Large multiethnic Candidate Gene Study for C-reactive protein levels: Identification of a novel association at CD36 in African Americans

Authors

Jaclyn Ellis, The University of North Carolina at Chapel Hill
Ethan M. Lange, The University of North Carolina at Chapel Hill
Jin Li, The University of North Carolina at Chapel Hill
Josee Dupuis, Framingham Heart Study
Jens Baumert, Helmholtz Center Munich German Research Center for Environmental Health
Jeremy D. Walston, Johns Hopkins School of Medicine
Brendan J. Keating, The Children's Hospital of Philadelphia
Peter Durda, University of Vermont College of Medicine
Ervin R. Fox, University of Mississippi Medical Center
Cameron D. Palmer, Broad Institute
Yan A. Meng, Broad Institute
Taylor Young, Broad Institute
Deborah N. Farlow, Broad Institute
Renate B. Schnabel, Universitäre Herz- und Gefäßzentrum UKE Hamburg GmbH
Carola S. Marzi, Helmholtz Center Munich German Research Center for Environmental Health
Emma Larkin, Vanderbilt University Medical Center
Lisa W. Martin, School of Medicine and Health Sciences
Joshua C. Bis, University of Washington School of Medicine
Paul Auer, University of Wisconsin-Milwaukee
Vasan S. Ramachandran, Boston University School of Medicine
Stacey B. Gabriel, Broad Institute
Monte S. Willis, The University of North Carolina at Chapel Hill
James S. Pankow, School of Public Health
George J. Papanicolaou, National Heart, Lung, and Blood Institute (NHLBI)
Jerome I. Rotter, University of California, Los Angeles
Christie M. Ballantyne, Baylor College of Medicine
Myron D. Gross, University of Minnesota Twin Cities
Guillaume Lettre, Institut de Cardiologie de Montreal
James G. Wilson, University of Mississippi Medical Center
Ulrike Peters, Fred Hutchinson Cancer Research Center
Wolfgang Koenig, Universitätsklinikum Ulm
Russell P. Tracy, University of Vermont College of Medicine

Document Type

Journal Article

Publication Date

1-1-2014

Journal

Human Genetics

Volume

133

Issue

8

DOI

10.1007/s00439-014-1439-z

Abstract

C-reactive protein (CRP) is a heritable biomarker of systemic inflammation and a predictor of cardiovascular disease (CVD). Large-scale genetic association studies for CRP have largely focused on individuals of European descent. We sought to uncover novel genetic variants for CRP in a multiethnic sample using the ITMAT Broad-CARe (IBC) array, a custom 50,000 SNP gene-centric array having dense coverage of over 2,000 candidate CVD genes. We performed analyses on 7,570 African Americans (AA) from the Candidate gene Association Resource (CARe) study and race-combined meta-analyses that included 29,939 additional individuals of European descent from CARe, the Women's Health Initiative (WHI) and KORA studies. We observed array-wide significance (p < 2.2 × 10-6) for four loci in AA, three of which have been reported previously in individuals of European descent (IL6R, p = 2.0 × 10 -6; CRP, p = 4.2 × 10-71; APOE, p = 1.6 × 10-6). The fourth significant locus, CD36 (p = 1.6 × 10 -6), was observed at a functional variant (rs3211938) that is extremely rare in individuals of European descent. We replicated the CD36 finding (p = 1.8 × 10-5) in an independent sample of 8,041 AA women from WHI; a meta-analysis combining the CARe and WHI AA results at rs3211938 reached genome-wide significance (p = 1.5 × 10-10). In the race-combined meta-analyses, 13 loci reached significance, including ten (CRP, TOMM40/APOE/APOC1, HNF1A, LEPR, GCKR, IL6R, IL1RN, NLRP3, HNF4A and BAZ1B/BCL7B) previously associated with CRP, and one (ARNTL) previously reported to be nominally associated with CRP. Two novel loci were also detected (RPS6KB1, p = 2.0 × 10-6; CD36, p = 1.4 × 10 -6). These results highlight both shared and unique genetic risk factors for CRP in AA compared to populations of European descent. © 2014 Springer-Verlag.

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