Caucasian descent assessed by self-report and
genetic ethnic grouping.
The UK Biobank Lung Exome Variant Evaluation (UK BiLEVE) study is a
subsample of the UK Biobank study selected on the basis of lung function (37). In additional
analyses, we performed MR-analyses in the UKB Biobank without the BiLEVE sample.
Genotyping
20
Approximately 450,000 of the participants have been/are being genotyped using the UK
Biobank Axiom array from Affymetrix. There are approximately 800,000 markers on this
array. The other approximately 50,000 samples were genotyped on the closely related UK
BiLEVE array. These are two very similar arrays with more than 95% common marker
content.
Hay fever, asthma, allergic sensitization and total IgE
Hay fever was defined as a positive answer to the question: ”Has a doctor ever told you that
you have had any of the following conditions? Hayfever, allergic rhinitis, or eczema”.
Asthma was defined as a positive answer to the question: “Has a doctor ever told you that
you have had any of the following conditions? Asthma” Allergic sensitization and total IgE
were not determined.
Due to the non-specific hay fever variable (i.e. including eczema), we assessed two different
variables concerning hay fever in additional analyses:
1) Self-reported medication for hay fever. This was assessed in the initial assessment visit
2006-2010 (N=364,071). First, from the complete list of >6000 recorded types of medication,
we manually excluded the medication that <100 persons were taking or which we knew was
not used in the treatment of hay fever. Second, for each of the remaining medication, we
assessed the general indication and excluded those not related to or too non-specific to
treatment of hay fever. We ended up with 31 entries. Persons reporting taking one or more of
the medication on the list were defined as having hay fever according to this definition, and
persons who did not were defined as not having hay fever.
2) Doctor diagnosed serious illness: hay fever. If the participants stated in the touch screen
questionnaire that they had other serious illnesses or disabilities, they were later asked by an
interviewer: “In the touch screen you selected that you have been told by a doctor that you
have other serious illnesses or disabilities, could you now tell me what they are?” If the
participant answered “hay fever” the participant was defined as having hay fever according to
this definition. Otherwise, the participants were defined as not having hay fever. This was
assessed in the initial assessment visit 2006-2010 (N=379,887).
Lung function
Forced expiratory volume in 1-second (FEV1) and forced vital capacity (FVC) were
measures at baseline by spirometry by a Vitalograph Pneumotrac 6800 (Vitalograph, UK)
operated via a PC for data capture and in order to visualise flow graphs from each test. The
spirometer was calibrated in the beginning of each day by the Spirotrac software supplied
with the Pneumotrac 6800. FEV1 and FVC were expressed in litres.
Alcohol status and intake
Participants were classified as non-drinkers or ever-drinkers (previous and current drinkers)
according to self-report. Alcohol intake of units of alcohol per week among those who
indicated drinking alcohol more often than once or twice a week was calculated as the sum of
the answers to the questions: Average weekly champagne plus white wine intake/fortified
wine intake/intake of other alcoholic drinks/red wine intake/spirits intake.
Ethics
Each participant has given informed consent. An independent Ethics and Governance Council
oversees adherence to the Ethics and Governance Framework (36).
21
Funding and acknowledgements
UK Biobank has received funding from the UK Medical Research Council, Wellcome Trust,
Department of Health, British Heart Foundation, Diabetes UK, Northwest Regional
Development Agency, Scottish Government, and Welsh Assembly Government. As
described in the manuscript, the MRC and Wellcome Trust played a key role in the decision
to establish UK Biobank, a large, population-based, prospective, open access resource that
would allow detailed investigations of the genetic and environmental determinants of the
diseases of middle and old age. The MRC, Wellcome Trust, Department of Health, and
Scottish Chief Scientist Office each have a representative on the UK Biobank Board. The
MRC and Wellcome Trust fund the independent Ethics and Governance Council (36).
Additional information
The genetic analyses are adjusted for principal components.
22
Supplementary tables Table S1. Descriptive statistics of study populations.
23
Male sex Age Serum total IgE, (IU/m) Hay fever Asthma Allergic sensitization
Study Alcohol status N % (N) Median P25 P75 Median P25 P75 % (N) % (N) % (N)
