Title | Pleiotropic genes for metabolic syndrome and inflammation. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Kraja 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 Authors | Borecki IB |
Corporate Authors | Cross 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 |
Journal | Mol Genet Metab |
Volume | 112 |
Issue | 4 |
Pagination | 317-38 |
Date Published | 2014 Aug |
ISSN | 1096-7206 |
Keywords | Biomarkers, 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. |
DOI | 10.1016/j.ymgme.2014.04.007 |
Alternate Journal | Mol Genet Metab |
PubMed ID | 24981077 |
PubMed Central ID | PMC4122618 |
Grant List | N01-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 HHSN268201100006C / HL / NHLBI NIH HHS / United States P20 MD006899 / MD / NIMHD NIH HHS / United States U01 HL108630 / HL / NHLBI NIH HHS / United States 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 N01HC48050 / HL / NHLBI NIH HHS / United States R01 HL080467 / HL / NHLBI NIH HHS / United States N01HC05187 / HL / NHLBI NIH HHS / United States R01 DK089256 / DK / NIDDK NIH HHS / United States HHSN268201100009C / HL / NHLBI NIH HHS / United States 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 N01HC45204 / HL / NHLBI NIH HHS / United States N01-HC-48048 / HC / NHLBI NIH HHS / United States 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 |