Journal Article

Recurring exon deletions in the HP (haptoglobin) gene contribute to lower blood cholesterol levels

Handsaker, Robert E, Boettger, Linda M, Kathiresan, Sekar, Salem, Rany M, McCarroll, Steven A, Peloso, Gina M, Hirschhorn, Joel N

2016

Overview

Steven McCarroll and colleagues present a detailed study of copy number variation of exons within the human HP (haptoglobin) gene. They show that HP exons undergo recurring deletions that, together with local SNP variation, influence LDL and total cholesterol levels in human populations. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 45 / 45/77 / 631/208/1516 / 631/208/212 / Agriculture / Animal Genetics and Genomics / Base Sequence / Biomedicine / Blood / Blood cholesterol / Cancer Research / Cholesterol / Cholesterol - blood / Exon (Molecular genetics) / Exons / Gene Frequency / Gene Function / Genetic aspects / Genetic Association Studies / Genetic polymorphisms / Genomes / Haplotypes / Haptoglobin / Haptoglobins - genetics / Health aspects / Human Genetics / Humans / Lipid metabolism / Molecular Sequence Data / Mutation / Polymorphism, Single Nucleotide / Properties / Proteins / Sequence Analysis, DNA / Sequence Deletion / Studies