The 1936 Cohort Non-drinkers 94 18.1 (17) 60.4 60.1 60.7 NA NA NA 11.7 (11) 8.51 (8) 10.6 (10)
Ever-drinkers 498 52.8 (263) 60.5 60.2 60.8 NA NA NA 9.4 (47) 6.4 (32) 14.9 (74)
All 592 47.3 (280) 60.5 60.2 60.8 NA NA NA 9.8 (58) 6.8 (40) 14.2 (84)
Allergy98 Non-drinkers 221 20.4 (45) 33.1 24.8 44.7 35.7 10.5 99.6 25.8 (57) 13.1 (29) 36.2 (80)
Ever-drinkers 927 51.6 (478) 39.0 30.0 51.7 37.7 13.1 109.0 27.1 (251) 10.5 (97) 38.7 (359)
All 1148 45.6 (523) 38.0 28.7 51.3 37.3 12.4 107.5 26.8 (308) 11.0 (126) 38.2 (439)
CCHS Non-drinkers 1944 24.6 (479) 66.1 56.1 73.8 NA NA NA 9.2 (179) 7.3 (141) NA
Ever-drinkers 7041 49.8 (3504) 58.7 45.5 69.0 NA NA NA 11.6 (820) 5.8 (406) NA
All 8985 44.3 (3983) 60.5 47.8 70.3 NA NA NA 11.1 (999) 6.1 (547) NA
Health2006 Non-drinkers 151 37.8 (57) 50.0 34.0 60.0 NA NA NA 15.9 (24) 14.6 (22) 19.9 (30)
Ever-drinkers 2667 45.4 (1212) 50.0 40.0 60.0 NA NA NA 18.2 (485) 10.5 (279) 23.4 (625)
All 2818 45.0 (1269) 50.0 40.0 60.0 NA NA NA 18.1 (509) 10.7 (301) 23.2 (655)
Inter99 Non-drinkers 448 31.0 (139) 44.8 39.7 50.0 25.6 10.4 70.7 NA 12.0 (54) 35.0 (157)
Ever-drinkers 4432 50.8 (2252) 45.1 40.0 50.3 28.3 10.6 75.9 NA 8.3 (368) 33.6 (1491)
All 4880 49.0 (2391) 45.1 40.0 50.2 28.2 10.6 75.6 NA 8.6 (422) 33.8 (1648)
DanFunD Non-drinkers 329 31.9 (105) 54 44 63 NA NA NA 19.1 (63) 13.1 (43) 22.5 (74)
Ever-drinkers 6764 47.0 (3178) 54 44 63 NA NA NA 18.8 (1272) 9.8 (662) 25.9 (1752)
All 7093 46.3 (3283) 54 44 63 NA NA NA 18.8 (1335) 9.9 (705) 25.7 (1826)
KORA Non-drinkers NA NA NA NA NA NA NA NA NA NA NA
Ever-drinkers NA NA NA NA NA NA NA NA NA NA NA
All 1255 46.3 (581) 49.0 39.0 59.0 53.0 20.0 145.0 18.2 (229) 7.0 (88) 46.4 (581)
NEO Non-drinkers 842 29.7 (250) 56.0 50.0 61.0 NA NA NA NA 13.9 (117) NA
Ever-drinkers 4713 51.7 (2435) 57.0 51.0 61.0 NA NA NA NA 10.0 (473) NA
All 5557 48.3 (2685) 57.0 51.0 61.0 NA NA NA NA 10.6 (590) NA
NSHD Non-drinkers 162 36.4 (59) 53 53 53 NA NA NA 22.0 (33) 13.9 (21) NA
Ever-drinkers 2513 50.7 (1275) 53 53 53 NA NA NA 23.8 (564) 9.8 (232) NA
24
All 2675 49.9 (1334) 53 53 53 NA NA NA 23.7 (597) 10.0 (253) NA
Prosper Non-drinkers 2439 32.1 (784) 75.2 72.7 78.1 NA NA NA NA 2.8 (69) NA
Ever-drinkers 3065 61.1 (1873) 74.7 72.2 77.6 NA NA NA NA 2.7 (84) NA
All 5504 48.3 (2657) 75.0 72.4 77.9 NA NA NA NA 2.8 (153) NA
Rotterdam Non-drinkers 1123 24.4 (274) 67.1 60.0 74.0 NA NA NA NA 2.7 (30) NA
Ever-drinkers 6854 46.1 (3160) 62.0 58.0 69.6 NA NA NA NA 2.6 (176) NA
All 7977 43.0 (3434) 62.5 58.2 70.5 NA NA NA NA 2.6 (206) NA
SHIP Non-drinkers 1364 33.4 (456) 54.0 36.0 67.0 33.8 14.5 93.7 7.3 (100) 1.1 (15) NA
Ever-drinkers 2361 57.5 (1357) 48.0 36.0 60.0 37.6 17.6 112.0 8.7 (206) 0.8 (19) NA
All 3725 48.7 (1813) 50.0 36.0 62.0 36.2 16.4 104.0 8.2 (306) 0.9 (34) NA
SHIP TREND Non-drinkers 116 35.3 (41) 54.0 42.0 65.0 NA NA NA 14.7 (17) 6.0 (7) NA
Ever-drinkers 870 44.9 (391) 50.0 40.0 60.0 NA NA NA 14.3 (124) 3.9 (34) NA
All 986 43.8 (432) 50.0 40.0 61.0 NA NA NA 14.3 (141) 4.2 (41) NA
1958 BC Non-drinkers 124 31.4 (39) 42 42 42 21.0 8.5 65.0 13.7 (17) 5.7 (7) 13.7 (17)
Ever-drinkers 2296 53.3 (1223) 42 42 42 27.0 11.0 67.0 19.2 (441) 5.8 (133) 17.2 (394)
All 2420 52.1 (1262) 42 42 42 27.0 11.0 67.0 18.9 (458) 5.8 (140) 17.0 (411)
Dan-Monica10 Non-drinkers 313 24.0 (75) 61.4 51.4 71.1 NA NA NA 9.9 (31) 8.6 (27) 13.7 (43)
Ever-drinkers 1949 53.9 (1050) 51.9 42.0 61.8 NA NA NA 14.9 (290) 6.3 (123) 18.8 (366)
All 2262 49.7 (1125) 52.0 42.1 61.9 NA NA NA 14.2 (321) 6.6 (150) 18.1 (409)
GOYA Males Non-drinkers 52 100 (52) 46 40.5 55.5 NA NA NA 11.5 (6) 0 (0) NA
Ever-drinkers 738 100 (738) 46 41 53 NA NA NA 13.1 (97) 4.9 (36) NA
All 790 100 (790) 46 41 53 NA NA NA 13.0 (103) 4.6 (36) NA
UK Biobank Non-drinkers 12884 24.8 (3191) 61 54 66 NA NA NA 20.4 (2631) 13.1 (1686) NA
Ever-drinkers 394883 46.6 (184188) 58 51 63 NA NA NA 23.0 (90791) 11.5 (45297) NA
All 407767 46.0 (187379) 58 51 63 NA NA NA 22.9 (93422) 11.5 (46983) NA
Abbreviations: 1958 BC, British 1958 Birth Cohort; Allergy98, Copenhagen Allergy study; CCHS, Copenhagen City Heart Study; GOYA, Genomics of extremely
Overweight Young Adults; HUNT, Nord-Trøndelag Health Study; IgE, immunoglobulin E; Inter99, Intervention 1999; IQR, interquartile range; HW, Hardy Weinberg
Equilibrium; KORA, The Cooperative Health Research in the Region of Augsburg; MAF, minor allele frequency; Monica, Monitoring of trends and determinants in
Cardiovascular Diseases; NA, not available; NEO, Netherlands Epidemiology of Obesity; NSHD, National Survey of Health and Development; PROSPER, PROspective
Study of Pravastatin in the Elderly at Risk; SHIP, Study of Health in Pomerania; UK Biobank, United Kingdom Biobank.
25
Table S2. Serum total IgE-levels according to study group, alcohol status and the rs1229984 genotype.
