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dc.contributor.authorWheeler, Eleanoren
dc.contributor.authorLeong, Aen
dc.contributor.authorLiu, C-Ten
dc.contributor.authorHivert, M-Fen
dc.contributor.authorStrawbridge, RJen
dc.contributor.authorPodmore, Claraen
dc.contributor.authorLi, Men
dc.contributor.authorYao, Jen
dc.contributor.authorSim, Xen
dc.contributor.authorHong, Jen
dc.contributor.authorChu, AYen
dc.contributor.authorZhang, Wen
dc.contributor.authorWang, Xen
dc.contributor.authorChen, Pen
dc.contributor.authorMaruthur, NMen
dc.contributor.authorPorneala, BCen
dc.contributor.authorSharp, Stephenen
dc.contributor.authorJia, Yen
dc.contributor.authorKabagambe, EKen
dc.contributor.authorChang, L-Cen
dc.contributor.authorChen, W-Men
dc.contributor.authorElks, CEen
dc.contributor.authorEvans, DSen
dc.contributor.authorFan, Qen
dc.contributor.authorGiulianini, Fen
dc.contributor.authorGo, MJen
dc.contributor.authorHottenga, J-Jen
dc.contributor.authorHu, Yen
dc.contributor.authorJackson, AUen
dc.contributor.authorKanoni, Sen
dc.contributor.authorKim, YJen
dc.contributor.authorKleber, MEen
dc.contributor.authorLadenvall, Cen
dc.contributor.authorLecoeur, Cen
dc.contributor.authorLim, S-Hen
dc.contributor.authorLu, Yen
dc.contributor.authorMahajan, Aen
dc.contributor.authorMarzi, Cen
dc.contributor.authorNalls, MAen
dc.contributor.authorNavarro, Pen
dc.contributor.authorNolte, IMen
dc.contributor.authorRose, LMen
dc.contributor.authorRybin, DVen
dc.contributor.authorSanna, Sen
dc.contributor.authorShi, Yen
dc.contributor.authorStram, DOen
dc.contributor.authorTakeuchi, Fen
dc.contributor.authorTan, SPen
dc.contributor.authorvan der Most, PJen
dc.contributor.authorVan Vliet-Ostaptchouk, JVen
dc.contributor.authorWong, Aen
dc.contributor.authorYengo, Len
dc.contributor.authorZhao, Wen
dc.contributor.authorGoel, Aen
dc.contributor.authorMartinez Larrad, MTen
dc.contributor.authorRadke, Den
dc.contributor.authorSalo, Pen
dc.contributor.authorTanaka, Ten
dc.contributor.authorvan Iperen, EPAen
dc.contributor.authorAbecasis, Gen
dc.contributor.authorAfaq, Sen
dc.contributor.authorAlizadeh, BZen
dc.contributor.authorBertoni, AGen
dc.contributor.authorBonnefond, Aen
dc.contributor.authorBöttcher, Yen
dc.contributor.authorBottinger, EPen
dc.contributor.authorCampbell, Hen
dc.contributor.authorCarlson, ODen
dc.contributor.authorChen, C-Hen
dc.contributor.authorCho, YSen
dc.contributor.authorGarvey, WTen
dc.contributor.authorGieger, Cen
dc.contributor.authorGoodarzi, MOen
dc.contributor.authorGrallert, Hen
dc.contributor.authorHamsten, Aen
dc.contributor.authorHartman, CAen
dc.contributor.authorHerder, Cen
dc.contributor.authorHsiung, CAen
dc.contributor.authorHuang, Jen
dc.contributor.authorIgase, Men
dc.contributor.authorIsono, Men
dc.contributor.authorKatsuya, Ten
dc.contributor.authorKhor, C-Cen
dc.contributor.authorKiess, Wen
dc.contributor.authorKohara, Ken
dc.contributor.authorKovacs, Pen
dc.contributor.authorLee, Jen
dc.contributor.authorLee, W-Jen
dc.contributor.authorLehne, Ben
dc.contributor.authorLi, Hen
dc.contributor.authorLiu, Jen
dc.contributor.authorLobbens, Sen
dc.contributor.authorLuan, Jian'anen
dc.contributor.authorLyssenko, Ven
dc.contributor.authorMeitinger, Ten
dc.contributor.authorMiki, Ten
