Polymorphisms of Alcohol Metabolizing Enzymes in Indigenous Mexican Population: Unusual High Frequency of CYP2E1*c2 Allele

Abstract

Background: Alcohol abuse represents the major identified etiological factor of cirrhosis in Me´xico. ADH1B, ALDH2, and CYP2E1 have been considered candidate genes in alcohol-related diseases. Controversial results probably due to ethnic differences, among other factors, have been reported. Mexican Mestizos (MES) derive from the combination of indigenous, Spaniard, and African genes. Huichols (HUI) constitute an indigenous group from western Mexico with no racial admixture. We determined ADH1B*2, ALDH2*2, and CYP2E1*c2 allele frequencies in healthy HUI and MES from western Mexico. Lipid and hepatic profile were also carried out.Methods: One hundred and one HUI and 331 MES subjects were studied. Genotype and allele frequency were assessed through polymerase chain reaction-restriction fragment length polymorphism after DNA isolation from peripheral leukocytes. Commercial kits for lipid and hepatic determinations were used.Results: Polymorphic allele distribution in HUI was: 0% ADH1B*2, 0.5% ALDH2*2, 51.5% CYP2E1*c2; in MES: 3.4% ADH1B*2, 0% ALDH2*2, 16.1% CYP2E1*c2. Frequency of ADH1B*2 was statistically (p < 0.001) lower in HUI than MES. CYP2E1*c2 polymorphic allele was significantly higher (p < 0.0001) in HUI than MES. Hepatic profile was normal in both groups. HUI showed a better lipid profile than MES independently of genotype.Conclusions: Huichols exhibited the highest CYP2E1*c2 allele frequency of the world documented up to this date; meanwhile, ADH1B*2 and ALDH2*2 were practically absent. This feature could be useful in the understanding of Mexican population gene composition, alcohol metabolism, and alcoholic liver disease development. However, further association studies are necessary. The heterogeneity of Mexican population was evidenced by the significantly different distribution of CYP2E1*c2 allele observed among different regions of the country. Lipid and hepatic values were not associated to genotype. This report constitutes the first study dealing with gene polymorphisms of alcohol metabolizing enzymes conducted in HUI.

Genetic Polymorphisms of Genes Coding to Alcohol‐Metabolizing Enzymes in Western Mexicans: Association of CYP2E1*c2/CYP2E1*5B Allele with Cirrhosis and Liver Function

“…Functional significance of this polymorphism may be attributed to its localization in presumed DNA responding element for hepatic transcription factor 1 (Hayashi et al, 1991;Watanabe et al, 1994). Major frequencies of CYP2E1*c2 polymorphic allele corresponded to Chinese (30%; Tan et al, 2000) and Japanese populations (30.9%; Morita et al, 2009) until recently, when the highest frequency reported is in Huichols (51%; Gordillo-Bastidas et al, 2010), an indigenous group from Western Central Mexico. Various studies have demonstrated that carrying c2 allele may lead to increased risk to develop alcoholic liver disease (Cichoz-Lach et al, 2006;Konishi et al, 2003;Pirmohamed et al, 1995).…”

“…In an effort to better understand the bases underlying this nosological entity, a variety of studies describing possible molecular and pathophysiological factors involved have been accomplished (Bastidas-Ramı´rez et al, 2002;Gordillo-Bastidas et al, 2010;Herna´ndez-Nazara´et al, 2008;Nun˜o-Gonza´lez et al, 2005). Ethnicity influence over differential susceptibility to alcoholic liver disease has widely been determined (Douds et al, 2003).…”

“…DNA was obtained through the modified Miller's procedure (Cuevas-Covarrubias et al, 2002;Miller et al, 1988;Gordillo-Bastidas et al, 2010). Finally, DNA was resuspended in 300 ll of sterile deionized water and spectrophotometric quantification at 260 ⁄ 280 nm was accomplished.…”

Ethnic Differences in Presentation and Severity of Alcoholic Liver Disease

“…Finally, Garcia‐Banuelos and colleagues () showed a significant increase in the presence of the CYP2E1 c2 allele in cirrhotics from western Mexico. Comparing ethnicities, the CYP2E1*c2 allele has been shown to occur with high frequency in Mexican Americans when compared to Europeans (Gordillo‐Bastidas et al., ).…”

Model for end-stage liver disease-Na score or Maddrey discrimination function index, which score is best?

“…Excessive alcohol consumption is a social problem in example, several studiesin Mexican-American and Mestizo populations have identified a virtual absence of some of the alcohol "protective" genes variations (ADH1B and ALDH2) and a high frequency of CPY2E c2polymorphic allele, which result in increased enzymatic activity,augmented acetaldehyde production, and more severe liver damage [33,34] . Many strategies have been used to predict morbidity and mortality in AH allowing a better medical support for those very ill patients.…”