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

Nature Genetics volume 48, pages 359366 (2016) | Download Citation

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.

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Acknowledgements

We thank C. Usher for comments on the manuscript and work on the figures. This work was supported by a grant from the National Human Genome Research Institute (R01HG006855 to S.A.M.). The Yerkes Center (grant P51OD011132) provided primate DNA samples. R.M.S. was supported by a US National Institutes of Health/National Heart, Lung, and Blood Institute K99 award (1K99HL122515-01A1) and an advanced postdoctoral fellowship award from the Juvenile Diabetes Research Foundation (JDRF 3-APF-2014-111-A-N). G.M.P. was supported by the National Heart, Lung, and Blood Institute of the US National Institutes of Health under award K01HL125751.

Author information

Affiliations

  1. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • Linda M Boettger
    • , Rany M Salem
    • , Robert E Handsaker
    • , Joel N Hirschhorn
    •  & Steven A McCarroll
  2. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Linda M Boettger
    • , Rany M Salem
    • , Robert E Handsaker
    • , Gina M Peloso
    • , Sekar Kathiresan
    • , Joel N Hirschhorn
    •  & Steven A McCarroll
  3. Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Rany M Salem
    •  & Joel N Hirschhorn
  4. Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Rany M Salem
    •  & Joel N Hirschhorn
  5. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA

    • Gina M Peloso
    •  & Sekar Kathiresan

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Contributions

L.M.B., S.A.M. and R.E.H. designed the experiments for understanding HP structural evolution. R.M.S., L.M.B. and G.M.P. performed imputation and association analyses of cholesterol cohorts. L.M.B. performed computational analyses of HapMap and 1000 Genomes Project data, constructed the imputation reference panels and performed all laboratory experiments. L.M.B. and S.A.M. wrote the manuscript. J.N.H. and S.K. provided advice on data analysis. All authors contributed to interpretations of data and to revisions of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Steven A McCarroll.

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    Supplementary Text and Figures

    Supplementary Figures 1–9, Supplementary Tables 1–15 and Supplementary Note.

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    Supplementary Data Set

    Reference panels for imputation of HP structural alleles.

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DOI

https://doi.org/10.1038/ng.3510

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