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Association of Genetic Variants Related to Gluteofemoral vs Abdominal Fat Distribution With Type 2 Diabetes, Coronary Disease, and Cardiovascular Risk Factors.

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dc.contributor.authorLotta, Luca A
dc.contributor.authorWittemans, Laura BL
dc.contributor.authorZuber, Verena
dc.contributor.authorStewart, Isobel D
dc.contributor.authorSharp, Stephen J
dc.contributor.authorLuan, Jian'an
dc.contributor.authorDay, Felix R
dc.contributor.authorLi, Chen
dc.contributor.authorBowker, Nicholas
dc.contributor.authorCai, Lina
dc.contributor.authorDe Lucia Rolfe, Emanuella
dc.contributor.authorKhaw, Kay-Tee
dc.contributor.authorPerry, John RB
dc.contributor.authorO'Rahilly, Stephen
dc.contributor.authorScott, Robert A
dc.contributor.authorSavage, David B
dc.contributor.authorBurgess, Stephen
dc.contributor.authorWareham, Nicholas J
dc.contributor.authorLangenberg, Claudia
dc.contributor.orcidWittemans, Laura [0000-0001-6588-938X]
dc.contributor.orcidZuber, Verena [0000-0001-9827-1877]
dc.contributor.orcidSharp, Stephen [0000-0003-2375-1440]
dc.contributor.orcidLuan, Jian'an [0000-0003-3137-6337]
dc.contributor.orcidDay, Felix [0000-0003-3789-7651]
dc.contributor.orcidLi, Chen [0000-0002-6423-6325]
dc.contributor.orcidBowker, Nicholas [0000-0002-8794-894X]
dc.contributor.orcidCai, Lina [0000-0003-2598-8388]
dc.contributor.orcidDe Lucia Rolfe, Emanuella [0000-0003-3542-2767]
dc.contributor.orcidPerry, John [0000-0001-6483-3771]
dc.contributor.orcidO'Rahilly, Stephen [0000-0003-2199-4449]
dc.contributor.orcidSavage, David [0000-0002-7857-7032]
dc.contributor.orcidBurgess, Stephen [0000-0001-5365-8760]
dc.contributor.orcidWareham, Nicholas [0000-0003-1422-2993]
dc.contributor.orcidLangenberg, Claudia [0000-0002-5017-7344]
dc.date.accessioned2019-01-08T00:30:59Z
dc.date.available2019-01-08T00:30:59Z
dc.date.issued2018-12-25
dc.description.abstractIMPORTANCE: Body fat distribution, usually measured using waist-to-hip ratio (WHR), is an important contributor to cardiometabolic disease independent of body mass index (BMI). Whether mechanisms that increase WHR via lower gluteofemoral (hip) or via higher abdominal (waist) fat distribution affect cardiometabolic risk is unknown. OBJECTIVE: To identify genetic variants associated with higher WHR specifically via lower gluteofemoral or higher abdominal fat distribution and estimate their association with cardiometabolic risk. DESIGN, SETTING, AND PARTICIPANTS: Genome-wide association studies (GWAS) for WHR combined data from the UK Biobank cohort and summary statistics from previous GWAS (data collection: 2006-2018). Specific polygenic scores for higher WHR via lower gluteofemoral or via higher abdominal fat distribution were derived using WHR-associated genetic variants showing specific association with hip or waist circumference. Associations of polygenic scores with outcomes were estimated in 3 population-based cohorts, a case-cohort study, and summary statistics from 6 GWAS (data collection: 1991-2018). EXPOSURES: More than 2.4 million common genetic variants (GWAS); polygenic scores for higher WHR (follow-up analyses). MAIN OUTCOMES AND MEASURES: BMI-adjusted WHR and unadjusted WHR (GWAS); compartmental fat mass measured by dual-energy x-ray absorptiometry, systolic and diastolic blood pressure, low-density lipoprotein cholesterol, triglycerides, fasting glucose, fasting insulin, type 2 diabetes, and coronary disease risk (follow-up analyses). RESULTS: Among 452 302 UK Biobank participants of European ancestry, the mean (SD) age was 57 (8) years and the mean (SD) WHR was 0.87 (0.09). In genome-wide analyses, 202 independent genetic variants were associated with higher BMI-adjusted WHR (n = 660 648) and unadjusted WHR (n = 663 598). In dual-energy x-ray absorptiometry analyses (n = 18 330), the hip- and waist-specific polygenic scores for higher WHR were specifically associated with lower gluteofemoral and higher abdominal fat, respectively. In follow-up analyses (n = 636 607), both polygenic scores were associated with higher blood pressure and triglyceride levels and higher risk of diabetes (waist-specific score: odds ratio [OR], 1.57 [95% CI, 1.34-1.83], absolute risk increase per 1000 participant-years [ARI], 4.4 [95% CI, 2.7-6.5], P < .001; hip-specific score: OR, 2.54 [95% CI, 2.17-2.96], ARI, 12.0 [95% CI, 9.1-15.3], P < .001) and coronary disease (waist-specific score: OR, 1.60 [95% CI, 1.39-1.84], ARI, 2.3 [95% CI, 1.5-3.3], P < .001; hip-specific score: OR, 1.76 [95% CI, 1.53-2.02], ARI, 3.0 [95% CI, 2.1-4.0], P < .001), per 1-SD increase in BMI-adjusted WHR. CONCLUSIONS AND RELEVANCE: Distinct genetic mechanisms may be linked to gluteofemoral and abdominal fat distribution that are the basis for the calculation of the WHR. These findings may improve risk assessment and treatment of diabetes and coronary disease.
