Association Analysis of C-Reactive Protein Levels in European Americans and African Americans Sequenced Through the NHLBI Exome-Sequencing Project. U. M. Schick1,2, P. L. Auer1,2,3, D. S. Kim4, E. J. Benjamin5,6,7,8,9, J. C. Bis10, E. Boerwinkle11, C. S. Carlson1, J. Dupuis5,12, M. Fornage13, L. Hsu1,14, R. D. Jackson15, C. Kooperberg1, L. Lange16, H. Lin17, S. M. Leal18, A. C. Morrison11, N. Pankratz19, U. Peters1, B. Psaty10,14,20,21, S. S. Rich22, R. Tracy23, J. G. Wilson24, M. D. Gross2,19, A. P. Reiner1,2,25 on behalf of the NHLBI GO Exome Sequencing Project 1) Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 2) Equal Contribution; 3) Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, USA; 4) Department of Genome Sciences, University of Washington, Seattle WA, USA; 5) National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA; 6) Department of Medicine and Department of Epidemiology, Boston University School of Medicine, Boston, MA, USA; 7) Section of Cardiovascular Medicine and Section of Preventive Medicine, Boston University School of Medicine, Boston, MA, USA; 8) Cardiology Division, Massachusetts General Hospital, Boston, MA, USA; 9) Boston University School of Medicine's Whitaker Cardiovascular Institute, Evans Memorial Medicine Department, Boston, MA, USA; 10) Cardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, WA, USA; 11) Human Genetics Center, University of Texas Health Science Center, School of Public Health, Houston, TX, USA; 12) Department of Biostatistics, Boston University School of Medicine, Boston, MA, USA,; 13) Brown Foundation Institute of Molecular Medicine and Human Genetics Center, Division of Epidemiology, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA; 14) Department of Biostatistics, University of Washington, Seattle, WA , USA; 15) Division of Endocrinology, Diabetes, and Metabolism, Ohio State University, Columbus, OH, USA; 16) Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC, USA; 17) Department of Medicine, Boston University School of Medicine, Boston, MA, USA; 18) Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; 19) Department of Lab Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA; 20) Department of Epidemiology and Department of Health Services, University of Washington, Seattle, WA, USA; 21) Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA; 22) Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA; 23) Departments of Biochemistry and Pathology, University of Vermont, Burlington, VT, USA; 24) Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA; 25) Department of Epidemiology, University of Washington, Seattle, WA, USA.

   Introduction: C-reactive protein (CRP) is a systemic marker of inflammation with predictive value in assessing cardiovascular risk. Genome-wide association studies (GWAS) have identified ~25 loci associated with CRP levels, however taken together these common variants explain only a small proportion of the phenotypic variance of CRP levels. Methods: We performed exome sequencing in 3,379 unrelated Americans of European (EA) and African (AA) ancestry through the NHLBI Exome Sequencing Project (ESP). The aims of this study were to 1) assess whether these 25 known CRP GWAS loci also contain rare coding variants associated with CRP levels, and 2) perform an exploratory exome-wide search for rare variants associated with CRP levels. Validation data sets included independent samples genotyped in ESP on the exome chip and exome sequence data from the Cohorts for Heart and Aging Research in Genetic Epidemiology consortium (CHARGE). Results: In single variant tests within CRP GWAS loci, novel rare coding variants in CRP (rs77832441 (T59M)) and TOMM40 (rs112849259 (synonymous)) were associated with decreased CRP levels. In the combined ESP discovery sample and validation samples, the CRP T59M variant was associated with more than a 60% reduction in CRP levels (meta-analysis P<1.65x10-15). At the gene level, rare coding variation in candidate genes PPP1R3B (P=2.61x10-4) and RORA (P=1.31x10-4) was associated with CRP in the ESP AA discovery sample with suggestive evidence of replication of RORA in ESP exome chip samples (P=0.062). Gene burden tests of PIGW reached exome-wide significance in race-combined ESP gene-based tests (P=2.10 x10-6), but failed to replicate in independent CHARGE sequencing and ESP exome chip samples. Conclusion: Overall, our results suggest that variants distributed across the allele-frequency spectrum within candidate genes identified by GWAS contribute to variation in CRP levels.

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