title: Association of exome sequences with plasma C-reactive protein levels in >9000 participants.
abstract: C-reactive protein (CRP) concentration is a heritable systemic marker of inflammation that is associated with cardiovascular disease risk. Genome-wide association studies have identified CRP-associated common variants associated in ∼25 genes. Our aims were to apply exome sequencing to (1) assess whether the candidate loci contain rare coding variants associated with CRP levels and (2) perform an exome-wide search for rare variants in novel genes associated with CRP levels. We exome-sequenced 6050 European-Americans (EAs) and 3109 African-Americans (AAs) from the NHLBI-ESP and the CHARGE consortia, and performed association tests of sequence data with measured CRP levels. In single-variant tests across candidate loci, a novel rare (minor allele frequency = 0.16%) CRP-coding variant (rs77832441-A; p.Thr59Met) was associated with 53% lower mean CRP levels (P = 2.9 × 10(-6)). We replicated the association of rs77832441 in an exome array analysis of 11 414 EAs (P = 3.0 × 10(-15)). Despite a strong effect on CRP levels, rs77832441 was not associated with inflammation-related phenotypes including coronary heart disease. We also found evidence for an AA-specific association of APOE-ε2 rs7214 with higher CRP levels. At the exome-wide significance level (P < 5.0 × 10(-8)), we confirmed associations for reported common variants of HNF1A, CRP, IL6R and TOMM40-APOE. In gene-based tests, a burden of rare/lower frequency variation in CRP in EAs (P ≤ 6.8 × 10(-4)) and in retinoic acid receptor-related orphan receptor α (RORA) in AAs (P = 1.7 × 10(-3)) were associated with CRP levels at the candidate gene level (P < 2.0 × 10(-3)). This inquiry did not elucidate novel genes, but instead demonstrated that variants distributed across the allele frequency spectrum within candidate genes contribute to CRP levels.
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Ursula M
authors.initials: UM
authors.lastname: Schick
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Auer
authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Bis
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Honghuang
authors.initials: H
authors.lastname: Lin
authors.affiliation: Human Genetics Center, School of Public Health.
authors.forename: Peng
authors.initials: P
authors.lastname: Wei
authors.affiliation: Department of Lab Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Pankratz
authors.affiliation: Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Lange
authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Brody
authors.affiliation: Cardiovascular Division, Department of Medicine Division of Statistical Genomics, Washington University School of Medicine, Saint Louis, MO 63110, USA.
authors.forename: Nathan O
authors.initials: NO
authors.lastname: Stitziel
authors.affiliation: Department of Genome Sciences.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Kim
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Carlson
authors.affiliation: Human Genetics Center, School of Public Health Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Myriam
authors.initials: M
authors.lastname: Fornage
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Jeffery
authors.initials: J
authors.lastname: Haessler
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA Department of Biostatistics.
authors.forename: Li
authors.initials: L
authors.lastname: Hsu
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Rebecca D
authors.initials: RD
authors.lastname: Jackson
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Kooperberg
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Leal
authors.affiliation: Department of Epidemiology, Cardiovascular Health Research Unit Department of Medicine Department of Health Services Group Health Research Institute, Group Health Cooperative, Seattle, WA 98101, USA.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.affiliation: Human Genetics Center, School of Public Health Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: Departments of Biochemistry and Pathology, University of Vermont, Burlington, VT 05401, USA.
authors.forename: Russell
authors.initials: R
authors.lastname: Tracy
authors.affiliation: Division of Cardiology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Ardissino
authors.affiliation: Division of Cardiology, Department of Medicine and Center for Human Genetics, Duke University, Durham, NC, USA.
authors.forename: Svati
authors.initials: S
authors.lastname: Shah
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Medicine Department of Computational Medicine and Bioinformatics Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Cristen
authors.initials: C
authors.lastname: Willer
authors.affiliation: The Charles Bronfman Institute for Personalized Medicine The Mindich Child Health and Development Institute, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Loos
authors.affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Malmö, Malmö, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.affiliation: Division of Cardiology, University of Ottawa Heart Institute, Ottawa, ON, Canada.
authors.forename: Ruth
authors.initials: R
authors.lastname: Mcpherson
authors.affiliation: Department of Vascular Medicine Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands.
authors.forename: Kees
authors.initials: K
authors.lastname: Hovingh
authors.affiliation: The Institute for Translational Medicine and Therapeutics and The Cardiovascular Institute, Perleman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Muredach
authors.initials: M
authors.lastname: Reilly
authors.affiliation: Cardiovascular Medicine, Radcliffe Department of Medicine Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Hugh
authors.initials: H
authors.lastname: Watkins
authors.affiliation: Department of Medicine, University of Verona School of Medicine, Verona, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Girelli
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Pierre
authors.initials: P
authors.lastname: Fontanillas
authors.affiliation: Center for Cardiovascular Disease Prevention, Division of Preventative Medicine, Brigham and Women's Hospital, 900 Commonwealth Drive, Boston, MA 02115, USA.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Chasman
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Stacey B
authors.initials: SB
authors.lastname: Gabriel
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Gibbs
authors.affiliation: Department of Genome Sciences.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sekar
authors.initials: S
authors.lastname: Kathiresan
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Peters
authors.affiliation: National Heart, Lung, and Blood Institute's, Boston University's Framingham Heart Study, Framingham, MA 01702, USA Department of Biostatistics.
authors.forename: Josée
authors.initials: J
authors.lastname: Dupuis
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA and.
authors.forename: James G
authors.initials: JG
authors.lastname: Wilson
authors.affiliation: Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.affiliation: Human Genetics Center, School of Public Health.
authors.forename: Alanna C
authors.initials: AC
authors.lastname: Morrison
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA National Heart, Lung, and Blood Institute's, Boston University's Framingham Heart Study, Framingham, MA 01702, USA Department of Epidemiology, Boston University School of Public Health, Boston, MA 02118, USA.
authors.forename: Emelia J
authors.initials: EJ
authors.lastname: Benjamin
authors.affiliation: Department of Lab Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Myron D
authors.initials: MD
authors.lastname: Gross
authors.forename: Alex P
authors.initials: AP
authors.lastname: Reiner
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D002097:C-Reactive Protein / Q000235:genetics* / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000097:blood* / Q000235:genetics; D015331:Cohort Studies; D059472:Exome; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics; D006801:Humans; D008297:Male; D010949:Plasma / Q000737:chemistry; D020641:Polymorphism, Single Nucleotide; D019947:Receptors, Interleukin-6 / Q000235:genetics; D012307:Risk Factors; D044465:White People / Q000235:genetics
chemical_list: C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; C508603:IL6R protein, human; D019947:Receptors, Interleukin-6; D002097:C-Reactive Protein