To date, no common genetic variant is known to be associated with levels of alcohol intake in populations of European ancestry. We have identified one genetic variant in one of the genes involved in alcohol metabolism (ADH1B), which predicts alcohol intake in a cohort of 50-70 year old British men of white ethnic origin (N=4000). The minor allele frequency in Europeans ranges between 1% and 3%. This variant has recently been reported to be highly protective of aerodigestive tract cancers in a pooled analysis of 5 cohorts, with a more marked effect among heavy drinkers compared to moderate drinkers, and no evidence of an effect in lifelong teetotallers, suggesting the effect is purely due to a gene-environment interaction (1). In laboratory experiments, individuals with at least one copy of the variant have been shown to metabolise ethanol 100 times faster than those with two copies of the common allele (2).

ADH1B has three alleles - ADH1B*1 is 47Arg and 369Arg (common allele, common SNPs at both sites), ADH1B*2 is 47His and 369Arg (variant at site rs1229984 and common at site rs2066702), ADH1B*3 is 47Arg and 369Cys (common and variant, respectively, not found among Europeans). According to Osier (3), the double variant is in theory possible but has not been observed. The ADH1B*2 (almost fully captured by the SNP rs1229984) is the variant associated with protective effect for alcoholism (the His variant is the fast metabolizer, resulting in much higher levels of acetaldehyde). Although this has been observed e.g. among Jewish university students in the US who exhibited higher alcohol elimination rates (His/His greater than Arg/His greater than Arg/Arg) (4), environmental factors (e.g. social setting) have been shown to account for more marked differences in frequency and amount of drinking than ADH1B genotypes (5), with students drinking considerably more than other adults from the Jewish community.

There have been many speculations about selection operating on ADH1B*47His allele in East Asia (see, for example, (6)), Han conducted a comprehensive study of 54 SNPs in 42 populations on the ADH cluster, finding the first evidence of selection for the locus but doubting its link to the 'modern' phenotype of alcoholism (7). However, among Irish and Danish, no variation was observed at site ADH1B Arg47His (rs1229984), nor at rs28626993 (intron3) (see Han et al (7)).

There are inconsistencies in the literature that cannot confirm a clear effect of the rare variant of this SNP on alcohol intake in Caucasian populations, mainly due to lack of power. We have recently investigated the association between the ADH1B variant rs1229984 and alcohol consumption in approximately 4000 middle-aged British men who attended prostate cancer screening. This is a case-control study nested in cohort from the ProtecT study, and alcohol consumption in these men is significantly varied, with many classified as heavy drinkers. Excluding men of ethnicity different from 'white', we noted that the presence of the rare allele for this SNP was associated with lower alcohol consumption. Notably our results would be consistent with the gene-environment interaction effect reported by Hashibe and colleagues (1), however no direct data on alcohol intake are available for a formal comparison.

Given the initial evidence that this SNP is associated with alcohol drinking in men with such high levels of the phenotype (alcohol drinking), we aim at replicating such findings in ALSPAC using genotype and alcohol data collected from the mothers during several times in their life, which we expect to be reflecting on average lower intakes, and to be of better quality (smaller measurement error).

Concept * Specific Measure * Person * Source * Time

Alcohol intake * self-reported alcohol intake * Mother * Questionnaire * ALL

(markers) * smoking * Mother * " * ALL

* socio-economic status variables * " * " * "

* height, weight * " * " * "