ArticleHuman molecular genetics2015
Association of exome sequences with plasma C-reactive protein levels in >9000 participants.
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Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers, 2 of them syntheses that pooled it.
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31citing papers in PubMed, 2 pooled it
3.2field-weighted citation impact, top 8% of its field
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Who cites it
31 citing papers in PubMed, 2 syntheses or guidelines pooled it, 43 citations in OpenAlex.
- Burden of rare exome sequence variants in PROC gene is associated with venous thromboembolism: a population-based study.Journal of thrombosis and haemostasis : JTH · 2020Pooled it
- Rare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk.Circulation. Cardiovascular genetics · 2016Pooled it
- The association between APOE allele variants and inflammatory markers in a large-scale Chinese population.Lipids in health and disease · 2025Article
- Genetic insights into CRP levels in Indian adolescents: confirming adult genetic associations.Molecular genetics and genomics : MGG · 2025Article
- Stools from a human APOEe2 donor reduces amyloid and tau pathology and increases neuroinflammation in a 3xTg AD mouse model.Frontiers in aging neuroscience · 2025Article
- Whole genome sequencing based analysis of inflammation biomarkers in the Trans-Omics for Precision Medicine (TOPMed) consortium.Human molecular genetics · 2024Article
- Genetic variant rs1205 is associated with COVID-19 outcomes: The Strong Heart Study and Strong Heart Family Study.PloS one · 2024Article
- Rare functional variants in the CRP and G6PC genes modify the relationship between obesity and serum C-reactive protein in white British population.Molecular genetics & genomic medicine · 2023Article
- Whole-exome sequence analysis of anthropometric traits illustrates challenges in identifying effects of rare genetic variants.HGG advances · 2023Article
- Article
- Molecular Biology Networks and Key Gene Regulators for Inflammatory Biomarkers Shared by Breast Cancer Development: Multi-Omics Systems Analysis.Biomolecules · 2021Article
- Pro-inflammatory cytokine polymorphisms and interactions with dietary alcohol and estrogen, risk factors for invasive breast cancer using a post genome-wide analysis for gene-gene and gene-lifestyle interaction.Scientific reports · 2021Article
- Genetically determined elevated C-reactive protein associated with primary colorectal cancer risk: Mendelian randomization with lifestyle interactions.American journal of cancer research · 2021Article
- Inflammation and cardiovascular disease: From mechanisms to therapeutics.American journal of preventive cardiology · 2020Review
- Allelic Heterogeneity at the CRP Locus Identified by Whole-Genome Sequencing in Multi-ancestry Cohorts.American journal of human genetics · 2020Article
- Genetically Predicted C-Reactive Protein Associated With Postmenopausal Breast Cancer Risk: Interrelation With Estrogen and Cancer Molecular Subtypes Using Mendelian Randomization.Frontiers in oncology · 2020Article
- Pro-inflammatory cytokine polymorphisms in ONECUT2 and HNF4A and primary colorectal carcinoma: a post genome-wide gene-lifestyle interaction study.American journal of cancer research · 2020Article
- A Rare Variant Nonparametric Linkage Method for Nuclear and Extended Pedigrees with Application to Late-Onset Alzheimer Disease via WGS Data.American journal of human genetics · 2019Article
- C-reactive protein gene 1846C>T polymorphism is associated with increased risk and clinical features of lung cancer: a case-control study.Bioscience reports · 2019Article
- Article
Corrections and comments
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Authors and funding
46 authors at 20 institutions in 7 countries.
Ursula M SchickPublic Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Paul L AuerPublic Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA.
Joshua C BisCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA.
Honghuang LinDepartment of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
Peng WeiHuman Genetics Center, School of Public Health.
Nathan PankratzDepartment of Lab Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
Leslie A LangeDepartment of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
Jennifer BrodyCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA.
Nathan O StitzielCardiovascular Division, Department of Medicine Division of Statistical Genomics, Washington University School of Medicine, Saint Louis, MO 63110, USA.
Daniel S KimDepartment of Genome Sciences.
Christopher S CarlsonPublic Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Myriam FornageHuman Genetics Center, School of Public Health Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Jeffery HaesslerPublic Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Li HsuPublic Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA Department of Biostatistics.
Rebecca D JacksonDivision of Endocrinology, Diabetes, and Metabolism, Ohio State University, Columbus, OH 43210, USA.
Charles KooperbergPublic Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Suzanne M LealCenter for Statistical Genetics, Department of Molecular and Human Genetics.
Bruce M PsatyDepartment of Epidemiology, Cardiovascular Health Research Unit Department of Medicine Department of Health Services Group Health Research Institute, Group Health Cooperative, Seattle, WA 98101, USA.
