Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
22577853
TITLE
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.
ABSTRACT
BACKGROUND NlmCategory: 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 (EtOH) and NADH reoxidation.
METHODS NlmCategory: METHODS
Nine hundred fifty single nucleotide polymorphisms (SNPs) spanning 14 genes (ACN9, ACSS1, ACSS2, ALDH1A1, CAT, CYP2E1, GOT1, GOT2, MDH1, MDH2, SLC25A10, SLC25A11, SLC25A12, SLC25A13) 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 NlmCategory: RESULTS
A CYP2E1 promoter SNP (rs4838767, minor allele frequency 0.008) exceeded the threshold for study-wide significance (4.01 × 10(-5) ) for 2 early BAC, 8 BrAC measures, and the peak BrAC. For each phenotype, the minor C allele was related to a lower alcohol concentration, most strongly for the fourth BrAC (p = 2.07 × 10(-7) ) explaining ~8% of the phenotypic variance. We also observed suggestive patterns of association with variants in ALDH1A1 and on chromosome 17 near SLC25A11 for aspects of blood and breath alcohol metabolism. An SNP upstream of GOT1 (rs2490286) reached study-wide significance for multivariate BAC metabolism (p = 0.000040).
CONCLUSIONS NlmCategory: 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 European-descent subjects. However, based on the breath alcohol data, variation in the promoter of CYP2E1 may play a role in preabsorptive or early hepatic alcohol metabolism, but more samples are required to validate this finding.
Copyright 2012 by the Research Society on Alcoholism.
DATE PUBLISHED
2012 Dec
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2011/07/12
accepted 2012/03/19
aheadofprint 2012/05/11
entrez 2012/05/15 06:00
pubmed 2012/05/15 06:00
medline 2013/05/18 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Lind PA Lind Penelope A PA Molecular Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, Australia. Penelope.Lind@qimr.edu.au
Macgregor S Macgregor Stuart S
Heath AC Heath Andrew C AC
Madden PA Madden Pamela A F PA
Montgomery GW Montgomery Grant W GW
Martin NG Martin Nicholas G NG
Whitfield JB Whitfield John B JB
INVESTIGATORS
JOURNAL
VOLUME: 36
ISSUE: 12
TITLE: Alcoholism, clinical and experimental research
ISOABBREVIATION: Alcohol. Clin. Exp. Res.
YEAR: 2012
MONTH: Dec
DAY:
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1530-0277
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Alcohol Clin Exp Res
COUNTRY: England
ISSNLINKING: 0145-6008
NLMUNIQUEID: 7707242
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Twin Study
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
AA07535 NIAAA NIH HHS United States
AA07728 NIAAA NIH HHS United States
AA11998 NIAAA NIH HHS United States
AA13320 NIAAA NIH HHS United States
AA13321 NIAAA NIH HHS United States
AA14041 NIAAA NIH HHS United States
AA17688 NIAAA NIH HHS United States
DA012854 NIDA NIH HHS United States
DA019951 NIDA NIH HHS United States
K05 AA017688 NIAAA NIH HHS United States
K08 DA019951 NIDA NIH HHS United States
P60 AA011998 NIAAA NIH HHS United States
R01 AA007535 NIAAA NIH HHS United States
R01 AA007728 NIAAA NIH HHS United States
R01 AA013320 NIAAA NIH HHS United States
R01 AA013321 NIAAA NIH HHS United States
R01 AA014041 NIAAA NIH HHS United States
R56 DA012854 NIDA NIH HHS United States
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Adolescent
Adult
Cytochrome P-450 CYP2E1 metabolism
Ethanol metabolism
Female metabolism
Gene Frequency metabolism
Genetic Variation genetics
Genotype genetics
Humans genetics
Male genetics
NAD metabolism
Oxidation-Reduction metabolism
Phenotype metabolism
Polymorphism, Single Nucleotide genetics
Twins, Dizygotic genetics
Twins, Monozygotic genetics
Young Adult genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0U46U6E8UK NAD
3K9958V90M Ethanol
EC 1.14.13.- Cytochrome P-450 CYP2E1
OTHER ID's
OTHERID SOURCE
NIHMS458896 NLM
PMC3729587 NLM