Recurring exon deletions in the HP (haptoglobin) gene contribute to lower blood cholesterol levels
Recurring exon deletions in the HP (haptoglobin) gene contribute to lower blood cholesterol levels
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DOI：
10.1038/ng.3510
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发表时间：
2016-04-01
期刊：
影响因子：
30.8
通讯作者：
McCarroll, Steven A.
中科院分区：
文献类型：
--
作者：
Boettger, Linda M.;Salem, Rany M.;McCarroll, Steven A.
在人类中鉴定的第一个蛋白质多态性之一涉及丰富的血液蛋白结合珠蛋白。HP基因（编码触珠蛋白）的两个外显子表现出影响HP蛋白结构和多聚化的拷贝数变异。这种多态性的进化起源和医学相关性尚不确定。在这里，我们表明，这种变化可能是由许多重复的缺失，更具体地说，这些外显子的古人类特异性重复的逆转。虽然这种多态性在全基因组遗传学研究中很大程度上是不可见的，但我们描述了一种通过SNP单倍型插补来分析它的方法，并在22，288名个体中发现这些HP外显子缺失与LDL和总胆固醇水平降低相关。我们进一步表明，这些缺失，以及影响HP表达的SNP，似乎驱动胆固醇水平与HP附近SNP的强烈关联。HP中的重复外显子缺失可能通过降低血液中的胆固醇水平来增强人类健康。
One of the first protein polymorphisms identified in humans involves the abundant blood protein haptoglobin. Two exons of the HP gene (encoding haptoglobin) exhibit copy number variation that affects HP protein structure and multimerization. The evolutionary origins and medical relevance of this polymorphism have been uncertain. Here we show that this variation has likely arisen from many recurring deletions, more specifically, reversions of an ancient hominin-specific duplication of these exons. Although this polymorphism has been largely invisible to genome-wide genetic studies thus far, we describe a way to analyze it by imputation from SNP haplotypes and find among 22,288 individuals that these HP exonic deletions associate with reduced LDL and total cholesterol levels. We further show that these deletions, and a SNP that affects HP expression, appear to drive the strong association of cholesterol levels with SNPs near HP. Recurring exonic deletions in HP likely enhance human health by lowering cholesterol levels in the blood.