Shah S H, Kraus W E, Crossman D C, Granger C B, Haines J L, Jones C J H, Mooser V, Huang L, Haynes C, Dowdy E, Vega G L, Grundy S M, Vance J M, Hauser E R
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Ann Hum Genet. 2006 Nov;70(Pt 6):738-48. doi: 10.1111/j.1469-1809.2006.00288.x.
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.
冠状动脉疾病（CAD）和血脂异常具有很强的遗传成分。异质性使评估诸如CAD等复杂疾病的遗传学变得复杂；纳入与疾病相关的表型可能有助于减少异质性。我们假设在CAD研究中纳入脂蛋白将提高定位基因的能力、缩小连锁峰、识别表型亚组，并阐明既定风险因素对遗传结果的贡献。我们在346个早发性CAD家庭中使用血清脂蛋白和微卫星标记进行了有序子集分析（OSA）和数量性状连锁分析（QTL）。OSA定义了同质亚组，并在按平均脂蛋白值对家庭进行排序后计算整个染色体的lod分数。QTL使用方差成分分析。我们发现，在高密度脂蛋白胆固醇较高、低密度脂蛋白和总胆固醇较低、甘油三酯较低且CAD风险因素较少的家庭中，与3q13染色体的连锁显著增加（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在胆固醇较高的家庭中识别出5q34染色体上的连锁，这可能代表一种遗传性脂蛋白表型。识别出多个QTL，其中最强的是：5q14染色体上的总胆固醇（LOD 4.3）；20p12上的低密度脂蛋白（LOD 3.97）；3p14上的高密度脂蛋白（LOD 1.65）；18q22上的甘油三酯（LOD 1.43）；以及3q27 - 28上的高密度脂蛋白/总胆固醇比值（LOD 2.06）。我们的研究结果表明，早发性CAD家庭中存在病因异质性，可能是由于脂蛋白表型的不同影响。正在对候选基因进行研究。
