Meta-Analysis of Genome-Wide Association Studies in >80 000 Subjects Identifies Multiple Loci for C-Reactive Protein Levels

被引：419

作者：

Dehghan, Abbas ^{[1
]}

Dupuis, Josee ^{[2
,3
,4
]}

Barbalic, Maja ^{[5
,6
]}

Bis, Joshua C. ^{[7
]}

Eiriksdottir, Gudny ^{[8
]}

Lu, Chen ^{[2
]}

Pellikka, Niina ^{[9
]}

Wallaschofski, Henri ^{[10
]}

Kettunen, Johannes ^{[11
]}

Henneman, Peter ^{[12
]}

Baumert, Jens ^{[13
]}

Strachan, David P. ^{[14
]}

Fuchsberger, Christian ^{[15
,16
]}

Vitart, Veronique ^{[17
]}

Wilson, James F. ^{[18
]}

Pare, Guillaume ^{[19
]}

Naitza, Silvia ^{[20
]}

Rudock, Megan E. ^{[21
]}

Surakka, Ida ^{[22
]}

de Geus, Eco J. C. ^{[23
]}

Alizadeh, Behrooz Z. ^{[24
]}

Guralnik, Jack ^{[25
]}

Shuldiner, Alan ^{[26
]}

Tanaka, Toshiko ^{[27
,28
]}

Zee, Robert Y. L. ^{[29
]}

Schnabel, Renate B. ^{[30
]}

Nambi, Vijay ^{[31
,32
]}

Kavousi, Maryam ^{[1
]}

Ripatti, Samuli ^{[22
]}

Nauck, Matthias ^{[10
]}

Smith, Nicholas L. ^{[33
,34
]}

Smith, Albert V. ^{[8
]}

Sundvall, Jouko ^{[35
]}

Scheet, Paul ^{[36
]}

Liu, Yongmei ^{[21
]}

Ruokonen, Aimo ^{[37
]}

Rose, Lynda M. ^{[29
]}

Larson, Martin G. ^{[3
,4
]}

Hoogeveen, Ron C. ^{[31
,32
]}

Freimer, Nelson B. ^{[19
]}

Teumer, Alexander ^{[38
]}

Tracy, Russell P. ^{[39
,40
]}

Launer, Lenore J. ^{[25
]}

Buring, Julie E. ^{[29
]}

Yamamoto, Jennifer F. ^{[3
,4
]}

Folsom, Aaron R. ^{[41
]}

Sijbrands, Eric J. G. ^{[42
]}

Pankow, James ^{[41
]}

Elliott, Paul ^{[43
]}

Keaney, John F. ^{[3
,4
]}

机构：

[1] Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands

[2] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[3] NHLBI, Framingham, MA USA

[4] Boston Univ, Framingham Heart Study, Framingham, MA USA

[5] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA

[6] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX USA

[7] Univ Washington, Dept Med, Seattle, WA USA

[8] Iceland Heart Assoc, Kopavogur, Iceland

[9] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Unit Publ Hlth Genom, Helsinki, Finland

[10] Ernst Moritz Arndt Univ Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany

[11] Wellcome Trust Sanger Inst, Dept Human Genet, Cambridge, England

[12] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands

[13] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany

[14] St Georges Univ London, Div Community Hlth Sci, London, England

[15] European Acad Bozen Bolzano EURAC, Inst Med Genet, Bolzano, Italy

[16] Univ Lubeck, Affiliated Inst, Lubeck, Germany

[17] Western Gen Hosp, Inst Genet & Mol Med, Med Res Council Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland

[18] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland

[19] Harvard Univ, Sch Med, Ctr Cardiovasc Dis Prevent, Boston, MA USA

[20] CNR, Ist Neurogenet & Neurofarmacol, Cagliari, Italy

[21] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent, Wake Forest, NC USA

[22] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland

[23] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands

[24] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Unit Genet Epidemiol & Bioinformat, Groningen, Netherlands

[25] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA

[26] Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA

[27] NIA, Clin Res Branch, Baltimore, MD 21224 USA

[28] Medstar Res Inst, Baltimore, MD USA

[29] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA

[30] Johannes Gutenberg Univ Mainz, Dept Med, Mainz, Germany

[31] Baylor Coll Med, Dept Med, Houston, TX 77030 USA

[32] Methodist DeBakey Heart & Vasc Ctr, Ctr Cardiovasc Prevent, Houston, TX USA

[33] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

[34] Seattle Epidemiol Res & Informat Ctr, Dept Vet Affairs, Off Res & Dev, Seattle, WA USA

[35] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Unit Dis Risk, Helsinki, Finland

[36] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA

[37] Univ Oulu, Dept Clin Chem, Oulu, Finland

[38] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany

[39] Colchester Res Facil, Dept Pathol, Colchester, VT USA

[40] Colchester Res Facil, Dept Biochem, Colchester, VT USA

[41] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA

[42] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands

[43] Univ London Imperial Coll Sci Technol & Med, Med Res Council Hlth Protect Agcy Ctr Environm &, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England

