Yang Min, Tsuang John, Wan Yu-Jui Yvonne
Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
Alcohol Clin Exp Res. 2007 Dec;31(12):1991-2000. doi: 10.1111/j.1530-0277.2007.00533.x.
Studies regarding the association between the 4 polymorphisms of CYP2E1 (CYP2E1*1D, *5B, *6, and *1B) and alcoholism are inconsistent and inconclusive. The purpose of the present study was to clarify previously discordant studies by haplotype analysis in the Mexican American population.
The 4 polymorphisms of CYP2E1 were studied in 334 alcoholics and 365 controls. Genotype, allele, and haplotype frequency comparisons between alcoholics and controls were assessed. Patterns of linkage disequilibrium (LD) at CYP2E1 were determined. Reconstructed haplotypes were tested for associations with clinical phenotypes (age onset of drinking, Maxdrinks, and smoking status).
No significant associations between the 4 polymorphisms of CYP2E1 and alcoholism were revealed by single allele tests. High LD was found between the CYP2E1 c2 and C alleles in Mexican Americans. Eleven haplotypes were present in the 699 participants. The 6 main haplotypes with frequencies higher than 1% made up 97% of the total halpotypes. The frequency of subjects carrying H6 (1C-c2-C-A2) was significantly higher in alcoholics than in controls (p = 0.0001). In contrast, the frequencies of H7 (1C-c2-C-A1) and H10 (1C-c2-D-A1) were significantly lower in alcoholics than in controls (p = 0.0072 for H7 and p = 0.0407 for H10). The frequency of H6 was significantly higher in alcoholics who had late onset of drinking than in nonalcoholic controls. Furthermore, the frequencies of H6 haplotype were also consistently higher in groups who had high number of maximum drinks (9 to 32 drinks) than in controls. When smokers are excluded, the frequencies of H6, H7, and H9 (1C-c2-D-A2) showed statistically significant differences between alcoholics and controls (p < 0.05). Moreover, the association between H6 and alcoholism become more robust when smokers are excluded. Furthermore, the frequency of H1 (1C-c1-D-A2) in alcoholic-smokers was much higher than in alcoholic-nonsmokers (p = 0.0028). In contrast, alcoholic-smokers carried less H2 (1C-c1-D-A1) in comparison with alcoholic-nonsmokers (p = 0.0417). The H3 (1D-c2-C-A2) frequency in alcoholic-smokers was much lower than in alcoholic-nonsmokers (p = 0.0042) and control-smokers (p = 0.0363).
Our data demonstrate that carrying haplotype H6 might enhance susceptibility to developing alcoholism, but possessing the H7 or H10 haplotype appears to decrease this susceptibility. The H6, H7, and H9 haplotypes may play certain roles in different clinical phenotypes in Mexican American alcoholics. In addition, our data suggest that the H1, H2, and H3 haplotypes are associated with alcohol drinking and smoking. These results support that haplotype analysis is much more informative than single allele analysis. Our findings clearly indicate the importance of H6 haplotype in alcohol drinking in Mexican Americans.
关于细胞色素P450 2E1（CYP2E1）的4种多态性（CYP2E1*1D、*5B、6和1B）与酒精中毒之间关联的研究结果并不一致且尚无定论。本研究的目的是通过单倍型分析来澄清墨西哥裔美国人中先前存在争议的研究。
对334名酒精中毒者和365名对照者进行CYP2E1的4种多态性研究。评估了酒精中毒者与对照者之间的基因型、等位基因和单倍型频率比较。确定了CYP2E1处的连锁不平衡（LD）模式。对重建的单倍型与临床表型（饮酒起始年龄、最大饮酒量和吸烟状况）的关联性进行了检测。
单等位基因检测未发现CYP2E1的4种多态性与酒精中毒之间存在显著关联。在墨西哥裔美国人中发现CYP2E1的c2和C等位基因之间存在高度连锁不平衡。699名参与者中存在11种单倍型。频率高于1%的6种主要单倍型占总单倍型的97%。携带H6（1C-c2-C-A2）的酒精中毒者频率显著高于对照者（p = 0.0001）。相反，酒精中毒者中H7（1C-c2-C-A1）和H10（1C-c2-D-A1）的频率显著低于对照者（H7为p = 0.0072，H10为p = 0.0407）。饮酒起始较晚的酒精中毒者中H6的频率显著高于非酒精中毒对照者。此外，最大饮酒量较高（9至32杯）的组中H6单倍型的频率也始终高于对照者。排除吸烟者后，酒精中毒者与对照者之间H6、H7和H9（1C-c2-D-A2）的频率显示出统计学显著差异（p < 0.05）。此外，排除吸烟者后，H6与酒精中毒之间的关联变得更强。此外，酒精中毒吸烟者中H1（1C-c1-D-A2）的频率远高于酒精中毒非吸烟者（p = 0.0028）。相反，与酒精中毒非吸烟者相比，酒精中毒吸烟者携带的H2（1C-c1-D-A1）较少（p = 0.0417）。酒精中毒吸烟者中H3（1D-c2-C-A2）的频率远低于酒精中毒非吸烟者（p = 0.0042）和吸烟对照者（p = 0.0363）。
我们的数据表明，携带单倍型H6可能会增加患酒精中毒的易感性，但拥有H7或H10单倍型似乎会降低这种易感性。H6、H7和H9单倍型可能在墨西哥裔美国酒精中毒者的不同临床表型中发挥一定作用。此外，我们的数据表明H1、H2和H3单倍型与饮酒和吸烟有关。这些结果支持单倍型分析比单等位基因分析提供的信息更多。我们的研究结果清楚地表明了H6单倍型在墨西哥裔美国人饮酒中的重要性。