Study Alcohol status Genotype* Number Median P25 P75
Allergy Non-drinkers Wild type 215 36.9 10.5 100.0
Variant 6 17.5 8.4 29.9
Ever-drinkers Wild type 914 37.7 13.1 109.0
Variant 13 38.3 23.9 153.0
Inter99 Non-drinkers Wild type 422 25.1 10.5 68.7
Variant 26 40.3 9.6 132.0
Ever-drinkers Wild type 4272 28.5 10.6 76.1
Variant 160 20.8 10.2 71.5
SHIP Non-drinkers Wild type 990 34.0 14.5 97.2
Variant 86 28.9 14.2 83.2
Ever-drinkers Wild type 1786 37.8 17.6 112.0
Variant 145 33.1 15.0 104.0
1958 BC Non-drinkers Wild type 117 23.0 9.0 66.0
Variant 7 5.0 3.0 33.0
Ever-drinkers Wild type 2172 27.0 11.0 67.0
Variant 124 31.0 12.0 72.5
KORA** Non-drinkers Wild type NA NA NA NA
Variant NA NA NA NA
Ever-drinkers Wild type NA NA NA NA
Variant NA NA NA NA
* ‘Wild type’ refers to major allele homozygotes, and ‘Variant’ refers to heterozygotes and minor allele
homozygotes. ** Alcohol status is not available.
Abbreviations: Allergy98, Copenhagen Allergy study; 1958 BC, British 1958 Birth Cohort; IgE,
immunoglobulin E; Inter99, Intervention 1999; SHIP, Study of Health in Pomerania.
26
Table S3. Allele frequencies for the rs1229984 SNP in the participating studies
Study Major
homozygotes Heterozygotes
Minor
homozygotes MAF
HW, p-
value Total
Allergy98 1129 19 0 0.008 0.777 1148
1958 BC 2289 131 0 0.027 0.171 2420
CCHS 8583 396 6 0.023 0.515 8985
Dan-Monica10 2173 89 0 0.020 0.340 2262
GOYA Males 752 38 0 0.025 0.489 790
Health2006 2718 97 3 0.018 0.031 2818
Inter99 4694 181 5 0.020 0.051 4880
DanFunD 6846 245 2 0.018 0.899 7093
KORA 1099 149 7 0.070 0.358 1255
NEO 5192 362 3 0.033 0.195 5557
NSHD 2550 125 0 0.023 0.216 2675
The 1936 Cohort 559 33 0 0.028 0.485 592
Prosper 5319 185 0 0.017 0.205 5504
Rotterdam 7471 504 2 0.032 0.027 7977
SHIP 3447 276 2 0.038 0.140 3725
SHIP TREND 915 70 1 0.036 0.776 986
UK Biobank 389674 17869 224 0.022 0.192 407767
Abbreviations: Allergy98, Copenhagen Allergy study; 1958 BC, British, 1958 Birth Cohort; CCHS, Copenhagen City
Heart Study; GOYA, Genomics of extremely Overweight Young Adults; Inter99, Intervention 1999; HW, Hardy
Weinberg Equilibrium; KORA, The Cooperative Health Research in the Region of Augsburg; MAF, minor allele
frequency; Monica, Monitoring of trends and determinants in Cardiovascular Diseases; NEO, Netherlands
Epidemiology of Obesity; NSHD, National Survey of Health and Development; PROSPER, PROspective Study of
Pravastatin in the Elderly at Risk; SHIP, Study of Health in Pomerania; UK Biobank, United Kingdom Biobank.
27
Table S4. Study-specific measures of hay fever, asthma, allergic sensitization, and serum total IgE.
Study Hay fever Asthma Allergic
sensitization
Serum total
IgE
1958 BC
A positive answer to the
question: “Have you ever
had hay fever?”
A positive answer to the
question: “Have you ever had
hay asthma?”
Serum specific
IgE positivity
against inhalant
allergens
HYTEC-
automated
enzyme
immunoassay
Dan-
Monica10
A positive answer to the
question: “Has a doctor ever
told you that you had
allergic hay fever?”
A positive answer to the
question: “Has a doctor ever
told you that you had asthma?”
Serum specific
IgE positivity
against inhalant
allergens
NA
GOYA Males
A positive answer to the
question: “Does food,
medicine or grass give you
hay fever?”
A positive answer to the
question: “Do you suffer from
Asthma?”
NA NA
Health2006
A positive answer to the
question: “Has a doctor ever
told you that you had hay
fever?”
A positive answer to the
question: “Has a doctor ever
told you that you had asthma?”
Serum specific
IgE positivity
against inhalant
allergens
NA
HUNT2
A positive answer to the
question: “Do you have hay
fever or nasal allergies?”
A positive answer to the
question: “Do you have or
have you had asthma?”
NA NA
Inter99 NA
A positive answer to the
question: “Has a doctor ever
told you that you had asthma?”
Serum specific
IgE positivity
against inhalant
allergens
IMMULITE_
2000 Allergy
Immunoassay
System
DanFunD
A positive answer to the
question: ”Has a doctor ever
told you that you had/have
hay fever?”
A positive answer to the
question: ”Has a doctor ever
told you that you had/have
asthma ?”
Serum specific
IgE positivity
against inhalant
allergens
NA
KORA
A positive answer to the
question: “Has a doctor ever
told you that you had hay
fever?”
A positive answer to the
question: “Has a doctor ever
told you that you had asthma?”
Serum specific
IgE positivity
against inhalant
allergens
NA
NSHD
A positive answer to the
question: “Have you ever
had hay fever?” or “Have
you had hay fever in the
last 10 years?”
A positive answer to the
question: “Have you ever had
asthma?” or “Have you had
asthma in the last 10 years?”
NA NA
The 1936
Cohort
A positive answer to the
question: “Has a doctor ever
told you that you had hay
fever?”
A positive answer to the
question: “Has a doctor ever
told you that you had asthma?”
Serum specific
IgE positivity
against inhalant
allergens
NA
SHIP
A confirmative answer to
the question: “Do you
sometimes or all the time
suffer from hay fever?”
The participants were defined
as having allergic asthma or
not according to self-reported
questionnaire information.
NA
Latex IgE test
on the BN II
Nephelometer
(Dade Behring
Marburg
GmbH,
Marburg,
Germany)
SHIP TREND
Self-reported doctor-
diagnosed “allergy to house
dust mite” or “pollen
allergy”
Participants who reported to
have bronchial asthma NA
NA
CCHS
A positive answer to the
question: “Does food,
medicine, grass animals etc.
give you, hay fever?”
