Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data.

Holmes MV1, Dale CE2, Zuccolo L3, Silverwood RJ4, Guo Y5, Ye Z6, Prieto-Merino D2, Dehghan A7, Trompet S8, Wong A9, Cavadino A10, Drogan D11,Padmanabhan S12, Li S13, Yesupriya A14, Leusink M15, Sundstrom J16, Hubacek JA17, Pikhart H18, Swerdlow DI19, Panayiotou AG20, Borinskaya SA21, Finan C19, Shah S22, Kuchenbaecker KB23, Shah T19, Engmann J19, Folkersen L24, Eriksson P24, Ricceri F25, Melander O26, Sacerdote C25, Gamble DM27,Rayaprolu S28, Ross OA28, McLachlan S29, Vikhireva O18, Sluijs I30, Scott RA6, Adamkova V31, Flicker L32, Bockxmeer FM33, Power C10, Marques-Vidal P34,Meade T2, Marmot MG35, Ferro JM36, Paulos-Pinheiro S37, Humphries SE38, Talmud PJ38, Mateo Leach I39, Verweij N39, Linneberg A40, Skaaby T40,Doevendans PA41, Cramer MJ41, Harst Pv42, Klungel OH15, Dowling NF14, Dominiczak AF12, Kumari M19, Nicolaides AN43, Weikert C11, Boeing H11, Ebrahim S2, Gaunt TR3, Price JF29, Lannfelt L44, Peasey A18, Kubinova R45, Pajak A46, Malyutina S47, Voevoda MI48, Tamosiunas A49, Maitland-van der Zee AH15,Norman PE50, Hankey GJ51, Bergmann MM11, Hofman A7, Franco OH7, Cooper J52, Palmen J38, Spiering W53, Jong PA54, Kuh D9, Hardy R9, Uitterlinden AG7, Ikram MA7, Ford I55, Hyppönen E56, Almeida OP57, Wareham NJ6, Khaw KT58, Hamsten A59, Husemoen LL40, Tjønneland A60, Tolstrup JS61, Rimm E62, Beulens JW30, Verschuren WM63, Onland-Moret NC30, Hofker MH64, Wannamethee SG65, Whincup PH66, Morris R65, Vicente AM67, Watkins H68, Farrall M68, Jukema JW8, Meschia J27, Cupples LA69, Sharp SJ6, Fornage M70, Kooperberg C71, LaCroix AZ71, Dai JY71, Lanktree MB72, Siscovick DS73, Jorgenson E74, Spring B75, Coresh J76, Li YR77, Buxbaum SG78, Schreiner PJ79, Ellison RC80, Tsai MY81, Patel SR82, Redline S83, Johnson AD84, Hoogeveen RC85,Hakonarson H86, Rotter JI87, Boerwinkle E88, Bakker PI89, Kivimaki M18, Asselbergs FW90, Sattar N91, Lawlor DA3, Whittaker J92, Davey Smith G3, Mukamal K93, Psaty BM94, Wilson JG95, Lange LA96, Hamidovic A97, Hingorani AD19, Nordestgaard BG98, Bobak M18, Leon DA2, Langenberg C6, Palmer TM99, Reiner AP71, Keating BJ100, Dudbridge F2, Casas JP101; InterAct Consortium.

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Abstract

OBJECTIVE:

To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease.

DESIGN:

Mendelian randomisation meta-analysis of 56 epidemiological studies.

PARTICIPANTS:

261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers.

MAIN OUTCOME MEASURES:

Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption.

RESULTS:

Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)).

CONCLUSIONS:

Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.