dc.contributor.authorMiljkovic, Ien
dc.contributor.authorMoon, Sen
dc.contributor.authorMulas, Aen
dc.contributor.authorMüller, Gen
dc.contributor.authorMüller-Nurasyid, Men
dc.contributor.authorNagaraja, Ren
dc.contributor.authorNauck, Men
dc.contributor.authorPankow, JSen
dc.contributor.authorPolasek, Oen
dc.contributor.authorProkopenko, Ien
dc.contributor.authorRamos, PSen
dc.contributor.authorRasmussen-Torvik, Len
dc.contributor.authorRathmann, Wen
dc.contributor.authorRich, SSen
dc.contributor.authorRobertson, NRen
dc.contributor.authorRoden, Men
dc.contributor.authorRoussel, Ren
dc.contributor.authorRudan, Ien
dc.contributor.authorScott, RAen
dc.contributor.authorScott, WRen
dc.contributor.authorSennblad, Ben
dc.contributor.authorSiscovick, DSen
dc.contributor.authorStrauch, Ken
dc.contributor.authorSun, Len
dc.contributor.authorSwertz, Men
dc.contributor.authorTajuddin, SMen
dc.contributor.authorTaylor, KDen
dc.contributor.authorTeo, Y-Yen
dc.contributor.authorTham, YCen
dc.contributor.authorTönjes, Aen
dc.contributor.authorWareham, Nicholasen
dc.contributor.authorWillemsen, Gen
dc.contributor.authorWilsgaard, Ten
dc.contributor.authorHingorani, ADen
dc.contributor.authorEPIC-CVD Consortium,en
dc.contributor.authorEPIC-InterAct Consortium,en
dc.contributor.authorLifelines Cohort Study,en
dc.contributor.authorEgan, Jen
dc.contributor.authorFerrucci, Len
dc.contributor.authorHovingh, GKen
dc.contributor.authorJula, Aen
dc.contributor.authorKivimaki, Men
dc.contributor.authorKumari, Men
dc.contributor.authorNjølstad, Ien
dc.contributor.authorPalmer, CNAen
dc.contributor.authorSerrano Ríos, Men
dc.contributor.authorStumvoll, Men
dc.contributor.authorWatkins, Hen
dc.contributor.authorAung, Ten
dc.contributor.authorBlüher, Men
dc.contributor.authorBoehnke, Men
dc.contributor.authorBoomsma, DIen
dc.contributor.authorBornstein, SRen
dc.contributor.authorChambers, JCen
dc.contributor.authorChasman, DIen
dc.contributor.authorChen, Y-DIen
dc.contributor.authorChen, Y-Ten
dc.contributor.authorCheng, C-Yen
dc.contributor.authorCucca, Fen
dc.contributor.authorde Geus, EJCen
dc.contributor.authorDeloukas, Pen
dc.contributor.authorEvans, MKen
dc.contributor.authorFornage, Men
dc.contributor.authorFriedlander, Yen
dc.contributor.authorFroguel, Pen
dc.contributor.authorGroop, Len
dc.contributor.authorGross, MDen
dc.contributor.authorHarris, TBen
dc.contributor.authorHayward, Cen
dc.contributor.authorHeng, C-Ken
dc.contributor.authorIngelsson, Een
dc.contributor.authorKato, Nen
dc.contributor.authorKim, B-Jen
dc.contributor.authorKoh, W-Pen
dc.contributor.authorKooner, JSen
dc.contributor.authorKörner, Aen
dc.contributor.authorKuh, Den
dc.contributor.authorKuusisto, Jen
dc.contributor.authorLaakso, Men
dc.contributor.authorLin, Xen
dc.contributor.authorLiu, Yen
dc.contributor.authorLoos, RJFen
dc.contributor.authorMagnusson, PKEen
dc.contributor.authorMärz, Wen
dc.contributor.authorMcCarthy, MIen
dc.contributor.authorOldehinkel, AJen
dc.contributor.authorOng, Kennethen
dc.contributor.authorPedersen, NLen
dc.contributor.authorPereira, MAen
dc.contributor.authorPeters, Aen
dc.contributor.authorRidker, PMen
dc.contributor.authorSabanayagam, Cen
dc.contributor.authorSale, Men
dc.contributor.authorSaleheen, Den