A positive answer to the
question: “Do you have
asthma?"
NA NA
28
NEO NA General practitioner record
code R96 (asthma) NA NA
Allergy98
A positive answer to the
question: “Have you had
hay fever in the last 12
months?”
A positive answer to the
question: “Have you had
asthma in the last 12 months?”
Serum specific
IgE positivity
against inhalant
allergens
Immulite
(Siemens,
Erlangen,
Germany)
Prosper NA
A self-reported diagnosis of
asthma in the adverse events
database
NA NA
Rotterdam NA Physician-diagnosed asthma NA NA
UK Biobank
A positive answer to the
question: ”Has a doctor ever
told you that you have had
any of the following
conditions? Hayfever,
allergic rhinitis, or eczema”
A positive answer to the
question: “Has a doctor ever
told you that you have had any
of the following conditions?
Asthma”
NA NA
Abbreviations: 1958 BC, Allergy98, Copenhagen Allergy study; British 1958 Birth Cohort; CCHS, Copenhagen City
Heart Study; GOYA, Genomics of extremely Overweight Young Adults; HUNT, Nord-Trøndelag Health Study; IgE,
immunoglobulin E; Inter99, Intervention 1999; KORA, The Cooperative Health Research in the Region of Augsburg;
Monica, Monitoring of trends and determinants in Cardiovascular Diseases; NA, not available; NEO, Netherlands
Epidemiology of Obesity; NSHD, National Survey of Health and Development; PROSPER, PROspective Study of
Pravastatin in the Elderly at Risk; SHIP, Study of Health in Pomerania; UK Biobank, United Kingdom Biobank.
Main supplementary figures
Figure S1. Random effects meta-analysis of the associations between the rs1229984 genotype (major homozygotes vs.
minor homozygotes and heterozygotes) and the logarithm transformed alcohol intake. Abbreviations: Allergy98,
Copenhagen Allergy study; 1958 BC, British 1958 Birth Cohort; CCH, Copenhagen City Heart Study; Inter99,
Intervention 1999; NEO, Netherlands Epidemiology of Obesity; NSHD, National Survey of Health and Development;
SHIP, Study of Health in Pomerania.
NOTE: Weights are from random effects analysis
Overall (I-squared = 45.8%, p = 0.024)
NSHD
The 1936 Cohort
CCH
SHIP TREND
GOYA Males
Monica10
Prosper
UK Biobank
Rotterdam
NEO
study
SHIP
Allergy98
Inter99
Health2006
1958 BC
DanFunD
0.17 (0.12, 0.22)
0.23 (0.05, 0.42)
0.02 (-0.35, 0.38)
0.27 (0.17, 0.38)
0.21 (-0.08, 0.49)
0.20 (-0.11, 0.51)
0.11 (-0.10, 0.33)
-0.00 (-0.19, 0.19)
0.15 (0.13, 0.16)
-0.02 (-0.19, 0.16)
0.23 (0.10, 0.35)
ES (95% CI)
0.13 (-0.02, 0.28)
0.10 (-0.38, 0.58)
0.32 (0.17, 0.47)
0.33 (0.11, 0.54)
0.06 (-0.06, 0.17)
0.27 (0.14, 0.39)
0.17 (0.12, 0.22)
0.23 (0.05, 0.42)
0.02 (-0.35, 0.38)
0.27 (0.17, 0.38)
0.21 (-0.08, 0.49)
0.20 (-0.11, 0.51)
0.11 (-0.10, 0.33)
-0.00 (-0.19, 0.19)
0.15 (0.13, 0.16)
-0.02 (-0.19, 0.16)
0.23 (0.10, 0.35)
ES (95% CI)
0.13 (-0.02, 0.28)
0.10 (-0.38, 0.58)
0.32 (0.17, 0.47)
0.33 (0.11, 0.54)
0.06 (-0.06, 0.17)
0.27 (0.14, 0.39)
0-.576 0 .576
Estimate for alcohol-increasing genotype
Log(alcohol intake)
30
Figure S2. Random effects meta-analysis of the associations between the rs1229984 genotype (major homozygotes vs.
minor homozygotes and heterozygotes) and hay fever in all and by alcohol status. Abbreviations: Allergy98,
Copenhagen Allergy study; 1958 BC, British 1958 Birth Cohort; CCH, Copenhagen City Heart Study; KORA,
Cooperative Health Research in the Region of Augsburg; NEO, Netherlands Epidemiology of Obesity; NSHD, National
Survey of Health and Development; SHIP, Study of Health in Pomerania.
NOTE: Weights are from random effects analysis
.
.
.
