Study of Mexican Americans shows that polymorphisms of the CYP2E1 gene enhance susceptibility to alcoholism

Mexican Americans make up 66 percent of the U.S. Hispanic population and, when compared to other ethnic groups, show high rates of heavy drinking and alcohol-related problems.

First-of-its-kind research that examines haplotypes -- clusters of genetic polymorphisms -- of the CYP2E1 gene among a Mexican-American population has found that carrying haplotype H6 may enhance susceptibility to developing alcoholism.

Results are published in the December issue of Alcoholism: Clinical & Experimental Research.

"The prevalence rate of heavy drinking among male Mexican Americans is three times higher than that of non-Hispanic male populations," said Yu-Jui Yvonne Wan, professor of pharmacology and director of the Liver Center at the University of Kansas Medical Center. "Mexican Americans have also been found to have more alcohol-related problems -- such as withdrawal, tolerance, and accidents -- than Caucasians. Furthermore, Hispanics are more likely than Caucasians to continue their alcohol dependence once it begins."

Wan, who is the study's corresponding author, has been studying minority-health related issues for more than 15 years. She said that alcohol consumption by Hispanics also appears to lead to greater health-related complications.

"In comparison with Caucasians, Hispanics have a higher prevalence of hepatitis C, a serious infectious liver disease that greatly increases the risk for liver damage in heavy drinkers," she said. "Hispanics with alcoholic liver disease also appear to do significantly less well than those from other ethnic backgrounds."

Given the apparent susceptibility of Mexican Americans to alcohol-related problems, as well as previous inconsistent and inconclusive findings of the association between alcoholism and polymorphisms of the CYP2E1 gene, Wan designed her study to address both issues.

"Our study is the first to use a genetic haplotype approach to investigate an association of the four polymorphisms of the CYP2E1 gene -- CYP2E1*1D, *5B, *6, and *1B -- and alcoholism in the Mexican American population," she said. "A haplotype is the combination of marker alleles on a single chromosome. Haplotype analysis allows us to explore potential interactions among alleles and thus can be more informative than individual allele analysis."

Researchers recruited 699 Mexican Americans living within a 50-mile radius of Los Angeles for this study: 334 alcoholics and 365 non-alcoholics or "controls." All participants provided blood samples and clinical data for genotype, allele, and haplotype frequency comparisons. Haplotypes were also tested for associations with clinical phenotypes such as age of drinking onset, maximum number of drinks within a 24-hour period, and smoking status.

"Our data demonstrate that haplotype analysis is more informative than individual allele analysis," said Wan. "More specifically, subjects carrying haplotype H6, the combination of the four alleles -- 1C, c2, C and A2 -- appear to have increased susceptibility to developing alcoholism."

Results also indicate that H6 is associated with late-age onset of drinking as well as heavy drinking. In addition, the H1, H2 and H3 haplotypes were associated with alcohol consumption and smoking.

"Linkage disequilibrium (LD) is often termed 'allelic' association," explained Wan. "When alleles at two distinctive loci occur more frequently than expected given the known allele frequencies, the alleles are said to be in linkage disequilibrium. For instance, our study found that the CYP2E1 c2 allele is in linkage disequilibrium with the CYP2E1 C allele in Mexican Americans, which means the two alleles frequently coexist in one chromosome. Our data also showed that the c2 and C allele are linked with each other more tightly in alcoholics than in non-alcoholics. This suggests that an individual with both c2 and C alleles is more susceptible to alcoholism. These and other findings support the notion that LD is population specific, and the risk factor of alcoholism might be population specific as well."

Wan recommended that future studies examine the "functional significance" of the H6 haplotype. "Whether H6 changes enzyme activity or alcohol-induced enzyme activity needs to be examined," she said. "Although only five percent of Mexican alcoholics have the H6 haplotype, it is important to use the same approach to study other ethnic groups, particularly Asians, who have high frequency of both c2 and C alleles. Furthermore, since elevated CYP2E1 causes oxidative stress, polymorphisms of this gene might also have an impact in other disease processes such as cancer."

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