Pleiotropic genes for metabolic syndrome and inflammation

被引：98

作者：

Kraja, Aldi T. ^{[1
,2
]}

Chasman, Daniel I. ^{[3
,55
]}

North, Kari E. ^{[4
,5
]}

Reiner, Alexander P. ^{[6
]}

Yanek, Lisa R. ^{[7
]}

Kilpelainen, Tuomas O. ^{[8
]}

Smith, Jennifer A. ^{[9
]}

Dehghan, Abbas ^{[10
]}

Dupuis, Josee ^{[12
,13
]}

Johnson, Andrew D. ^{[14
,15
]}

Feitosa, Mary F. ^{[1
,2
]}

Tekola-Ayele, Fasil ^{[11
,16
]}

Chu, Audrey Y. ^{[3
,55
]}

Nolte, Ilja M. ^{[17
]}

Dastani, Zari ^{[18
]}

Morris, Andrew ^{[19
]}

Pendergrass, Sarah A. ^{[20
,21
]}

Sun, Yan V. ^{[22
,23
]}

Ritchie, Marylyn D. ^{[24
]}

Vaez, Ahmad ^{[17
]}

Lin, Honghuang ^{[25
]}

Ligthart, Symen ^{[10
]}

Marullo, Letizia ^{[19
,26
]}

Rohde, Rebecca ^{[4
,5
]}

Shao, Yarning ^{[4
,5
]}

Ziegler, Mark A. ^{[27
]}

Im, Hae Kyung ^{[28
]}

Schnabel, Renate B. ^{[29
]}

Jorgensen, Torben ^{[30
,31
]}

Jorgensen, Marit E. ^{[32
]}

Hansen, Torben ^{[8
]}

Pedersen, Oluf ^{[8
]}

Stolk, Ronald P. ^{[17
]}

Snieder, Harold ^{[17
]}

Hofman, Albert ^{[10
]}

Uitterlinden, Andre G. ^{[33
]}

Franco, Oscar H. ^{[10
]}

Ikram, M. Arfan ^{[10
]}

Richards, J. Brent ^{[18
,34
,35
]}

Rotimi, Charles ^{[11
,16
]}

Wilson, James G. ^{[36
]}

Lange, Leslie ^{[37
]}

Ganesh, Santhi K. ^{[38
]}

Nalls, Mike ^{[39
]}

Rasmussen-Torvik, Laura J. ^{[40
]}

Pankow, James S.

Coresh, Josef ^{[42
]}

Tang, Weihong

Kao, W. H. Linda ^{[43
]}

Boerwinkle, Eric ^{[41
,44
]}

机构：

[1] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63108 USA

[2] Washington Univ, Sch Med, Ctr Genome Sci & Syst Biol, St Louis, MO 63108 USA

[3] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA

[4] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA

[5] Univ N Carolina, Gillings Sch Global Publ Hlth, Carolina Ctr Genome Sci, Chapel Hill, NC USA

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

[7] Johns Hopkins Univ, Sch Med, Dept Med, Div Gen Internal Med, Baltimore, MD USA

[8] Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark

[9] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA

[10] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

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

[12] NHLBI, Framingham, MA USA

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

[14] NHLBI, Div Intramural Res, Framingham, MA USA

[15] NHLBIs Framingham Heart Study, Framingham, MA USA

[16] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA

[17] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands

[18] McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada

[19] Univ Oxford, Welcome Trust Ctr Human Genet, Oxford, England

[20] Penn State Univ, Eberly Coll Sci, Dept Biochem & Mol Biol, University Pk, PA 16802 USA

[21] Penn State Univ, Eberly Coll Sci, Huck Inst Life Sci, University Pk, PA 16802 USA

[22] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA

[23] Emory Univ, Sch Med, Dept Biomed Informat, Atlanta, GA 30322 USA

[24] Penn State Univ, Dept Biochem & Mol Biol, University Pk, PA 16802 USA

[25] Boston Univ, Sch Med, Dept Med, Sect Computat Biomed, Boston, MA 02118 USA

[26] Univ Ferrara, Dept Life Sci & Biotechnol, I-44100 Ferrara, Italy

[27] Washington Univ, Sch Med, MSIBS Program, Div Biostat, St Louis, MO USA

[28] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA

[29] Univ Heart Ctr Hamburg Eppendorf, Dept Gen & Intervent Cardiol, Hamburg, Germany

