Feitosa Mary F, Province Michael A, Heiss Gerardo, Arnett Donna K, Myers Richard H, Pankow James S, Hopkins Paul N, Borecki Ingrid B
Division of Statistical Genomics, Center for Genome Sciences, Washington University School of Medicine, 660 S. Euclid, Campus Box 8067, St. Louis, MO 63110-1093, USA.
Atherosclerosis. 2007 Jan;190(1):232-7. doi: 10.1016/j.atherosclerosis.2006.02.006. Epub 2006 Mar 9.
A genome-wide linkage scan was conducted to identify regions potentially having quantitative trait loci (QTLs) influencing high-density lipoprotein (HDL) cholesterol. We found suggestive evidence of a QTL (lod score (LOD)=1.75, p=0.00224, and q=0.07649) influencing the variation of plasma levels of age- and sex-adjusted HDL-cholesterol on chromosome 15q21 at marker D15S659 in the NHLBI FHS data. Owing to the perturbations to lipid profiles associated with diabetes, the analysis was repeated excluding diabetic subjects from the sample. The lod score increased from 1.75 to 2.71 (p=0.00021, q=0.05392) at the same chromosome 15 location, despite the reduction in sample size. This finding indicates that the inclusion of diabetic subjects in the analysis may confound the presence of a QTL for HDL-cholesterol on 15q21. Because of the known effects of important covariates such as metabolic variables and lifestyle habits that may interact with a putative QTL, we also analyzed HDL-cholesterol with a progressive adjustment. When body mass index, smoking, and habitual alcohol intake were added to age- and sex-adjustment, we found strong evidence for linkage in the complete sample (LOD=4.77, p=0.0000013, and q=0.00016) as well as in the non-diabetic sub-sample (LOD=4.52, p=0.0000025, and q=0.00026) on chromosome 15q21 (between D15S659 and D15S195 markers). These results suggest that there are multiple pathways and factors involving genetic and environmental effects influencing HDL-cholesterol levels, and by taking some of these known factors into account, we obtained strong evidence of a QTL influencing HDL-cholesterol levels. While this putative QTL may also have an effect in diabetes, our data suggest a more pronounced role in non-diabetics. A prominent candidate gene residing within the linkage region on 15q21 is hepatic lipase (HL), which has a major role in lipoprotein metabolism.
进行了全基因组连锁扫描，以确定可能存在影响高密度脂蛋白（HDL）胆固醇的数量性状基因座（QTL）的区域。在国家心肺血液研究所（NHLBI）弗雷明汉心脏研究（FHS）数据中，我们在15号染色体q21区域的标记D15S659处发现了一个影响年龄和性别校正后的HDL胆固醇血浆水平变异的QTL的提示性证据（对数优势分数（LOD）=1.75，p=0.00224，q=0.07649）。由于糖尿病会对血脂谱产生干扰，因此在样本中排除糖尿病患者后重复进行分析。尽管样本量减少，但在15号染色体的相同位置，LOD分数从1.75增加到了2.71（p=0.00021，q=0.05392）。这一发现表明，分析中纳入糖尿病患者可能会混淆15q21上HDL胆固醇QTL的存在。由于诸如代谢变量和生活方式习惯等重要协变量可能与假定的QTL相互作用，已知它们会产生影响，因此我们还采用逐步调整的方法分析了HDL胆固醇。当将体重指数、吸烟和习惯性饮酒纳入年龄和性别校正时，我们在15q21染色体（在标记D15S659和D15S195之间）的完整样本（LOD=4.77，p=0.0000013，q=0.00016）以及非糖尿病子样本（LOD=4.52，p=0.0000025，q=0.00026）中发现了连锁的有力证据。这些结果表明，存在多种涉及遗传和环境效应的途径和因素影响HDL胆固醇水平，并且通过考虑其中一些已知因素，我们获得了一个影响HDL胆固醇水平的QTL的有力证据。虽然这个假定的QTL在糖尿病中可能也有作用，但我们的数据表明它在非糖尿病患者中作用更显著。位于15q21连锁区域内的一个重要候选基因是肝脂酶（HL），它在脂蛋白代谢中起主要作用。
