Polymorphism study of seven SNPs at ADH genes in 15 Chinese populations

摘要

With the great accomplishment of Human Genome Project, researchers could now take advantage of abundant convenient and timesaving methods and approaches to study multifactor diseases. Among these, SNPs (single nucleotide polymorphism) and haplotypes analyses are two effective ways. The advantages of constructing special disease-related haplotypes with several htSNPs (haplotype tag SNPs) lie in their effectiveness for susceptible people screening as well as their reliability to investigate the genetic structure of different populations. Therefore such methods were selected in the present study to define genetic variation of 7 SNPs at ADH genes in 15 Chinese populations.As a multifactor polygenetic disorder, alcoholism involves complex gene-with-gene and gene-with-environment interactions, of which alcohol metabolism significantly changes the drinking behavior and the development of alcoholism as a biological determinant (Edenberg 2000). The seven known human genes coding for alcohol dehydrogenase (ADH7, ADH1C, ADH1B, ADH1A, ADH6, ADH4, ADH5) exist in a cluster extending ～380 kb on the long arm of chromosome 4 (4q21–23). Three of these seven genes, ADH1A, ADH1B and ADH1C, which were believed to be the most important genes in the metabolism of ethanol, were classified as class I ADH genes and exist in a much tighter cluster of only ～80 kb. Although quite similar in sequence and structure, variants of class I ADH genes exhibited different functional activity. For example, the enzyme produced by variant ADH1B*2 had a much higher Vmax (340 μM min?1) compared to the enzyme produced by ADH1B*1 (Vmax 9 μM min?1) (Edenberg et al. 1997). Here, the nomenclature of “ADH1B*2”, “ADH1B*1” is from an old system based on the protein difference. But obviously, it is not adequate for analyses on the genomic level since each of them is composed of two different polymorphic SNP sites. For example, the ADH1B*1 allele is composed of 47Arg and 369Arg, while the ADH1B*2 allele is composed of 47His and 369Arg. In order to make it clearer and more appropriate for haplotype analysis, we follow the new nomenclature system used by Osier et al. (2002), specifying all sites individually.On the other hand, ADH genes exhibited significant genetic polymorphism and ethnic variation. The most visible evidences were that allele frequency and expected heterozygosity of ADH SNPs varied distinctly among different groups. For example, data from ALFRED (Allele Frequency Database) showed that allele frequency of ADH1B 47His was 0.6 in East Asian populations. While for ADH1B Arg369Cys site, the mutation rate of Arg to Cys was 0 in Asian groups, but was as high as 0.15 in African groups (Osier et al. 2001). Taken together, it's reasonable to consider ADH genes as suitable candidate genes for population genetics study. Therefore, in order to study the genetic variation of class I ADH genes in different Chinese groups, seven SNPs were selected for analysis.