@article{ebe212f5bab446069a93f4e0c1f436f3,
title = "Whole exome sequencing in the Framingham heart study identifies rare variation in HYAL2 that influences platelet aggregation",
abstract = "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.",
keywords = "Epidemiological studies, Gene mutations, Platelet physiology, Polymorphisms, Thrombosis",
author = "Eicher, {John D.} and Chen, {Ming Huei} and Pitsillides, {Achilleas N.} and Honghuang Lin and Narayanan Veeraraghavan and Brody, {Jennifer A.} and Metcalf, {Ginger A.} and Muzny, {Donna M.} and Gibbs, {Richard A.} and Becker, {Diane M.} and Becker, {Lewis C.} and Nauder Faraday and Mathias, {Rasika A.} and Yanek, {Lisa R.} and Eric Boerwinkle and {Adrienne Cupples}, L. and Johnson, {Andrew D.}",
note = "Funding Information: We thank all individuals for their participation in this study. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U. S. Department of Health and Human Services. The Framingham Heart Study is conducted and supported by the NHLBI in collaboration with Boston University (Contract No. N01-HC-25195), its contract with Affymetrix, Inc., for genome-wide genotyping services (Contract No. N02-HL-6-4278 and Contract No. HHSN268201500001I), and for quality control by Framingham Heart Study investigators using genotypes in the SNP Health Association Resource (SHARe) project. The computational work reported on in this paper was performed on the Shared Computing Cluster, administered by Boston University{\textquoteright}s Research Computing Services (www.bu.edu/tech/support/research/) and on the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute grant R01HL105756. Funding support for “Building on GWAS for NHLBI-diseases: the U. S. CHARGE Consortium” was provided by the NIH through the American Recovery and Reinvestment Act of (5RC2HL102419). Data for “Building on GWAS for NHLBI-diseases: the U. S. CHARGE Consortium” were provided by Eric Boerwinkle (ARIC), L. Adrienne Cupples (FHS), and Bruce Psaty (CHS). Sequencing was carried out at the Baylor Genome Center (U54 HG003273). The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at http: //exac.broadinstitute.org/about. GeneSTAR was funded by grants from the National Institutes of Health/National Heart, Lung, and Blood Institute (U01 HL72518, HL087698, HL112064) and by a grant from the National Institutes of Health/National Center for Research Resources (M01-RR000052) to the Johns Hopkins General Clinical Research Center. Publisher Copyright: {\textcopyright} Schattauer 2017.",
year = "2017",
doi = "10.1160/TH16-09-0677",
language = "English (US)",
volume = "117",
pages = "1083--1092",
journal = "Thrombosis and Haemostasis",
issn = "0340-6245",
publisher = "Schattauer GmbH",
number = "6",
}