Eric BoerwinkleHuman Genetics Center, School of Public Health Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Russell TracyDepartments of Biochemistry and Pathology, University of Vermont, Burlington, VT 05401, USA.
Diego ArdissinoDivision of Cardiology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
Svati ShahDivision of Cardiology, Department of Medicine and Center for Human Genetics, Duke University, Durham, NC, USA.
Cristen WillerDepartment of Internal Medicine, Division of Cardiovascular Medicine Department of Computational Medicine and Bioinformatics Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
Ruth LoosThe 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.
Olle MelanderDepartment of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Malmö, Malmö, Sweden.
Ruth McphersonDivision of Cardiology, University of Ottawa Heart Institute, Ottawa, ON, Canada.
Kees HovinghDepartment of Vascular Medicine Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands.
Muredach ReillyThe Institute for Translational Medicine and Therapeutics and The Cardiovascular Institute, Perleman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Hugh WatkinsCardiovascular Medicine, Radcliffe Department of Medicine Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Domenico GirelliDepartment of Medicine, University of Verona School of Medicine, Verona, Italy.
Pierre FontanillasProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Daniel I ChasmanCenter for Cardiovascular Disease Prevention, Division of Preventative Medicine, Brigham and Women's Hospital, 900 Commonwealth Drive, Boston, MA 02115, USA.
Stacey B GabrielProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Richard GibbsHuman Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Deborah A NickersonDepartment of Genome Sciences.
Sekar KathiresanProgram 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.
Ulrike PetersPublic Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Josée DupuisNational Heart, Lung, and Blood Institute's, Boston University's Framingham Heart Study, Framingham, MA 01702, USA Department of Biostatistics.
James G WilsonDepartment of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA and.
Stephen S RichCenter for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908, USA.
Alanna C MorrisonHuman Genetics Center, School of Public Health.
Emelia J BenjaminDepartment 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.
Myron D GrossDepartment of Lab Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
Alex P Reiner
Cohorts for Heart and Aging Research in Genomic Epidemiology
National Heart, Lung, and Blood Institute GO Exome Sequencing Project
Fred Hutch Cancer Center · USCenter for Human Genetics · USBoston University · USBroad Institute · USUniversity of Minnesota · USUniversity of Washington · USAcademic Medical Center · NLBaylor College of Medicine · USBrigham and Women's Hospital · USBrown Foundation · USChild Health and Development Institute · USGroup Health Cooperative · USHarvard University · USJackson Memorial Hospital · USLund University · SENational Heart Lung and Blood Institute · USOffice of Public Health Genomics · USOspedale di Parma · ITThe Ohio State University · USUniversity of Michigan–Ann Arbor · US
Funding
The Human Genome Sequencing CenterU54HG003273 · NHGRI · BAYLOR COLLEGE OF MEDICINE · PI GIBBS, RICHARD A · 2004 to 2015
$341.3MBuilding on GWAS for NHLBI-disease: the CHARGE consortiumRC2HL102419 · NHLBI · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · PI BOERWINKLE, ERIC A. · 2009 to 2010
$27.6MGenome-Wide Association Analysis in Essential Hypertension (FEHGAS study)R01HL086694 · NHLBI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI ARAVINDA CHAKRAVARTI · 2007 to 2026