All
Monica10
Health2006
Allergy98
1958 BC
Kora
The 1936 Cohort
SHIP
SHIP TREND
CCH
NSHD
DanFunD
UK Biobank
GOYA Males
Subtotal (I-squared = 19.6%, p = 0.245)
Non-drinkers
Monica10
Health2006
SHIP
SHIP TREND
CCH
NSHD
DanFunD
UK Biobank
Subtotal (I-squared = 0.0%, p = 0.820)
Ever-drinkers
Monica10
Health2006
Allergy98
1958 BC
The 1936 Cohort
SHIP
SHIP TREND
CCH
NSHD
DanFunD
UK Biobank
GOYA Males
Subtotal (I-squared = 35.8%, p = 0.104)
study
0.99 (0.51, 1.94)
0.74 (0.46, 1.19)
0.63 (0.25, 1.63)
1.05 (0.66, 1.65)
0.72 (0.48, 1.10)
0.57 (0.21, 1.56)
0.85 (0.56, 1.31)
1.15 (0.56, 2.40)
1.04 (0.75, 1.45)
0.73 (0.49, 1.09)
0.73 (0.54, 0.99)
0.99 (0.95, 1.02)
5.53 (0.75, 40.85)
0.90 (0.81, 1.01)
0.47 (0.10, 2.30)
0.42 (0.10, 1.76)
0.75 (0.38, 1.50)
0.60 (0.06, 6.14)
1.26 (0.62, 2.56)
1.70 (0.20, 14.69)
0.91 (0.25, 3.35)
0.99 (0.83, 1.19)
0.97 (0.82, 1.14)
1.14 (0.54, 2.40)
0.78 (0.47, 1.30)
0.32 (0.11, 0.98)
0.99 (0.63, 1.57)
0.40 (0.14, 1.14)
0.91 (0.53, 1.57)
1.21 (0.56, 2.63)
0.98 (0.68, 1.42)
0.70 (0.46, 1.06)
0.72 (0.53, 0.98)
0.99 (0.95, 1.02)
5.14 (0.69, 38.05)
0.88 (0.75, 1.03)
ratio (95% CI)
Odds
0.99 (0.51, 1.94)
0.74 (0.46, 1.19)
0.63 (0.25, 1.63)
1.05 (0.66, 1.65)
0.72 (0.48, 1.10)
0.57 (0.21, 1.56)
0.85 (0.56, 1.31)
1.15 (0.56, 2.40)
1.04 (0.75, 1.45)
0.73 (0.49, 1.09)
0.73 (0.54, 0.99)
0.99 (0.95, 1.02)
5.53 (0.75, 40.85)
0.90 (0.81, 1.01)
0.47 (0.10, 2.30)
0.42 (0.10, 1.76)
0.75 (0.38, 1.50)
0.60 (0.06, 6.14)
1.26 (0.62, 2.56)
1.70 (0.20, 14.69)
0.91 (0.25, 3.35)
0.99 (0.83, 1.19)
0.97 (0.82, 1.14)
1.14 (0.54, 2.40)
0.78 (0.47, 1.30)
0.32 (0.11, 0.98)
0.99 (0.63, 1.57)
0.40 (0.14, 1.14)
0.91 (0.53, 1.57)
1.21 (0.56, 2.63)
0.98 (0.68, 1.42)
0.70 (0.46, 1.06)
0.72 (0.53, 0.98)
0.99 (0.95, 1.02)
5.14 (0.69, 38.05)
0.88 (0.75, 1.03)
ratio (95% CI)
Odds
1.0245 1 40.9
Odds ratio for alcohol-increasing genotype
Hay fever
31
Figure S3. Random effects meta-analysis of the associations between the rs1229984 genotype (major homozygotes vs.
minor homozygotes and heterozygotes) and asthma in all and by alcohol status. Abbreviations: Allergy98, Copenhagen
Allergy study; 1958 BC, British 1958 Birth Cohort; CCH, Copenhagen City Heart Study; Inter99, Intervention 1999;
KORA, Cooperative Health Research in the Region of Augsburg; NEO, Netherlands Epidemiology of Obesity; NSHD,
National Survey of Health and Development; SHIP, Study of Health in Pomerania.
32
NOTE: Weights are from random effects analysis
.
.
.
AllMonica10Health2006Inter99Allergy98ProsperRotterdam1958 BCKoraThe 1936 CohortSHIPSHIP TRENDNEOCCHNSHDDanFunDUK BiobankGOYA MalesSubtotal (I-squared = 13.6%, p = 0.295)
Non-drinkersMonica10Health2006Inter99Allergy98ProsperRotterdamSHIPSHIP TRENDNEOCCHDanFunDUK BiobankSubtotal (I-squared = 0.0%, p = 0.844)
Ever-drinkersMonica10Health2006Inter99Allergy98ProsperRotterdam1958 BCThe 1936 CohortSHIP TRENDNEOCCHNSHDDanFunDUK BiobankGOYA MalesSubtotal (I-squared = 30.7%, p = 0.124)
study
0.82 (0.37, 1.82)0.67 (0.38, 1.19)0.94 (0.56, 1.56)0.47 (0.15, 1.44)0.83 (0.36, 1.90)1.68 (0.82, 3.42)0.54 (0.30, 0.98)0.88 (0.47, 1.68)2.39 (0.31, 18.17)2.71 (0.37, 19.86)1.59 (0.38, 6.75)1.04 (0.74, 1.47)0.82 (0.56, 1.22)0.75 (0.43, 1.31)0.66 (0.46, 0.96)0.99 (0.94, 1.04)1.81 (0.24, 13.63)0.91 (0.80, 1.02)
0.90 (0.11, 7.33)0.64 (0.12, 3.29)0.55 (0.20, 1.54)0.75 (0.08, 6.77)1.03 (0.25, 4.30)0.87 (0.26, 2.97)1.22 (0.16, 9.35)0.28 (0.02, 3.34)2.23 (0.88, 5.67)0.68 (0.36, 1.30)0.94 (0.20, 4.34)0.91 (0.74, 1.13)0.90 (0.75, 1.08)
0.80 (0.34, 1.87)0.69 (0.38, 1.26)1.12 (0.61, 2.03)0.40 (0.11, 1.49)0.74 (0.26, 2.05)2.20 (0.90, 5.39)0.51 (0.28, 0.93)1.85 (0.24, 14.44)2.93 (0.39, 21.83)0.92 (0.63, 1.36)0.93 (0.57, 1.52)0.68 (0.39, 1.19)0.64 (0.44, 0.94)1.00 (0.95, 1.04)1.79 (0.24, 13.48)0.87 (0.73, 1.03)
ratio (95% CI)Odds
0.82 (0.37, 1.82)0.67 (0.38, 1.19)0.94 (0.56, 1.56)0.47 (0.15, 1.44)0.83 (0.36, 1.90)1.68 (0.82, 3.42)0.54 (0.30, 0.98)0.88 (0.47, 1.68)2.39 (0.31, 18.17)2.71 (0.37, 19.86)1.59 (0.38, 6.75)1.04 (0.74, 1.47)0.82 (0.56, 1.22)0.75 (0.43, 1.31)0.66 (0.46, 0.96)0.99 (0.94, 1.04)1.81 (0.24, 13.63)0.91 (0.80, 1.02)
0.90 (0.11, 7.33)0.64 (0.12, 3.29)0.55 (0.20, 1.54)0.75 (0.08, 6.77)1.03 (0.25, 4.30)0.87 (0.26, 2.97)1.22 (0.16, 9.35)0.28 (0.02, 3.34)2.23 (0.88, 5.67)0.68 (0.36, 1.30)0.94 (0.20, 4.34)0.91 (0.74, 1.13)0.90 (0.75, 1.08)
0.80 (0.34, 1.87)0.69 (0.38, 1.26)1.12 (0.61, 2.03)0.40 (0.11, 1.49)0.74 (0.26, 2.05)2.20 (0.90, 5.39)0.51 (0.28, 0.93)1.85 (0.24, 14.44)2.93 (0.39, 21.83)0.92 (0.63, 1.36)0.93 (0.57, 1.52)0.68 (0.39, 1.19)0.64 (0.44, 0.94)1.00 (0.95, 1.04)1.79 (0.24, 13.48)0.87 (0.73, 1.03)
ratio (95% CI)Odds
1.0241 1 41.5
Odds ratio for alcohol-increasing genotype
Asthma
33
Figure S4. Random effects meta-analysis of the associations between the rs1229984 genotype (major homozygotes vs.
minor homozygotes and heterozygotes) and allergic sensitization in all and by alcohol status. Abbreviations: Allergy98,
Copenhagen Allergy study; 1958 BC, British 1958 Birth Cohort; Inter99, Intervention 1999; KORA, Cooperative
Health Research in the Region of Augsburg.
