Hamon Sara C, Kardia Sharon L R, Boerwinkle Eric, Liu Kiang, Klos Kathy L E, Clark Andrew G, Sing Charles F
Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-0618, USA.
Hum Hered. 2006;61(2):87-96. doi: 10.1159/000093384. Epub 2006 May 19.
Evaluate the consistency of the contribution of interactions between single nucleotide polymorphism (SNP) genotype effects to variation in measures of lipid metabolism across ethnic strata within gender.
We considered 80 SNPs within the apolipoprotein (APO) A1/C3/A4/A5 gene cluster using an over-parameterized general linear model to identify SNPs whose genotype effects combine non-additively to influence plasma levels of high density lipoprotein cholesterol (HDL-C), total cholesterol (TC) and triglycerides (TG) in a consistent manner across ethnic strata. We analyzed population-based samples of unrelated 18 to 30 year old African-Americans (n = 1,858) and European-Americans (n = 1,973) ascertained without regard to health at four field centers (Birmingham, Ala.; Chicago, Ill.; Minneapolis, Minn. and Oakland, Calif., USA) by the Coronary Artery Risk Development in Young Adults (CARDIA) study. To identify which SNP genotype effects combine non-additively we used a two-tier analysis strategy. We first required that pairs of SNPs show statistically significant non-additivity in both ethnic strata within a gender, where experiment-wise significance was evaluated using a permutation test to determine the probability of observing the number of tests significant in both ethnic strata by chance alone. Second, we required no significant evidence of heterogeneity of the relationship between the phenotype and the two SNP genotypes across ethnic strata and across field centers within each ethnic group. From this strategy we identified ten pairs of SNPs, involving thirteen SNPs, that displayed statistically significant non-additivity of SNP genotype effects on TC. Only one of these thirteen SNPs had statistically significant genotype effects that were consistent across samples.
Our analyses suggest that ignoring the contribution of interactions between SNP genotype effects when modeling multi-SNP genotype-phenotype relationships may result in an underestimate of the contribution of genetic variation to variation in quantitative cardiovascular disease (CVD) risk factor traits.
评估单核苷酸多态性（SNP）基因型效应之间的相互作用对不同性别种族阶层脂质代谢指标变化的贡献的一致性。
我们使用一个超参数化的一般线性模型来考虑载脂蛋白（APO）A1/C3/A4/A5基因簇内的80个SNP，以识别其基因型效应以非加性方式组合，从而在不同种族阶层中一致地影响高密度脂蛋白胆固醇（HDL-C）、总胆固醇（TC）和甘油三酯（TG）血浆水平的SNP。我们分析了来自基于人群的样本，这些样本是年龄在18至30岁之间的非亲属非裔美国人（n = 1,858）和欧裔美国人（n = 1,973），由美国四个现场中心（阿拉巴马州伯明翰市；伊利诺伊州芝加哥市；明尼苏达州明尼阿波利斯市；加利福尼亚州奥克兰市）的青年动脉粥样硬化风险发展（CARDIA）研究确定，确定过程未考虑健康状况。为了识别哪些SNP基因型效应以非加性方式组合，我们使用了两层分析策略。我们首先要求成对的SNP在一个性别内的两个种族阶层中均显示出统计学上显著的非加性，其中通过置换检验评估实验性显著性，以确定仅偶然观察到在两个种族阶层中显著的检验数量的概率。其次，我们要求在不同种族阶层以及每个种族群体内的不同现场中心之间，表型与两个SNP基因型之间的关系不存在显著的异质性证据。通过这种策略，我们识别出了十对SNP，涉及十三个SNP，它们在TC上显示出SNP基因型效应的统计学显著非加性。这十三个SNP中只有一个在样本间具有统计学上显著且一致的基因型效应。
我们的分析表明，在对多SNP基因型 - 表型关系进行建模时忽略SNP基因型效应之间相互作用的贡献，可能会导致对遗传变异对定量心血管疾病（CVD）风险因素性状变化的贡献估计不足。
