ADH single nucleotide polymorphism associations with alcohol metabolism in vivo

Abstract

We have previously found that variation in alcohol metabolism in Europeans is linked to the chromosome 4q region containing the ADH gene family. We have now typed 103 single nucleotide polymorphisms (SNPs) across this region to test for allelic associations with variation in blood and breath alcohol concentrations after an alcohol challenge. In vivo alcohol metabolism was modelled with three parameters that identified the absorption and rise of alcohol concentration following ingestion, and the rate of elimination. Alleles of ADH7 SNPs were associated with the early stages of alcohol metabolism, with additional effects in the ADH1A, ADH1B and ADH4 regions. Rate of elimination was associated with SNPs in the intragenic region between ADH7 and ADH1C, and across ADH1C and ADH1B. SNPs affecting alcohol metabolism did not correspond to those reported to affect alcohol dependence or alcohol-related disease. The combined SNP associations with early- and late-stage metabolism only account for approximately 20% of the total genetic variance linked to the ADH region, and most of the variance for in vivo alcohol metabolism linked to this region is yet to be explained.

Figure 1.

Comparison of single nucleotide polymorphism (SNP) associations across the ADH gene region. All data points are plotted as −log (p) (y-axis) against SNP location (x-axis, converted where necessary from the original publication to NCBI Build 36). For alcohol metabolism, the effects are estimated from the kinetic model of the time course of alcohol absorption and elimination. They are presented as the joint effect of parameters A₀ and k₁ (for early stages of alcohol absorption and metabolism), and parameter k₂, the rate of elimination of alcohol (for later stages of metabolism). Results are also shown for alcohol dependence (,–24), alcohol consumption (24) and alcohol-related upper aerodigestive cancers (25). The position of ADH genes is indicated by the boxes: A = ADH1A, B = ADH1B, C = ADH1C, 4 = ADH4, 5 = ADH5, 6 = ADH6, 7 = ADH7. Studies are distinguished as follows: this paper, early = effects on the absorption/distribution phase of alcohol pharmacokinetics, A₀ and k₁; this paper, late = effects on the elimination phase of alcohol pharmacokinetics, k₂; Macgregor (24) QF = alcohol intake from quantity and frequency data; Macgregor AD = alcohol dependence symptom count; Choi (21) AD = alcohol dependence diagnosis; Edenberg (22) COGA = alcohol dependence by COGA criteria; Edenberg DSM4 = alcohol dependence by DSM-IV criteria; Kuo (23) AD = alcohol dependence diagnosis; Luo (8) HWE EA and AA = alcohol dependence diagnosis using Hardy–Weinberg disequilibrium testing in European-Americans or African-Americans, respectively; Luo EA and AA = alcohol dependence diagnosis using allelic association test in European-Americans or African-Americans, respectively; Hashibe (25) Ca = case–control study of upper aerodigestive cancers.