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Pleiotropic genes for metabolic syndrome and inflammation.

TitlePleiotropic genes for metabolic syndrome and inflammation.
Publication TypeJournal Article
Year of Publication2014
AuthorsKraja AT, Chasman DI, North KE, Reiner AP, Yanek LR, Kilpeläinen TO, Smith JA, Dehghan A, Dupuis J, Johnson AD, Feitosa MF, Tekola-Ayele F, Chu AY, Nolte IM, Dastani Z, Morris A, Pendergrass SA, Sun YV, Ritchie MD, Vaez A, Lin H, Ligthart S, Marullo L, Rohde R, Shao Y, Ziegler MA, Im HKyung, Schnabel RB, Jørgensen T, Jørgensen ME, Hansen T, Pedersen O, Stolk RP, Snieder H, Hofman A, Uitterlinden AG, Franco OH, M Ikram A, J Richards B, Rotimi C, Wilson JG, Lange L, Ganesh SK, Nalls M, Rasmussen-Torvik LJ, Pankow JS, Coresh JJ, Tang W, Linda Kao WH, Boerwinkle E, Morrison AC, Ridker PM, Becker DM, Rotter JI, Kardia SLR, Loos RJF, Larson MG, Hsu Y-H, Province MA, Tracy R, Voight BF, Vaidya D, O'Donnell CJ, Benjamin EJ, Alizadeh BZ, Prokopenko I, Meigs JB
Secondary AuthorsBorecki IB
Corporate AuthorsCross Consortia Pleiotropy Group, Cohorts for Heart and, Aging Research in Genetic Epidemiology, Genetic Investigation of ANthropometric Traits Consortium, Global Lipids Genetics Consortium, Meta-Analyses of Glucose, Insulin-related traits Consortium, Global BPgen Consortium, ADIPOGen Consortium, Women's Genome Health Study, Howard University Family Study
JournalMol Genet Metab
Volume112
Issue4
Pagination317-38
Date Published2014 Aug
ISSN1096-7206
KeywordsBiomarkers, Computational Biology, Gene Regulatory Networks, Genetic Pleiotropy, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Inflammation, Meta-Analysis as Topic, Metabolic Syndrome, Phenotype, Quantitative Trait, Heritable
Abstract

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.

DOI10.1016/j.ymgme.2014.04.007
Alternate JournalMol Genet Metab
PubMed ID24981077
PubMed Central IDPMC4122618
Grant ListN01-HC-05187 / HC / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
U01 HL072518 / HL / NHLBI NIH HHS / United States
HHSN268201100001C / WH / WHI NIH HHS / United States
N01HC48048 / HL / NHLBI NIH HHS / United States
R01 DK078616 / DK / NIDDK NIH HHS / United States
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
R01 HL071025 / HL / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
UL1 TR000430 / TR / NCATS NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
HL081331 / HL / NHLBI NIH HHS / United States
HHSN268201100001I / HL / NHLBI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
N01-HC-45205 / HC / NHLBI NIH HHS / United States
HL054481 / HL / NHLBI NIH HHS / United States
HL59684 / HL / NHLBI NIH HHS / United States
Z01 AG000932 / ImNIH / Intramural NIH HHS / United States
K12 CA139160 / CA / NCI NIH HHS / United States
HL071025-01A1 / HL / NHLBI NIH HHS / United States
1R01 AG028321 / AG / NIA NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
N01-HC-48047 / HC / NHLBI NIH HHS / United States
UL1 TR001079 / TR / NCATS NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
N01HC48049 / HL / NHLBI NIH HHS / United States
HHSN268201100004I / HL / NHLBI NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
R01 HL092577 / HL / NHLBI NIH HHS / United States
N01HC45205 / HL / NHLBI NIH HHS / United States
R01 HL043851 / HL / NHLBI NIH HHS / United States
R01 HL087660 / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
U10 HL054464 / HL / NHLBI NIH HHS / United States
HHSN268201100046C / HL / NHLBI NIH HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
N01-HC-45204 / HC / NHLBI NIH HHS / United States
P30 DK079637 / DK / NIDDK NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R01 HL076784 / HL / NHLBI NIH HHS / United States
HHSN268201100003C / WH / WHI NIH HHS / United States
Z01-AG000932-06 / AG / NIA NIH HHS / United States
N01-HC-95095 / HC / NHLBI NIH HHS / United States
M01-RR000052 / RR / NCRR NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
HL58625-01A1 / HL / NHLBI NIH HHS / United States
R01 DK075681 / DK / NIDDK NIH HHS / United States
U01 HL054464 / HL / NHLBI NIH HHS / United States
MC_UU_12015/1 / MRC_ / Medical Research Council / United Kingdom
N01-HC-48050 / HC / NHLBI NIH HHS / United States
MC_U106179471 / MRC_ / Medical Research Council / United Kingdom
U10 HL054481 / HL / NHLBI NIH HHS / United States
CA047988 / CA / NCI NIH HHS / United States
U10 HL054457 / HL / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
1R01DK8925601 / DK / NIDDK NIH HHS / United States
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N01HC95095 / HL / NHLBI NIH HHS / United States
U01 HL081331 / HL / NHLBI NIH HHS / United States
HL054464 / HL / NHLBI NIH HHS / United States
HL087660 / HL / NHLBI NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
U01 HL054457 / HL / NHLBI NIH HHS / United States
HHSN271201100004C / AG / NIA NIH HHS / United States
G0701863 / MRC_ / Medical Research Council / United Kingdom
M01 RR000052 / RR / NCRR NIH HHS / United States
N01-HC-48049 / HC / NHLBI NIH HHS / United States
K24 DK080140 / DK / NIDDK NIH HHS / United States
N01 HC045134 / HC / NHLBI NIH HHS / United States
HHSN268201100002C / WH / WHI NIH HHS / United States
R01DK075681 / DK / NIDDK NIH HHS / United States
U01 HL72518 / HL / NHLBI NIH HHS / United States
090532 / WT_ / Wellcome Trust / United Kingdom
NR0224103 / NR / NINR NIH HHS / United States
HL054457 / HL / NHLBI NIH HHS / United States
R01 CA047988 / CA / NCI NIH HHS / United States
R01 HL059684 / HL / NHLBI NIH HHS / United States
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HL080467 / HL / NHLBI NIH HHS / United States
N01HC48047 / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
U01 HL054481 / HL / NHLBI NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
N01-HC-95100 / HC / NHLBI NIH HHS / United States
HHSN268201100002I / HL / NHLBI NIH HHS / United States
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R21 AR056405 / AR / NIAMS NIH HHS / United States
R01 HL117078 / HL / NHLBI NIH HHS / United States
1R01HL092577 / HL / NHLBI NIH HHS / United States
R01 AG028321 / AG / NIA NIH HHS / United States
HHSN268201100004C / WH / WHI NIH HHS / United States
1R01 HL64753 / HL / NHLBI NIH HHS / United States