dc.contributor.authorSaltevo, Jen
dc.contributor.authorSchwarz, PEen
dc.contributor.authorSheu, WHHen
dc.contributor.authorSnieder, Hen
dc.contributor.authorSpector, TDen
dc.contributor.authorTabara, Yen
dc.contributor.authorTuomilehto, Jen
dc.contributor.authorvan Dam, RMen
dc.contributor.authorWilson, JGen
dc.contributor.authorWilson, JFen
dc.contributor.authorWolffenbuttel, BHRen
dc.contributor.authorWong, TYen
dc.contributor.authorWu, J-Yen
dc.contributor.authorYuan, J-Men
dc.contributor.authorZonderman, ABen
dc.contributor.authorSoranzo, Nicoleen
dc.contributor.authorGuo, Xen
dc.contributor.authorRoberts, DJen
dc.contributor.authorFlorez, JCen
dc.contributor.authorSladek, Ren
dc.contributor.authorDupuis, Jen
dc.contributor.authorMorris, APen
dc.contributor.authorTai, E-Sen
dc.contributor.authorSelvin, Een
dc.contributor.authorRotter, JIen
dc.contributor.authorLangenberg, Claudiaen
dc.contributor.authorBarroso, Inesen
dc.contributor.authorMeigs, JBen
dc.date.accessioned2017-10-03T11:49:35Z
dc.date.available2017-10-03T11:49:35Z
dc.date.issued2017-09en
dc.identifier.issn1549-1277
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/267684
dc.description.abstractBACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes. METHODS & FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants. CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.
dc.languageengen
dc.language.isoenen
dc.publisherPublic Library of Science (PLoS)
dc.rightsCC0 1.0 Universal (CC0 1.0) Public Domain Dedicationen
dc.rights.urihttps://creativecommons.org/publicdomain/zero/1.0/en
dc.subjectDiabetes Mellitus, Type 2en
dc.subjectgenetic variationen
dc.subjectGenome-Wide Association Studyen
dc.subjectHemoglobin A, Glycosylateden
dc.subjecthumansen
dc.subjectphenotypeen
dc.subjectrisken
dc.titleImpact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysisen
dc.typeArticle
prism.endingPagee1002383
prism.issueIdentifier9en
prism.publicationDate2017en
prism.publicationNamePLoS Medicineen
prism.startingPagee1002383
prism.volume14en
dc.identifier.doi10.17863/CAM.13618
dcterms.dateAccepted2017-08-03en
rioxxterms.versionofrecord10.1371/journal.pmed.1002383en
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2017-09en
dc.contributor.orcidWheeler, Eleanor [0000-0002-8616-6444]
dc.contributor.orcidPodmore, Clara [0000-0002-2452-8067]
dc.contributor.orcidSharp, Stephen [0000-0003-2375-1440]
dc.contributor.orcidLuan, Jian'an [0000-0003-3137-6337]
dc.contributor.orcidWareham, Nicholas [0000-0003-1422-2993]
dc.contributor.orcidOng, Kenneth [0000-0003-4689-7530]
dc.contributor.orcidSoranzo, Nicole [0000-0003-1095-3852]
dc.contributor.orcidLangenberg, Claudia [0000-0002-5017-7344]
dc.contributor.orcidBarroso, Ines [0000-0001-5800-4520]
dc.identifier.eissn1549-1676
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (MC_UU_12015/1)
pubs.funder-project-idMRC (MC_UU_12015/2)
cam.issuedOnline2017-09-12en
cam.orpheus.successThu Jan 30 12:58:21 GMT 2020 - The item has an open VoR version.*
rioxxterms.freetoread.startdate2100-01-01


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CC0 1.0 Universal (CC0 1.0) Public Domain Dedication
Except where otherwise noted, this item's licence is described as CC0 1.0 Universal (CC0 1.0) Public Domain Dedication