Serum lipids in the GENECARD study of coronary artery disease identify quantitative trait loci and phenotypic subsets on chromosomes 3q and 5q
Serum lipids in the GENECARD study of coronary artery disease identify quantitative trait loci and phenotypic subsets on chromosomes 3q and 5q
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DOI：
10.1111/j.1469-1809.2006.00288.x
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发表时间：
2006-11-01
影响因子：
1.9
通讯作者：
Hauser, E. R.
中科院分区：
文献类型：
--
作者：
Shah, S. H.;Kraus, W. E.;Hauser, E. R.
冠状动脉疾病（CAD）和血脂异常有很强的遗传成分。异质性使评估复杂疾病（如CAD）的遗传学变得复杂;纳入疾病相关表型可能有助于减少异质性。我们假设，将脂蛋白在CAD的研究将增加功率映射基因，缩小连锁峰，确定表型子集，并阐明已建立的危险因素的遗传结果的贡献。我们进行了有序子集分析（OSA）和数量性状连锁（QTL）使用血清脂蛋白和微卫星标记在346个早发性CAD的家庭。OSA定义同质子集，并计算了平均脂蛋白值的家庭排名后，在染色体上的LOD分数。QTL采用方差分量分析。我们发现，在高密度脂蛋白胆固醇、低密度脂蛋白和总胆固醇、低甘油三酯和CAD风险因素较少的家族中，与染色体3q 13的连锁显著增加（LOD 5.10，p = 0.008），这可能是由于集中的非脂蛋白相关遗传效应。OSA在高胆固醇家族中发现了染色体5 q34上的连锁，可能代表了遗传性脂蛋白表型。确定了多个QTL，其中最强的是：染色体5 q14上的总胆固醇（LOD 4.3）; 20 p12上的LDL（LOD 3.97）; 3 p14上的HDL（LOD 1.65）; 18 q22上的甘油三酯（LOD 1.43）;和HDL/TC比值在3q 27 -28我们的研究结果提示早发CAD家族存在病因异质性，可能是由于脂蛋白表型的差异效应。候选基因正在研究中。
Coronary artery disease (CAD) and dyslipidemia have strong genetic components. Heterogeneity complicates evaluating genetics of complex diseases such as CAD; incorporating disease-related phenotypes may help reduce heterogeneity. We hypothesized that incorporating lipoproteins in a study of CAD would increase the power to map genes, narrow linkage peaks, identify phenotypic subsets, and elucidate the contribution of established risk factors to genetic results.We performed ordered subset analysis (OSA) and quantitative trait linkage (QTL) using serum lipoproteins and microsatellite markers in 346 families with early-onset CAD. OSA defined homogeneous subsets and calculated lod scores across a chromosome after ranking families by mean lipoprotein values. QTL used variance components analysis. We found significantly increased linkage to chromosome 3q13 (LOD 5.10, p = 0.008) in families with higher HDL cholesterol, lower LDL and total cholesterol, lower triglycerides, and fewer CAD risk factors, possibly due to a concentrated non-lipoprotein-related genetic effect. OSA identified linkage on chromosome 5q34 in families with higher cholesterol, possibly representing a hereditary lipoprotein phenotype. Multiple QTLs were identified, with the strongest for: total cholesterol on chromosome 5q14 (LOD 4.3); LDL on 20p12 (LOD 3.97); HDL on 3p14 (LOD 1.65); triglycerides on 18q22 (LOD 1.43); and HDL/TC ratio on 3q27-28 (LOD 2.06).Our findings suggest the presence of etiologic heterogeneity in families with early-onset CAD, potentially due to differential effects of lipoprotein phenotypes. Candidate genes are under investigation.