NOTE: Weights are from random effects analysis
.
.
.
AllMonica10Health2006Inter99Allergy981958 BCKoraThe 1936 CohortDanFunDSubtotal (I-squared = 29.6%, p = 0.192)
Non-drinkersMonica10Health2006Inter99Allergy98The 1936 CohortDanFunDSubtotal (I-squared = 12.6%, p = 0.335)
Ever-drinkersMonica10Health2006Inter99Allergy981958 BCThe 1936 CohortDanFunDSubtotal (I-squared = 40.5%, p = 0.121)
study
0.93 (0.54, 1.61)0.72 (0.46, 1.12)1.55 (1.10, 2.17)1.40 (0.54, 3.65)0.95 (0.60, 1.50)0.90 (0.64, 1.27)0.72 (0.29, 1.81)1.00 (0.74, 1.34)1.00 (0.83, 1.21)
1.47 (0.18, 11.91)0.22 (0.06, 0.83)0.74 (0.33, 1.68)3.59 (0.40, 31.93)0.91 (0.09, 9.02)0.85 (0.26, 2.79)0.74 (0.40, 1.36)
0.90 (0.51, 1.58)0.81 (0.50, 1.31)1.79 (1.23, 2.62)1.00 (0.33, 3.06)0.90 (0.57, 1.43)0.73 (0.27, 2.02)1.00 (0.74, 1.36)1.04 (0.81, 1.33)
ratio (95% CI)Odds
0.93 (0.54, 1.61)0.72 (0.46, 1.12)1.55 (1.10, 2.17)1.40 (0.54, 3.65)0.95 (0.60, 1.50)0.90 (0.64, 1.27)0.72 (0.29, 1.81)1.00 (0.74, 1.34)1.00 (0.83, 1.21)
1.47 (0.18, 11.91)0.22 (0.06, 0.83)0.74 (0.33, 1.68)3.59 (0.40, 31.93)0.91 (0.09, 9.02)0.85 (0.26, 2.79)0.74 (0.40, 1.36)
0.90 (0.51, 1.58)0.81 (0.50, 1.31)1.79 (1.23, 2.62)1.00 (0.33, 3.06)0.90 (0.57, 1.43)0.73 (0.27, 2.02)1.00 (0.74, 1.36)1.04 (0.81, 1.33)
ratio (95% CI)Odds
1.0313 1 31.9
Odds ratio for alcohol-increasing genotype
Allergic sensitization
Figure S5. Random effects meta-analysis of the associations between the rs1229984 genotype (major homozygotes vs.
minor homozygotes and heterozygotes) and the logarithm transformed serum total IgE in all and by alcohol status.
Abbreviations: Allergy98, Copenhagen Allergy study; 1958 BC, British 1958 Birth Cohort; IgE, immunoglobulin E;
Inter99, Intervention 1999; KORA, Cooperative Health Research in the Region of Augsburg.
NOTE: Weights are from random effects analysis
.
.
.
All
Inter99
Allergy98
1958 BC
Kora
SHIP
Subtotal (I-squared = 0.0%, p = 0.986)
Non-drinkers
Inter99
Allergy98
1958 BC
SHIP
Subtotal (I-squared = 48.5%, p = 0.120)
Ever-drinkers
Inter99
Allergy98
1958 BC
SHIP
Subtotal (I-squared = 0.0%, p = 0.489)
study
0.12 (-0.10, 0.33)
0.03 (-0.66, 0.72)
0.03 (-0.22, 0.27)
0.05 (-0.19, 0.28)
0.05 (-0.13, 0.24)
0.06 (-0.05, 0.17)
-0.30 (-0.87, 0.28)
0.83 (-0.46, 2.12)
1.04 (-0.07, 2.16)
0.04 (-0.26, 0.34)
0.16 (-0.31, 0.63)
0.18 (-0.05, 0.41)
-0.32 (-1.15, 0.51)
-0.03 (-0.28, 0.22)
0.05 (-0.18, 0.29)
0.06 (-0.07, 0.20)
ES (95% CI)
0.12 (-0.10, 0.33)
0.03 (-0.66, 0.72)
0.03 (-0.22, 0.27)
0.05 (-0.19, 0.28)
0.05 (-0.13, 0.24)
0.06 (-0.05, 0.17)
-0.30 (-0.87, 0.28)
0.83 (-0.46, 2.12)
1.04 (-0.07, 2.16)
0.04 (-0.26, 0.34)
0.16 (-0.31, 0.63)
0.18 (-0.05, 0.41)
-0.32 (-1.15, 0.51)
-0.03 (-0.28, 0.22)
0.05 (-0.18, 0.29)
0.06 (-0.07, 0.20)
ES (95% CI)
0-2.16 0 2.16
Estimate for alcohol-increasing genotype
Log(total IgE)
35
Figure S6. Random effects meta-analysis of the associations between alcohol status and hay fever in all. Abbreviations:
Allergy98, Copenhagen Allergy study; 1958 BC, British 1958 Birth Cohort; CCH, Copenhagen City Heart Study;
KORA, Cooperative Health Research in the Region of Augsburg; NEO, Netherlands Epidemiology of Obesity; NSHD,
National Survey of Health and Development; SHIP, Study of Health in Pomerania.