dc.description.sponsorshipThis study was funded by the United Kingdom’s Medical Research Council through grants MC_UU_12015/1, MC_PC_13046, MC_PC_13048 and MR/L00002/1. This work was supported by the MRC Metabolic Diseases Unit (MC_UU_12012/5) and the Cambridge NIHR Biomedical Research Centre and EU/EFPIA Innovative Medicines Initiative Joint Undertaking (EMIF grant: 115372). EPIC-InterAct Study funding: funding for the InterAct project was provided by the EU FP6 program (grant number LSHM_CT_2006_037197). D.B.S. and S.O’R. are supported by the Wellcome Trust (WT107064 and WT095515 respectively) the MRC Metabolic Disease Unit, the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre and the NIHR Rare Disease Translational Research Collaboration.
dc.format.mediumPrint
dc.identifier.doi10.17863/CAM.34918
dc.identifier.eissn1538-3598
dc.identifier.issn0098-7484
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/287606
dc.languageeng
dc.language.isoeng
dc.publisherAmerican Medical Association (AMA)
dc.publisher.urlhttp://dx.doi.org/10.1001/jama.2018.19329
dc.subjectAbdominal Fat
dc.subjectAdiposity
dc.subjectBody Mass Index
dc.subjectCardiovascular Diseases
dc.subjectCoronary Disease
dc.subjectDiabetes Mellitus, Type 2
dc.subjectFemale
dc.subjectGenetic Predisposition to Disease
dc.subjectGenetic Variation
dc.subjectGenome-Wide Association Study
dc.subjectHumans
dc.subjectMale
dc.subjectMiddle Aged
dc.subjectRisk Factors
dc.subjectWaist-Hip Ratio
dc.titleAssociation of Genetic Variants Related to Gluteofemoral vs Abdominal Fat Distribution With Type 2 Diabetes, Coronary Disease, and Cardiovascular Risk Factors.
dc.typeArticle
dcterms.dateAccepted2018-11-13
prism.endingPage2563
prism.issueIdentifier24
prism.publicationDate2018
prism.publicationNameJAMA
prism.startingPage2553
prism.volume320
pubs.funder-project-idMedical Research Council (MC_UU_12015/1)
pubs.funder-project-idCambridge University Hospitals NHS Foundation Trust (CUH) (146281)
pubs.funder-project-idWellcome Trust (107064/Z/15/Z)
pubs.funder-project-idMedical Research Council (MC_UU_12015/2)
pubs.funder-project-idDepartment of Health (via National Institute for Health Research (NIHR)) (NF-SI-0617-10149)
pubs.funder-project-idDepartment of Health (via National Institute for Health Research (NIHR)) (NF-SI-0512-10135)
pubs.funder-project-idEuropean Commission (602068)
pubs.funder-project-idMRC (MC_PC_13046)
pubs.funder-project-idMRC (MC_PC_13048)
pubs.funder-project-idMedical Research Council (G0401527)
pubs.funder-project-idMedical Research Council (G1000143)
pubs.funder-project-idMedical Research Council (MR/L003120/1)
pubs.funder-project-idMedical Research Council (MC_UU_12012/5)
pubs.funder-project-idMedical Research Council (MR/N003284/1)
pubs.funder-project-idBritish Heart Foundation (None)
pubs.funder-project-idMedical Research Council (MC_UU_00002/7)
pubs.funder-project-idMRC (1950385)
pubs.funder-project-idWellcome Trust (204623/Z/16/Z)
pubs.funder-project-idMedical Research Council (MC_PC_12012)
pubs.funder-project-idMedical Research Council (G0401527/1)
rioxxterms.licenseref.startdate2018-12
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionAM
rioxxterms.versionofrecord10.1001/jama.2018.19329

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