Genetic time-series analysis identifies a major QTL for in vivo alcohol metabolism not predicted by in vitro studies of structural protein polymorphism at the ADH1B or ADH1C loci
Genetic time-series analysis identifies a major QTL for in vivo alcohol metabolism not predicted by in vitro studies of structural protein polymorphism at the ADH1B or ADH1C loci
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DOI：
10.1007/s10519-005-3851-6
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发表时间：
2005-09-01
影响因子：
2.6
通讯作者：
Martin, NG
中科院分区：
文献类型：
--
作者：
Birley, AJ;Whitfield, JB;Martin, NG
摄入标准剂量的乙醇后，在3.5小时内通过血液（6个读数）和呼吸（10个读数）对参加酒精挑战双胞胎研究（ACTS）的412名MZ和DZ双胞胎样本中的酒精浓度进行了评估。几乎所有的参与者随后在已知影响体外ADH活性的ADH 1B和ADH 1C基因座中的两个多态性SNP上进行基因分型。在DZ对中，评估了覆盖4号染色体上包括ADH基因家族的20.5cM区域的14个微卫星标记，使用双变量单纯形设计研究了自相关血液和呼吸酒精读数的时间序列的变化。数量性状基因座（QTL）或QTL的ADH区域的贡献估计通过混合的似然加权身份下降概率。在ADH 1B和ADH 1C基因座的等位基因取代的影响，估计在模型的平均值的一部分，同时与性别和年龄的影响。有一个主要的贡献，酒精代谢的变异，由于QTL占约64%的加性遗传共变异共同血液和呼吸酒精读数在第一时间点。没有观察到ADH 1B * 47 His或ADH 1C * 349 Ile等位基因对体内代谢的影响，尽管这些等位基因在体外具有主要影响。这意味着，有一个主要的决定因素的变化，在体内乙醇代谢的ADH地区，不占这些多态性。这些数据的早期分析表明，酒精代谢与饮酒行为有关，并暗示该QTL可能对酒精依赖具有保护作用。
After ingestion of a standardized dose of ethanol, alcohol concentrations were assessed, over 3.5 hours from blood (six readings) and breath (10 readings) in a sample of 412 MZ and DZ twins who took part in an Alcohol Challenge Twin Study (ACTS). Nearly all participants were subsequently genotyped on two polymorphic SNPs in the ADH1B and ADH1C loci known to affect in vitro ADH activity. In the DZ pairs, 14 microsatellite markers covering a 20.5 cM region on chromosome 4 that includes the ADH gene family were assessed, Variation in the timed series of autocorrelated blood and breath alcohol readings was studied using a bivariate simplex design. The contribution of a quantitative trait locus (QTL) or QTL's linked to the ADH region was estimated via a mixture of likelihoods weighted by identity-by-descent probabilities. The effects of allelic substitution at the ADH1B and ADH1C loci were estimated in the means part of the model simultaneously with the effects sex and age. There was a major contribution to variance in alcohol metabolism due to a QTL which accounted for about 64% of the additive genetic covariation common to both blood and breath alcohol readings at the first time point. No effects of the ADH1B*47His or ADH1C*349Ile alleles on in vivo metabolism were observed, although these have been shown to have major effects in vitro. This implies that there is a major determinant of variation for in vivo alcohol metabolism in the ADH region that is not accounted for by these polymorphisms. Earlier analyses of these data suggested that alcohol metabolism is related to drinking behavior and imply that this QTL may be protective against alcohol dependence.