NOTE: Weights are from random effects analysis
Overall (I-squared = 0.0%, p = 0.985)
Monica10
DanFunD
UK Biobank
The 1936 Cohort
SHIP
study
Allergy98
SHIP TREND
Health2006
NSHD
CCH
1958 BC
GOYA Males
1.13 (1.08, 1.17)
1.20 (0.80, 1.80)
0.98 (0.74, 1.29)
1.13 (1.08, 1.18)
1.09 (0.53, 2.23)
1.16 (0.90, 1.50)
ratio (95% CI)
1.01 (0.71, 1.43)
0.91 (0.52, 1.59)
1.22 (0.78, 1.91)
1.09 (0.73, 1.62)
1.14 (0.95, 1.36)
1.49 (0.88, 2.52)
1.15 (0.48, 2.78)
Odds
1.13 (1.08, 1.17)
1.20 (0.80, 1.80)
0.98 (0.74, 1.29)
1.13 (1.08, 1.18)
1.09 (0.53, 2.23)
1.16 (0.90, 1.50)
ratio (95% CI)
1.01 (0.71, 1.43)
0.91 (0.52, 1.59)
1.22 (0.78, 1.91)
1.09 (0.73, 1.62)
1.14 (0.95, 1.36)
1.49 (0.88, 2.52)
1.15 (0.48, 2.78)
Odds
1.36 1 2.78
Ever-drinkers vs. non-drinkers
Hay fever
36
Figure S7. Random effects meta-analysis of the associations between alcohol status and asthma in all. Abbreviations:
Allergy98, Copenhagen Allergy study; 1958 BC, British 1958 Birth Cohort; CCH, Copenhagen City Heart Study;
KORA, Cooperative Health Research in the Region of Augsburg; NEO, Netherlands Epidemiology of Obesity; NSHD,
National Survey of Health and Development; SHIP, Study of Health in Pomerania.
NOTE: Weights are from random effects analysis
Overall (I-squared = 0.0%, p = 0.924)
1958 BC
DanFunD
Health2006
UK Biobank
NEO
Inter99
study
Rotterdam
SHIP
Prosper
NSHD
Allergy98
Monica10
SHIP TREND
CCH
0.85 (0.81, 0.89)
0.99 (0.45, 2.18)
0.73 (0.52, 1.02)
0.73 (0.46, 1.17)
0.86 (0.82, 0.91)
0.76 (0.61, 0.95)
0.70 (0.51, 0.95)
ratio (95% CI)
0.91 (0.61, 1.36)
0.83 (0.41, 1.67)
1.00 (0.72, 1.41)
0.68 (0.42, 1.10)
0.81 (0.51, 1.28)
0.76 (0.48, 1.19)
0.67 (0.29, 1.57)
Odds
0.84 (0.69, 1.04)
0.85 (0.81, 0.89)
0.99 (0.45, 2.18)
0.73 (0.52, 1.02)
0.73 (0.46, 1.17)
0.86 (0.82, 0.91)
0.76 (0.61, 0.95)
0.70 (0.51, 0.95)
ratio (95% CI)
0.91 (0.61, 1.36)
0.83 (0.41, 1.67)
1.00 (0.72, 1.41)
0.68 (0.42, 1.10)
0.81 (0.51, 1.28)
0.76 (0.48, 1.19)
0.67 (0.29, 1.57)
Odds
0.84 (0.69, 1.04)
1.29 1 3.45
Ever-drinkers vs. non-drinkers
Asthma
37
Figure S8. Random effects meta-analysis of the associations between alcohol status and allergic sensitization in all.
Abbreviations: Allergy98, Copenhagen Allergy study; 1958 BC, British 1958 Birth Cohort; CCH, Copenhagen City
Heart Study; KORA, Cooperative Health Research in the Region of Augsburg; NEO, Netherlands Epidemiology of
Obesity; NSHD, National Survey of Health and Development; SHIP, Study of Health in Pomerania.
NOTE: Weights are from random effects analysis
Overall (I-squared = 0.0%, p = 0.668)
Allergy98
The 1936 Cohort
DanFunD
Health2006
study
Inter99
Monica10
1958 BC
1.059 (0.936, 1.197)
0.955 (0.691, 1.320)
1.413 (0.687, 2.907)
1.119 (0.856, 1.463)
1.277 (0.841, 1.938)
Odds ratio (95% CI)
0.935 (0.760, 1.150)
1.222 (0.860, 1.738)
1.155 (0.681, 1.957)
1.059 (0.936, 1.197)
0.955 (0.691, 1.320)
1.413 (0.687, 2.907)
1.119 (0.856, 1.463)
1.277 (0.841, 1.938)
Odds ratio (95% CI)
0.935 (0.760, 1.150)
1.222 (0.860, 1.738)
1.155 (0.681, 1.957)
1.344 1 2.91
Ever-drinkers vs. non-drinkers
Allergic sensitization
38
Figure S9. Random effects meta-analysis of the associations between alcohol status and the logarithm transformed
serum total IgE. Abbreviations: Allergy98, Copenhagen Allergy study; 1958 BC, British 1958 Birth Cohort; IgE,
immunoglobulin E; Inter99, Intervention 1999; KORA, Cooperative Health Research in the Region of Augsburg.
NOTE: Weights are from random effects analysis
Overall (I-squared = 0.0%, p = 0.972)
Inter99
study
Allergy98
SHIP
1958 BC
0.01 (-0.06, 0.09)
0.02 (-0.13, 0.16)
ES (95% CI)
-0.01 (-0.24, 0.22)
0.01 (-0.10, 0.11)
0.07 (-0.19, 0.32)
0.01 (-0.06, 0.09)
0.02 (-0.13, 0.16)
ES (95% CI)
-0.01 (-0.24, 0.22)
0.01 (-0.10, 0.11)
0.07 (-0.19, 0.32)
0-.319 0 .319
Ever-drinkers vs. non-drinkers
Log(total IgE)
39
Figure S10. Random effects meta-analysis of the associations between alcohol intake and hay fever. Abbreviations:
Allergy98, Copenhagen Allergy study; 1958 BC, British 1958 Birth Cohort; CCH, Copenhagen City Heart Study;
KORA, Cooperative Health Research in the Region of Augsburg; NEO, Netherlands Epidemiology of Obesity; NSHD,
National Survey of Health and Development; SHIP, Study of Health in Pomerania.
