Han Yi, Oota Hiroki, Osier Michael V, Pakstis Andrew J, Speed William C, Odunsi Adekunle, Okonofua Friday, Kajuna Sylvester L B, Karoma Nganyirwa J, Kungulilo Selemani, Grigorenko Elena, Zhukova Olga V, Bonne-Tamir Batsheva, Lu Ru-B, Parnas Josef, Schulz Leslie O, Kidd Judith R, Kidd Kenneth K
Department of Genetics, Yale University, School of Medicine, New Haven, CT 06520-8005, USA.
Alcohol Clin Exp Res. 2005 Dec;29(12):2091-100. doi: 10.1097/01.alc.0000191769.92667.04.
Of the seven known human alcohol dehydrogenase (ADH) genes, the non-liver expressed ADH7 gene codes for the enzyme with the highest maximal activity for ethanol. Previous study from our laboratory has suggested that ADH7 has an epistatic role for protection against alcoholism based on a single ADH7 SNP.
We have now studied seven SNPs, additional populations for the SNP previously examined, and six more new SNPs, across 23 kb of ADH7 in 38 population samples originating from different geographical regions of the world.
The overall linkage disequilibrium is moderate to strong across this region even though considerable 7-SNP haplotype diversity is observed. This uncommonly high haplotype diversity is explained by high LD within each "half," the three upstream SNPs and the four downstream SNPs, but near randomization between the "halves." This division significantly simplified the haplotype pattern: only four major haplotypes account for almost all chromosomes in all populations in each "half."
The low linkage disequilibrium between these two "halves" suggests multiple recombination(s) have occurred in this region, specifically, within intron 7. The absence of strong LD between the functional variation in ADH1B that is strongly associated with alcoholism and any of the variation in ADH7 supports the genetic independence of ADH7 in association studies. Thus, the previously observed epistatic effect of ADH7 cannot be explained by its linkage disequilibrium with a causative factor in ADH1B.
在已知的7种人类乙醇脱氢酶（ADH）基因中，非肝脏表达的ADH7基因编码的酶对乙醇具有最高的最大活性。我们实验室之前的研究表明，基于单个ADH7单核苷酸多态性（SNP），ADH7在预防酒精中毒方面具有上位性作用。
我们现在研究了7个SNP，包括之前检测的SNP的更多人群样本，以及另外6个新的SNP，这些SNP分布在来自世界不同地理区域的38个群体样本的ADH7基因23 kb区域内。
尽管观察到相当大的7-SNP单倍型多样性，但该区域的总体连锁不平衡为中度至强度。这种异常高的单倍型多样性可以通过每个“半区”（上游3个SNP和下游4个SNP）内的高连锁不平衡来解释，但两个“半区”之间几乎是随机的。这种划分显著简化了单倍型模式：在每个“半区”的所有群体中，仅四种主要单倍型就几乎涵盖了所有染色体。
这两个“半区”之间的低连锁不平衡表明该区域发生了多次重组，具体发生在内含子7内。与酒精中毒密切相关的ADH1B功能变异与ADH7的任何变异之间不存在强连锁不平衡，这支持了ADH7在关联研究中的遗传独立性。因此，之前观察到的ADH7的上位性效应不能用其与ADH1B致病因素的连锁不平衡来解释。