[44] Univ N Carolina, Dept Genet, Dept Biostat, Chapel Hill, NC USA

[45] Amgen Inc, Cambridge, MA USA

[46] Natl Inst Hlth & Welf, Dept Life Course & Serv, Helsinki, Finland

[47] Univ Halle Wittenberg, Dept Med 3, Halle, Germany

[48] Univ Halle Wittenberg, Inst Med Epidemiol Biostat & Informat, Halle, Germany

[49] German Canc Res Ctr, Div Canc Epidemiol, D-6900 Heidelberg, Germany

[50] Ernst Moritz Arndt Univ Greifswald, Dept Pharmacol, Greifswald, Germany

来源：

CIRCULATION | 2011年 / 123卷 / 07期

关键词：

genetics; inflammation; meta-analysis; myocardial infarction; genome-wide association study; CORONARY-HEART-DISEASE; GENETICALLY ISOLATED POPULATION; NETHERLANDS TWIN REGISTER; EPIDEMIOLOGIC APPLICATIONS; COMMON VARIANTS; ALPHA-GENE; CRP GENE; DESIGN; INFLAMMATION; FRAMINGHAM;

D O I：

10.1161/CIRCULATIONAHA.110.948570

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background-C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels. Methods and Results-We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1) or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found a significant interaction of body mass index with LEPR (P < 2.9 x 10(-6)). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained approximate to 5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease. Conclusions-We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation. (Circulation. 2011; 123: 731-738.)

引用

页码：731 / U151

页数：91

共 77 条

[1] Merlin-rapid analysis of dense genetic maps using sparse gene flow trees [J].

Abecasis, GR ;

Cherny, SS ;

Cookson, WO ;

Cardon, LR .

NATURE GENETICS, 2002, 30 (01) :97-101

[2]

Andrew T, 2001, Twin Res, V4, P464, DOI 10.1375/1369052012803

[3]

[Anonymous], P 5 BERK S MATH STAT

[4]

[Anonymous], 2007, NATURE, V447, P661, DOI DOI 10.1038/NATURE05911

[5] Linkage disequilibrium in young genetically isolated Dutch population [J].

Aulchenko, YS ;

Heutink, P ;

Mackay, I ;

Bertoli-Avella, AM ;

Pullen, J ;

Vaessen, N ;

Rademaker, TAM ;

Sandkuijl, LA ;

Cardon, L ;

Oostra, B ;

van Duijn, CM .

EUROPEAN JOURNAL OF HUMAN GENETICS, 2004, 12 (07) :527-534

[6] GenABEL: an R library for genome-wide association analysis [J].

Aulchenko, Yurii S. ;

Ripke, Stephan ;

Isaacs, Aaron ;

Van Duijn, Cornelia M. .

BIOINFORMATICS, 2007, 23 (10) :1294-1296

[7] Novel genes identified in a high-density genome wide association study for nicotine dependence [J].

Bierut, Laura Jean ;

Madden, Pamela A. F. ;

Breslau, Naomi ;

Johnson, Eric O. ;

Hatsukami, Dorothy ;

Pomerleau, Ovide F. ;

Swan, Gary E. ;

Rutter, Joni ;

Bertelsen, Sarah ;

Fox, Louis ;

Fugman, Douglas ;

Goate, Alison M. ;

Hinrichs, Anthony L. ;

Konvicka, Karel ;

Martin, Nicholas G. ;

Montgomery, Grant W. ;

Saccone, Nancy L. ;

Saccone, Scott F. ;

Wang, Jen C. ;

Chase, Gary A. ;

Rice, John P. ;

Ballinger, Dennis G. .

HUMAN MOLECULAR GENETICS, 2007, 16 (01) :24-35

[8]

Boomsma DI, 2002, TWIN RES, V5, P401, DOI 10.1375/136905202320906174

[9] Netherlands Twin Register: From twins to twin families [J].

Boomsma, Dorret I. ;

de Geus, Eco J. C. ;

Vink, Jacqueline M. ;

Stubbe, Janine H. ;

Distel, Marijn A. ;

Hottenga, Jouke-Jan ;

Posthuma, Danielle ;

van Beijsterveldt, Toos C. E. M. ;

Hudziak, James J. ;

Bartels, Meike ;

Willemsen, Gonneke .

TWIN RESEARCH AND HUMAN GENETICS, 2006, 9 (06) :849-857

[10] GWAF: an R package for genome-wide association analyses with family data [J].

Chen, Ming-Huei ;

Yang, Qiong .

BIOINFORMATICS, 2010, 26 (04) :580-581

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Meta-Analysis of Genome-Wide Association Studies in &gt;80 000 Subjects Identifies Multiple Loci for C-Reactive Protein Levels

Meta-Analysis of Genome-Wide Association Studies in >80 000 Subjects Identifies Multiple Loci for C-Reactive Protein Levels