NOTE: Weights are from random effects analysis
Overall (I-squared = 50.3%, p = 0.023)
SHIP TREND
study
Monica10
NSHD
Health2006
UK Biobank
GOYA Males
The 1936 Cohort
CCH
Allergy98
SHIP
DanFunD
1958 BC
0.999 (0.995, 1.002)
1.001 (0.985, 1.018)
Odds ratio (95% CI)
1.007 (0.996, 1.018)
0.993 (0.982, 1.004)
0.985 (0.973, 0.997)
1.003 (1.002, 1.004)
0.986 (0.968, 1.005)
1.002 (0.973, 1.031)
0.999 (0.995, 1.003)
0.999 (0.980, 1.017)
0.989 (0.929, 1.053)
0.995 (0.988, 1.003)
1.006 (0.989, 1.024)
0.999 (0.995, 1.002)
1.001 (0.985, 1.018)
Odds ratio (95% CI)
1.007 (0.996, 1.018)
0.993 (0.982, 1.004)
0.985 (0.973, 0.997)
1.003 (1.002, 1.004)
0.986 (0.968, 1.005)
1.002 (0.973, 1.031)
0.999 (0.995, 1.003)
0.999 (0.980, 1.017)
0.989 (0.929, 1.053)
0.995 (0.988, 1.003)
1.006 (0.989, 1.024)
1.929 1 1.08
Per unit of alcohol
Hay fever
40
Figure S11. Random effects meta-analysis of the associations between alcohol intake and asthma. Abbreviations:
Allergy98, Copenhagen Allergy study; 1958 BC, British 1958 Birth Cohort; CCH, Copenhagen City Heart Study;
KORA, Cooperative Health Research in the Region of Augsburg; NEO, Netherlands Epidemiology of Obesity; NSHD,
National Survey of Health and Development; SHIP, Study of Health in Pomerania.
NOTE: Weights are from random effects analysis
Overall (I-squared = 43.2%, p = 0.034)
1958 BC
Inter99
CCH
GOYA Males
SHIP TREND
NEO
Prosper
DanFunD
The 1936 Cohort
Health2006
SHIP
Rotterdam
Monica10
UK Biobank
NSHD
Allergy98
study
0.9999 (0.9961, 1.0037)
0.9842 (0.9548, 1.0145)
0.9957 (0.9865, 1.0051)
1.0040 (0.9992, 1.0089)
1.0082 (0.9864, 1.0305)
1.0048 (0.9739, 1.0366)
0.9971 (0.9902, 1.0040)
1.0163 (1.0000, 1.0329)
0.9917 (0.9810, 1.0025)
1.0083 (0.9751, 1.0427)
0.9963 (0.9816, 1.0112)
0.9215 (0.7148, 1.1881)
1.1002 (1.0292, 1.1761)
0.9966 (0.9797, 1.0138)
1.0026 (1.0013, 1.0039)
0.9856 (0.9682, 1.0033)
0.9878 (0.9584, 1.0182)
Odds ratio (95% CI)
0.9999 (0.9961, 1.0037)
0.9842 (0.9548, 1.0145)
0.9957 (0.9865, 1.0051)
1.0040 (0.9992, 1.0089)
1.0082 (0.9864, 1.0305)
1.0048 (0.9739, 1.0366)
0.9971 (0.9902, 1.0040)
1.0163 (1.0000, 1.0329)
0.9917 (0.9810, 1.0025)
1.0083 (0.9751, 1.0427)
0.9963 (0.9816, 1.0112)
0.9215 (0.7148, 1.1881)
1.1002 (1.0292, 1.1761)
0.9966 (0.9797, 1.0138)
1.0026 (1.0013, 1.0039)
0.9856 (0.9682, 1.0033)
0.9878 (0.9584, 1.0182)
Odds ratio (95% CI)
1.715 1 1.4
Per unit of alcohol
Asthma
41
Figure S12. Random effects meta-analysis of the associations between alcohol intake and allergic sensitization.
Abbreviations: Allergy98, Copenhagen Allergy study; 1958 BC, British 1958 Birth Cohort; CCH, Copenhagen City
Heart Study; KORA, Cooperative Health Research in the Region of Augsburg; NEO, Netherlands Epidemiology of
Obesity; NSHD, National Survey of Health and Development; SHIP, Study of Health in Pomerania.
NOTE: Weights are from random effects analysis
Overall (I-squared = 13.3%, p = 0.328)
DanFunD
Monica10
Inter99
study
1958 BC
Health2006
The 1936 Cohort
Allergy98
1.00 (1.00, 1.01)
1.00 (1.00, 1.01)
1.01 (1.00, 1.02)
1.00 (1.00, 1.01)
ratio (95% CI)
1.01 (0.99, 1.02)
1.00 (0.99, 1.01)
1.01 (0.99, 1.03)
0.99 (0.97, 1.01)
odds
1.00 (1.00, 1.01)
1.00 (1.00, 1.01)
1.01 (1.00, 1.02)
1.00 (1.00, 1.01)
ratio (95% CI)
1.01 (0.99, 1.02)
1.00 (0.99, 1.01)
1.01 (0.99, 1.03)
0.99 (0.97, 1.01)
odds
1.97 1 1.03
Per unit of alcohol
Allergic sensitization
42
Figure S13. Random effects meta-analysis of the associations between alcohol intake and the logarithm transformed
serum total IgE. Abbreviations: Allergy98, Copenhagen Allergy study; 1958 BC, British 1958 Birth Cohort; IgE,
immunoglobulin E; Inter99, Intervention 1999; KORA, Cooperative Health Research in the Region of Augsburg.
NOTE: Weights are from random effects analysis
Overall (I-squared = 56.1%, p = 0.078)
1958 BC
study
Allergy98
Inter99
SHIP
0.01 (0.01, 0.02)
0.01 (0.00, 0.02)
ES (95% CI)
0.02 (0.01, 0.03)
0.01 (0.01, 0.01)
0.04 (0.01, 0.07)
0.01 (0.01, 0.02)
0.01 (0.00, 0.02)
ES (95% CI)
0.02 (0.01, 0.03)
0.01 (0.01, 0.01)
0.04 (0.01, 0.07)
0-.0653 0 .0653
Per unit of alcohol
Log(total IgE)
43
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