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Association Between In Vivo Alcohol Metabolism and Genetic Variation in Pathways that Metabolize the Carbon Skeleton of Ethanol and NADH Reoxidation in the Alcohol Challenge Twin Study
Author(s) -
Lind Penelope A.,
Macgregor Stuart,
Heath Andrew C.,
Madden Pamela A. F.,
Montgomery Grant W.,
Martin Nicholas G.,
Whitfield John B.
Publication year - 2012
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.2012.01829.x
Subject(s) - ethanol metabolism , single nucleotide polymorphism , alcohol , biology , genetics , metabolism , ethanol , biochemistry , chemistry , gene , genotype
Background Variation in alcohol metabolism affects the duration of intoxication and alcohol use. While the majority of genetic association studies investigating variation in alcohol metabolism have focused on polymorphisms in alcohol or aldehyde dehydrogenases, we have now tested for association with genes in alternative metabolic pathways that catalyze the carbon skeleton of ethanol ( E tO H ) and NADH reoxidation. Methods Nine hundred fifty single nucleotide polymorphisms ( SNP s) spanning 14 genes ( ACN 9 , ACSS 1 , ACSS 2 , ALDH 1A1, CAT , CYP 2E1 , GOT 1 , GOT 2 , MDH 1 , MDH 2 , SLC 25A10 , SLC 25A11 , SLC 25A12 , SLC 25A13 ) were genotyped in 352 young adults who participated in an alcohol challenge study. Traits tested were blood alcohol concentration (BAC), breath alcohol concentration (BrAC), peak alcohol concentration, and rates of alcohol absorption and elimination. Allelic association was tested using quantitative univariate and multivariate methods. Results A CYP 2 E 1 promoter SNP (rs4838767, minor allele frequency 0.008) exceeded the threshold for study‐wide significance (4.01 × 10 −5 ) for 2 early BAC , 8 Br AC measures, and the peak B r AC . For each phenotype, the minor C allele was related to a lower alcohol concentration, most strongly for the fourth B r AC ( p = 2.07 × 10 −7 ) explaining ~8% of the phenotypic variance. We also observed suggestive patterns of association with variants in ALDH 1 A 1 and on chromosome 17 near SLC 25 A 11 for aspects of blood and breath alcohol metabolism. An SNP upstream of GOT 1 (rs2490286) reached study‐wide significance for multivariate BAC metabolism ( p = 0.000040). Conclusions Overall, we did not find strong evidence that variation in genes coding for proteins that further metabolize the carbon backbone of acetaldehyde, or contribute to mechanisms for regenerating NAD from NADH , affects alcohol metabolism in our E uropean‐descent subjects. However, based on the breath alcohol data, variation in the promoter of CYP 2 E 1 may play a role in preabsorptive or early hepatic alcohol metabolism, but more samples are required to validate this finding.