Whole exome sequencing in the Framingham Heart Study identifies rare variation in HYAL2 that influences platelet aggregation

John D. Eicher; Ming-Huei Chen; Achilleas N. Pitsillides; Honghuang Lin; Narayanan Veeraraghavan; Jennifer A. Brody; Ginger A. Metcalf; Donna M. Muzny; Richard A. Gibbs; Diane M. Becker; Lewis C. Becker; Nauder Faraday; Rasika A. Mathias; Lisa R. Yanek; Eric Boerwinkle; L. Adrienne Cupples; Andrew D. Johnson

doi:10.1160/TH16-09-0677

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2017; 117(06): 1083-1092
DOI: 10.1160/TH16-09-0677

Cellular Haemostasis and Platelets

Schattauer GmbH

Whole exome sequencing in the Framingham Heart Study identifies rare variation in HYAL2 that influences platelet aggregation

John D. Eicher

¹Population Sciences Branch, National Heart, Lung, Blood Institute, National Institutes of Health, Framingham, Massachusetts, USA

²The Framingham Heart Study, Framingham, Massachusetts, USA

,

Ming-Huei Chen

¹Population Sciences Branch, National Heart, Lung, Blood Institute, National Institutes of Health, Framingham, Massachusetts, USA

²The Framingham Heart Study, Framingham, Massachusetts, USA

,

Achilleas N. Pitsillides

²The Framingham Heart Study, Framingham, Massachusetts, USA

,

Honghuang Lin

³Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA

,

Narayanan Veeraraghavan

⁴Rady Children’s Institute for Genomic Medicine, San Diego, California, USA

,

Jennifer A. Brody

⁵Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA

,

Ginger A. Metcalf

⁶Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA

,

Donna M. Muzny

⁶Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA

,

Richard A. Gibbs

⁶Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA

,

Diane M. Becker

⁷GeneSTAR Research Program, Department of Medicine, Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

,

Lewis C. Becker

⁷GeneSTAR Research Program, Department of Medicine, Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

⁸GeneSTAR Research Program, Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

,

Nauder Faraday

⁹GeneSTAR Research Program, Department of Anesthesiology & Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

,

Rasika A. Mathias

¹⁰GeneSTAR Research Program, Department of Medicine, Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

,

Lisa R. Yanek

⁷GeneSTAR Research Program, Department of Medicine, Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

,

Eric Boerwinkle

⁶Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA

⁷GeneSTAR Research Program, Department of Medicine, Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

,

L. Adrienne Cupples

²The Framingham Heart Study, Framingham, Massachusetts, USA

⁸GeneSTAR Research Program, Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

,

Andrew D. Johnson

¹Population Sciences Branch, National Heart, Lung, Blood Institute, National Institutes of Health, Framingham, Massachusetts, USA

²The Framingham Heart Study, Framingham, Massachusetts, USA

› Institutsangaben

Abstract

Summary

Inhibition of platelet reactivity is a common therapeutic strategy in secondary prevention of cardiovascular disease. Genetic and environmental factors influence inter-individual variation in platelet reactivity. Identifying genes that contribute to platelet reactivity can reveal new biological mechanisms and possible therapeutic targets. Here, we examined rare coding variation to identify genes associated with platelet reactivity in a population-based cohort. To do so, we performed whole exome sequencing in the Framingham Heart Study and conducted single variant and gene-based association tests against platelet reactivity to collagen, adenosine diphosphate (ADP), and epinephrine agonists in up to 1,211 individuals. Single variant tests revealed no significant associations (p<1.44×10^–7), though we observed a suggestive association with previously implicated MRVI1 (rs11042902, p = 1.95×10^–7). Using gene-based association tests of rare and low-frequency variants, we found significant associations of HYAL2 with increased ADP-induced aggregation (p = 1.07×10^–7) and GSTZ1 with increased epinephrine-induced aggregation (p = 1.62×10^–6). HYAL2 also showed suggestive associations with epinephrine-induced aggregation (p = 2.64×10^–5). The rare variants in the HYAL2 gene-based association included a missense variant (N357S) at a known N-glycosylation site and a nonsense variant (Q406*) that removes a glycophosphatidylinositol (GPI) anchor from the resulting protein. These variants suggest that improper membrane trafficking of HYAL2 influences platelet reactivity. We also observed suggestive associations of AR (p = 7.39×10^–6) and MAPRE1 (p = 7.26×10^–6) with ADP-induced reactivity. Our study demonstrates that gene-based tests and other grouping strategies of rare variants are powerful approaches to detect associations in population-based analyses of complex traits not detected by single variant tests and possible new genetic influences on platelet reactivity.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Epidemiological studies - platelet physiology - polymorphisms - thrombosis - gene mutations

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Referenzen

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