$21.2MMultiethnic Study of Type 2 Diabetes GenesU01DK085526 · NIDDK · BROAD INSTITUTE, INC. · PI ALTSHULER, DAVID, JABLONSKI, KATHLEEN ANN · 2009 to 2014
$15.7MEpidemiology of Venous Thrombosis & Pulmonary EmbolismR01HL059367 · NHLBI · UNIVERSITY OF MINNESOTA TWIN CITIES · PI TANG, WEIHONG · 1998 to 2024
$11.8MNorthwest Genomics CenterRC2HL102926 · NHLBI · UNIVERSITY OF WASHINGTON · PI GREEN, PHILIP P, NICKERSON, DEBORAH A · 2009 to 2009
$11.0MComprehensive Sequencing and Analysis of Variation in NHLBI CohortsRC2HL102925 · NHLBI · BROAD INSTITUTE, INC. · PI ALTSHULER, DAVID, GABRIEL, STACEY · 2009 to 2009
$10.2MExceptional Survival: Trajectories to Functional Aging (CHS All Stars)R01AG023629 · NIA · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI NEWMAN, ANNE B. · 2004 to 2016
$9.5MCHARGE Consortium: Omics Discovery for CVD and Aging PhenotypesR01HL105756 · NHLBI · UNIVERSITY OF WASHINGTON · PI Bruce M Psaty, NICHOLAS L SMITH · 2011 to 2026
$9.5MEPIDEMIOLOGY: OXIDATIVE STRESS AND EARLY ATHEROSCLEROSISR01HL053560 · NHLBI · UNIVERSITY OF MINNESOTA TWIN CITIES · PI GROSS, MYRON D, JACOBS, DAVID R · 1995 to 2014
$9.0MCancer Prevention Trng-Nutrition, Exercise &GeneticsR25CA094880 · NCI · UNIVERSITY OF WASHINGTON · PI WHITE, EMILY · 2002 to 2016
$7.3MCHS Events Follow-up StudyR01HL080295 · NHLBI · UNIVERSITY OF WASHINGTON · PI PSATY, BRUCE M · 2009 to 2014
$6.3MNCI NIH HHS R25 CA094880NCI NIH HHS R25CA094880NCI NIH HHS UM1 CA182913NHGRI NIH HHS U54 HG003273NHLBI NIH HHS 5RC2HL102419NHLBI NIH HHS HHSN268200800007CNHLBI NIH HHS HHSN268201000010CNHLBI NIH HHS HHSN268201000012CNHLBI NIH HHS HHSN268201100001INHLBI NIH HHS HHSN268201100002INHLBI NIH HHS HHSN268201100005CNHLBI NIH HHS HHSN268201100005GNHLBI NIH HHS HHSN268201100005INHLBI NIH HHS HHSN268201100006CNHLBI NIH HHS HHSN268201100007CNHLBI NIH HHS HHSN268201100007INHLBI NIH HHS HHSN268201100008CNHLBI NIH HHS HHSN268201100008INHLBI NIH HHS HHSN268201100009CNHLBI NIH HHS HHSN268201100009INHLBI NIH HHS HHSN268201100010CNHLBI NIH HHS HHSN268201100011INHLBI NIH HHS HHSN268201100012CNHLBI NIH HHS HHSN268201200036CNHLBI NIH HHS HL080295NHLBI NIH HHS HL087652NHLBI NIH HHS HL105756NHLBI NIH HHS N01 HC025195NHLBI NIH HHS N01 HC055222NHLBI NIH HHS N01 HC085079NHLBI NIH HHS N01 HC085080NHLBI NIH HHS N01 HC085081NHLBI NIH HHS N01 HC085082NHLBI NIH HHS N01 HC085083NHLBI NIH HHS N01 HC085086NHLBI NIH HHS N01-HC-25195NHLBI NIH HHS N01 HC55222NHLBI NIH HHS N02-HL-6-4278NHLBI NIH HHS R01 HL053560NHLBI NIH HHS R01 HL059367NHLBI NIH HHS R01 HL071862NHLBI NIH HHS R01HL071862NHLBI NIH HHS R01 HL080295NHLBI NIH HHS R01 HL086694NHLBI NIH HHS R01HL086694NHLBI NIH HHS R01 HL087641NHLBI NIH HHS R01HL087641NHLBI NIH HHS R01 HL087652NHLBI NIH HHS R01 HL105756NHLBI NIH HHS R01HL59367NHLBI NIH HHS RC2 HL102419NHLBI NIH HHS RC2 HL-102923NHLBI NIH HHS RC2 HL102923NHLBI NIH HHS RC2 HL-102924NHLBI NIH HHS RC2 HL102924NHLBI NIH HHS RC2 HL-102925NHLBI NIH HHS RC2 HL102925NHLBI NIH HHS RC2 HL-102926NHLBI NIH HHS RC2 HL102926NHLBI NIH HHS RC2 HL-103010NHLBI NIH HHS RC2 HL103010NHLBI NIH HHS U01 HL080295NIA NIH HHS AG023629NIA NIH HHS R01 AG023629NIA NIH HHS R56 AG023629NIDDK NIH HHS U01 DK085526NIDDK NIH HHS U01DK085526NIH HHS S10 OD020069NIMH NIH HHS F31 MH101905WHI NIH HHS HHSN268201100001CWHI NIH HHS HHSN268201100002C
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.
Indexed as
ExomeAdultBlack or African AmericanCardiovascular DiseasesCohort StudiesC-Reactive ProteinFemaleGene FrequencyGenetic Predisposition to DiseaseGenome-Wide Association StudyHepatocyte Nuclear Factor 1-alphaHumansMalePlasmaPolymorphism, Single NucleotideReceptors, Interleukin-6C-Reactive ProteinHepatocyte Nuclear Factor 1-alphaHNF1A protein, humanIL6R protein, humanReceptors, Interleukin-6
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