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冠心病(coronary heart disease,CHD)是一个复杂的遗传疾病,其发病率也受生活方式的影响,如吸烟和人体活动。全基因组关联研究已经检测到多个风险基因与冠心病相关联。然而报道的遗传变异仅占表现型变异的一小部分。生活方式对冠心病的影响机制仍然不清。本研究通过引入非加性效应的遗传分析,揭示非加性遗传的重要性,并用条件分析的方法研究了不同生活方式对种族人群遗传变异的影响。使用多族群研究动脉粥样硬化(Multi-Ethnic Study of Atherosclerosis,MESA)的数据,应用混合线性模型分析单核苷酸多态性(single nucleotidepolymorphisms,SNPs)变异与冠心病的关联。采用包括加性、显性、上位性及族群互作的遗传模型,研究了冠心病的复杂遗传体系。采用6种不同行为(步行,阅读、运输、运动、电视、吸烟)作为条件分析的协变量,探索了人类行为对冠心病的遗传影响。为实现个性化治疗的精准诊断,预测了人类不同行为对基因位点的特异遗传效应。总共检测到61个数量性状位点(quantitative trait SNPs,QTSs)和23对上位性位点,与表现型变异存在显著的相关性。采用不同模型估算的遗传率达64.58%~74.94%。我们观察到加性效应贡献只占总遗传率的一小部分(3.45%~5.72%)。相比之下,非加性效应占总遗传率的主要部分。基于不同生活方式的条件分析揭示,不同生活方式对冠心病遗传结构会产生较大影响。4个族群基于7个不同模型的遗传分析揭示,不同种群的冠心病具有显著的遗传特异性。
Coronary heart disease (CHD) is a complex genetic disease whose morbidity is also affected by lifestyles, such as smoking and human activities. Genome-wide association studies have detected multiple risk genes associated with coronary heart disease. However, the reported genetic variation accounted for only a small proportion of phenotypic variation. The impact of lifestyle on coronary heart disease remains unclear. In this study, the genetic analysis of non-additive effect was introduced to reveal the importance of non-additive genetic analysis and the effect of different life styles on the genetic variation of racial population. Using a multi-ethnic study of Atherosclerosis (MESA) data, a mixed-linear model was used to analyze the association of single nucleotide polymorphisms (SNPs) with coronary heart disease. Using genetic models including additive, dominant, epistatic and ethnic interactions, we studied the complex genetic system of coronary heart disease. Six different behaviors (walking, reading, transport, exercise, television, smoking) were used as the covariates of conditional analysis to explore the genetic effects of human behavior on coronary heart disease. In order to achieve accurate diagnosis of personalized treatment, we predict the specific genetic effect of different human behaviors on gene loci. In total, 61 quantitative trait SNPs (QTSs) and 23 pairs of epistatic sites were detected, which were significantly associated with phenotypic variation. The hereditary rates estimated by different models reached 64.58% ~ 74.94%. We observed that additive effects contributed only a small percentage of the total heritability (3.45% -5.72%). In contrast, non-additive effects accounted for a major part of the overall heritability. Condition analysis based on different lifestyles revealed that different life styles have a greater impact on the genetic structure of coronary heart disease. Genetic analysis of four ethnic groups based on seven different models revealed significant genetic specificity for coronary heart disease in different populations.