[30] Glostrup Cty Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark

[31] Univ Copenhagen, Fac Hlth Sci, Copenhagen, Denmark

[32] Steno Diabet Ctr, DK-2820 Gentofte, Denmark

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

[34] McGill Univ, Dept Med Human Genet Epidemiol & Biostat, Montreal, PQ H3A 2T5, Canada

[35] Kings Coll London, Dept Twin Res, London, England

[36] Univ Mississippi, Med Ctr, University, MS 38677 USA

[37] Univ N Carolina, Dept Genet, Chapel Hill, NC 27515 USA

[38] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA

[39] Natl Inst Aging, Neurogenet Lab, Mol Genet Sect, NIH, Bethesda, MD USA

[40] Northwestern Univ, Feinberg Sch Med, Chicago, IL USA

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

[42] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Med, Baltimore, MD USA

[43] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA

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

[45] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA

[46] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, Charles Bronfrnan Inst Personalized Med, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA

[47] Boston Univ, Dept Math & Stat, Boston, MA USA

[48] Harvard Univ, Sch Publ Hlth, Hebrew Senior Life Inst Aging Res, Harvard Med Sch & Mol & Integrat Physiol Sci, Boston, MA 02115 USA

[49] Univ Vermont, Coll Med, Burlington, VT 05401 USA

[50] Univ Penn, Perelman Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA

来源：

MOLECULAR GENETICS AND METABOLISM | 2014年 / 112卷 / 04期

基金：

英国医学研究理事会; 美国国家卫生研究院;

关键词：

Metabolic syndrome; Inflammatory markers; Pleiotropic associations; Meta-analysis; Regulome; GENOME-WIDE ASSOCIATION; DENSITY-LIPOPROTEIN CHOLESTEROL; CORONARY-HEART-DISEASE; INSULIN-RESISTANCE; CARDIOVASCULAR-DISEASE; SUSCEPTIBILITY LOCI; CIRCULATING ADIPONECTIN; GLUCOSE-HOMEOSTASIS; ARTERIAL STIFFNESS; HEPATIC STEATOSIS;

D O I：

10.1016/j.ymgme.2014.04.007

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Metabolic syndrome (MetS) has become a health and financial burden worldwide. The MetS definition captures clustering of risk factors that predict higher risk for diabetes mellitus and cardiovascular disease. Our study hypothesis is that additional to genes influencing individual MetS risk factors, genetic variants exist that influence MetS and inflammatory markers forming a predisposing MetS genetic network. To test this hypothesis a staged approach was undertaken. (a) We analyzed 17 metabolic and inflammatory traits in more than 85,500 participants from 14 large epidemiological studies within the Cross Consortia Pleiotropy Group. Individuals classified with MetS (NCEP definition), versus those without, showed on average significantly different levels for most inflammatory markers studied. (b) Paired average correlations between 8 metabolic traits and 9 inflammatory markers from the same studies as above, estimated with two methods, and factor analyses on large simulated data, helped in identifying 8 combinations of traits for follow-up in meta-analyses, out of 130,305 possible combinations between metabolic traits and inflammatory markers studied. (c) We performed correlated meta-analyses for 8 metabolic traits and 6 inflammatory markers by using existing GWAS published genetic summary results, with about 2.5 million SNPs from twelve predominantly largest GWAS consortia. These analyses yielded 130 unique SNPs/genes with pleiotropic associations (a SNP/gene associating at least one metabolic trait and one inflammatory marker). Of them twenty-five variants (seven loci newly reported) are proposed as MetS candidates. They map to genes MACF1, KIAA0754, GCKR, GRB14, COBLL1, LOC646736-IRS1, SLC39A8, NELFE, SKIV2L, STK19, TFAP2B, BAZ1B, BCL7B, TBL2, MLXIPL, LPL, TRIB1, ATXN2, HECTD4, PTPN11, ZNF664, PDXDC1, FTO, MC4R and TOMM40. Based on large data evidence, we conclude that inflammation is a feature of MetS and several gene variants show pleiotropic genetic associations across phenotypes and might explain a part of MetS correlated genetic architecture. These findings warrant further functional investigation. (C) 2014 Elsevier Inc. All rights reserved.

引用

页码：317 / 338

页数：22

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