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Nat Genet DOI:10.1038/ng.3510

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

Publication TypeJournal Article
Year of Publication2016
AuthorsBoettger, LM, Salem, RM, Handsaker, RE, Peloso, GM, Kathiresan, S, Hirschhorn, JN, McCarroll, SA
JournalNat Genet
Date Published2016 Apr
KeywordsBase Sequence, Cholesterol, Exons, Gene Frequency, Genetic Association Studies, Haplotypes, Haptoglobins, Humans, Molecular Sequence Data, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Sequence Deletion

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.


Alternate JournalNat. Genet.
PubMed ID26901066
PubMed Central IDPMC4811681
Grant ListK99 HL122515 / HL / NHLBI NIH HHS / United States
P51 OD011132 / OD / NIH HHS / United States
1K99HL122515-01A1 / HL / NHLBI NIH HHS / United States
R01 HG006855 / HG / NHGRI NIH HHS / United States
P51OD011132 / OD / NIH HHS / United States
R01HG006855 / HG / NHGRI NIH HHS / United States
K01HL125751 / HL / NHLBI NIH HHS / United States