title: Recurring exon deletions in the HP (haptoglobin) gene contribute to lower blood cholesterol levels.
abstract: 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.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Boettger
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Rany M
authors.initials: RM
authors.lastname: Salem
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Robert E
authors.identifier: http://orcid.org/0000-0002-3128-3547
authors.initials: RE
authors.lastname: Handsaker
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Gina M
authors.initials: GM
authors.lastname: Peloso
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: McCarroll
mesh_terms: D001483:Base Sequence; D002784:Cholesterol / Q000097:blood*; D005091:Exons; D005787:Gene Frequency; D056726:Genetic Association Studies; D006239:Haplotypes; D006242:Haptoglobins / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion
chemical_list: C485359:HP protein, human; D006242:Haptoglobins; D002784:Cholesterol