An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk.
BACKGROUND
Alcoholism is a complex, genetically influenced disorder the cause of which may be better understood through the study of genetically influenced phenotypes that mediate the risk. One such intermediate phenotype is the low level of response (LR) to alcohol. This project used a case-control approach to search for genes that may contribute to LR.


METHODS
Data were available from alcohol challenges at approximately age 20 and regarding the development of alcohol use disorders over the subsequent 20 years for 85 men, including 40 reported in a previous genetic analysis. LR was evaluated using oral consumption of 0.75 ml/kg of alcohol, after which changes in subjective feelings of intoxication and body sway were measured. Alcohol abuse and dependence were diagnosed by DSM-III-R criteria through structured interviews administered to both the participant and an informant (usually the spouse) 10, 15, and 20 years after initial testing. Four polymorphisms were evaluated, including the serotonin transporter HTTLPR promoter ins/del, GABAAalpha6 Pro385Ser, NPY Leu7Pro, and catalase 262C>T. Two of these, HTTLPR and GABAAalpha6 Pro385Ser, had been previously associated with LR and alcoholism in a preliminary study.


RESULTS
The HTTLPR L allele was significantly related to both the LR and alcoholism in an allele-dosage (stepwise) manner. Furthermore, the association remained when L alleles were subdivided into recently reported functional subtypes: the lowest LR was associated with genotypes correlated with the highest serotonin transporter expression. The GABAAalpha6 Ser385 allele showed a nonsignificant trend for association to a low LR, as had been previously observed, although the Ser385 allele is uncommon, and only 18 heterozygotes were in the current group. However, the six men with both LL and Pro385/Ser385 genotypes had the lowest LR, and each had developed alcoholism during follow-up. Neither NPY nor catalase was associated with either LR or alcoholic outcomes, although the sample did not have sufficient power for definitive conclusions.


CONCLUSIONS
This report strengthens the support for a relationship between the HTTLPR L and GABAAalpha6 Ser385 alleles to low alcohol LR and to alcoholism in a prospectively studied cohort evaluated for LR in young adulthood and before the onset of alcohol dependence.
Hu
Xianzhang
X
Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland, USA.
Oroszi
Gabor
G
Chun
Jeffrey
J
Smith
Tom L
TL
Goldman
David
D
Schuckit
Marc A
MA
D000328:Adult; D000428:Alcohol Drinking / Q000235:genetics*; D000437:Alcoholism / Q000235:genetics*; D000483:Alleles; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D026901:Membrane Transport Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D011446:Prospective Studies; D011963:Receptors, GABA-A / Q000235:genetics; D012307:Risk Factors; D050486:Serotonin Plasma Membrane Transport Proteins
D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011963:Receptors, GABA-A; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins