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Stratifying type 2 diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases
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نویسنده
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perry j.r.b. ,voight b.f. ,yengo l. ,amin n. ,dupuis j. ,ganser m. ,grallert h. ,navarro p. ,li m. ,qi l. ,steinthorsdottir v. ,scott r.a. ,almgren p. ,arking d.e. ,aulchenko y. ,balkau b. ,benediktsson r. ,bergman r.n. ,boerwinkle e. ,bonnycastle l. ,burtt n.p. ,campbell h. ,charpentier g. ,collins f.s. ,gieger c. ,green t. ,hadjadj s. ,hattersley a.t. ,herder c. ,hofman a. ,johnson a.d. ,kottgen a. ,kraft p. ,labrune y. ,langenberg c. ,manning a.k. ,mohlke k.l. ,morris a.p. ,oostra b. ,pankow j. ,petersen a.-k. ,pramstaller p.p. ,prokopenko i. ,rathmann w. ,rayner w. ,roden m. ,rudan i. ,rybin d. ,scott l.j. ,sigurdsson g. ,sladek r. ,thorleifsson g. ,thorsteinsdottir u. ,tuomilehto j. ,uitterlinden a.g. ,vivequin s. ,weedon m.n. ,wright a.f. ,hu f.b. ,illig t. ,kao l. ,meigs j.b. ,wilson j.f. ,stefansson k. ,van duijn c. ,altschuler d. ,morris a.d. ,boehnke m. ,mccarthy m.i. ,froguel p. ,palmer c.n.a. ,wareham n.j. ,groop l. ,frayling t.m. ,cauchi s.
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منبع
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plos genetics - 2012 - دوره : 8 - شماره : 5
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چکیده
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Common diseases such as type 2 diabetes are phenotypically heterogeneous. obesity is a major risk factor for type 2 diabetes,but patients vary appreciably in body mass index. we hypothesized that the genetic predisposition to the disease may be different in lean (bmi<25 kg/m2) compared to obese cases (bmi≥30 kg/m2). we performed two case-control genome-wide studies using two accepted cut-offs for defining individuals as overweight or obese. we used 2,112 lean type 2 diabetes cases (bmi<25 kg/m2) or 4,123 obese cases (bmi≥30 kg/m2),and 54,412 un-stratified controls. replication was performed in 2,881 lean cases or 8,702 obese cases,and 18,957 un-stratified controls. to assess the effects of known signals,we tested the individual and combined effects of snps representing 36 type 2 diabetes loci. after combining data from discovery and replication datasets,we identified two signals not previously reported in europeans. a variant (rs8090011) in the lama1 gene was associated with type 2 diabetes in lean cases (p = 8.4×10-9,or = 1.13 [95% ci 1.09-1.18]),and this association was stronger than that in obese cases (p = 0.04,or = 1.03 [95% ci 1.00-1.06]). a variant in hmg20a-previously identified in south asians but not europeans-was associated with type 2 diabetes in obese cases (p = 1.3×10-8,or = 1.11 [95% ci 1.07-1.15]),although this association was not significantly stronger than that in lean cases (p = 0.02,or = 1.09 [95% ci 1.02-1.17]). for 36 known type 2 diabetes loci,29 had a larger odds ratio in the lean compared to obese (binomial p = 0.0002). in the lean analysis,we observed a weighted per-risk allele or = 1.13 [95% ci 1.10-1.17],p = 3.2×10-14. this was larger than the same model fitted in the obese analysis where the or = 1.06 [95% ci 1.05-1.08],p = 2.2×10-16. this study provides evidence that stratification of type 2 diabetes cases by bmi may help identify additional risk variants and that lean cases may have a stronger genetic predisposition to type 2 diabetes. © 2012 perry et al.
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آدرس
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genetics of complex traits,peninsula medical school,university of exeter,exeter,united kingdom,wellcome trust centre for human genetics,university of oxford,oxford,united kingdom,department of twin research and genetic epidemiology,king's college london,london, United Kingdom, broad institute of harvard and massachusetts institute of technology,cambridge,ma, United States, cnrs umr 8199,genomics of metabolic diseases,lille, France, department of epidemiology,erasmus mc,rotterdam, Netherlands, department of biostatistics,boston university school of public health,boston,ma,united states,national heart,lung,and blood institute's framingham heart study,framingham,ma, United States, department of biostatistics and center for statistical genetics,university of michigan,ann arbor,mi, United States, research unit of molecular epidemiology,helmholtz zentrum muenchen,neuherberg, Germany, mrc human genetics unit,medical research council institute of genetics and molecular medicine,university of edinburgh,edinburgh, United Kingdom, johns hopkins bloomberg school of public health and epidemiology,baltimore,md, United States, departments of nutrition and epidemiology,harvard school of public health,boston,ma, United States, decode genetics,reykjavik, Iceland, mrc epidemiology unit,medical research council,cambridge, United Kingdom, diabetes and endocrinology research unit,department of clinical sciences,lund university,malmoe, Sweden, mckusick-nathans institute of genetic medicine,johns hopkins university school of medicine,baltimore,md, United States, department of epidemiology,erasmus mc,rotterdam, Netherlands, inserm cesp u1018,villejuif, France, landspitali university hospital,reykjavik,iceland,icelandic heart association,kopavogur, Iceland, diabetes and obesity research institute,cedars-sinai medical center,los angeles,ca, United States, university of texas health science center at houston,human genetics center,houston,tx, United States, national human genome research institute,national institutes of health,bethesda,md, United States, broad institute of harvard and massachusetts institute of technology,cambridge,ma, United States, centre for population health sciences,university of edinburgh,teviot place,edinburgh, United Kingdom, corbeil-essonnes hospital,department of endocrinology-diabetology,corbeil-essonnes, France, national human genome research institute,national institutes of health,bethesda,md, United States, institute of genetic epidemiology,helmholtz zentrum muenchen,neuherberg, Germany, broad institute of harvard and massachusetts institute of technology,cambridge,ma, United States, chu poitiers,department of endocrinology-diabetology,cic inserm 0801,inserm u927,university of medical and pharmaceutical sciences,poitiers, France, genetics of complex traits,peninsula medical school,university of exeter,exeter, United Kingdom, institute for clinical diabetology,german diabetes center,leibniz center for diabetes research,heinrich heine university düsseldorf,düsseldorf, Germany, department of epidemiology,erasmus mc,rotterdam, Netherlands, national heart,lung,and blood institute's framingham heart study,framingham,ma, United States, johns hopkins bloomberg school of public health and epidemiology,baltimore,md,united states,freiburg university clinic,renal division,freiburg, Germany, departments of nutrition and epidemiology,harvard school of public health,boston,ma, United States, cnrs umr 8199,genomics of metabolic diseases,lille, France, mrc epidemiology unit,medical research council,cambridge, United Kingdom, boston university school of public health,boston,ma, United States, department of genetics,university of north carolina,chapel hill,nc, United States, wellcome trust centre for human genetics,university of oxford,oxford, United Kingdom, erasmus university medical school,rotterdam, Netherlands, school of public health,division of epidemiology and community health,university of minnesota,minneapolis,mn, United States, institute of genetic epidemiology,helmholtz zentrum muenchen,neuherberg, Germany, center for biomedicine,european academy bozen/bolzano (eurac),bolzano,italy,department of neurology,general central hospital,bolzano,italy,department of neurology,university of lübeck,lübeck,germany,affiliated institute of the university of lübeck,lübeck, Germany, wellcome trust centre for human genetics,university of oxford,oxford,united kingdom,oxford centre for diabetes,endocrinology,and metabolism,university of oxford,oxford, United Kingdom, institute of biometrics and epidemiology,german diabetes center,leibniz center for diabetes research,heinrich heine university düsseldorf,düsseldorf, Germany, wellcome trust centre for human genetics,university of oxford,oxford, United Kingdom, institute for clinical diabetology,german diabetes center,leibniz center for diabetes research,heinrich heine university düsseldorf,düsseldorf,germany,department of metabolic diseases,university hospital düsseldorf,düsseldorf, Germany, centre for population health sciences,university of edinburgh,edinburgh, Germany, boston university data coordinating center,boston,ma, United States, department of biostatistics and center for statistical genetics,university of michigan,ann arbor,mi, United States, landspitali university hospital,reykjavik,iceland,icelandic heart association,kopavogur, Iceland, department of human genetics,faculty of medicine,mcgill university,montreal, Canada, decode genetics,reykjavik, Iceland, decode genetics,reykjavik,iceland,faculty of medicine,university of iceland,reykjavík, Iceland, diabetes prevention unit,national institute for health and welfare,helsinki,finland,south ostrobothnia central hospital,seinäjoki,finland,red recava grupo rd06/0014/0015,hospital universitario la paz,madrid,spain,centre for vascular prevention,danube-university krems,krems, Austria, department of internal medicine,erasmus mc,rotterdam, Netherlands, cnrs umr 8199,genomics of metabolic diseases,lille, France, genetics of complex traits,peninsula medical school,university of exeter,exeter, United Kingdom, mrc human genetics unit,medical research council institute of genetics and molecular medicine,university of edinburgh,edinburgh, United Kingdom, departments of nutrition and epidemiology,harvard school of public health,boston,ma, United States, research unit of molecular epidemiology,helmholtz zentrum muenchen,neuherberg,germany,hannover unified biobank,hannover medical school,hannover, Germany, johns hopkins bloomberg school of public health and epidemiology,baltimore,md, United States, general medicine division,massachusetts general hospital and department of medicine,harvard medical school,boston,ma, United States, centre for population health sciences,university of edinburgh,teviot place,edinburgh, United Kingdom, decode genetics,reykjavik,iceland,faculty of medicine,university of iceland,reykjavík, Iceland, department of epidemiology,erasmus mc,rotterdam, Netherlands, broad institute of harvard and massachusetts institute of technology,cambridge,ma, United States, biomedical research institute,ninewells hospital and medical school,university of dundee,dundee, United Kingdom, department of biostatistics and center for statistical genetics,university of michigan,ann arbor,mi, United States, wellcome trust centre for human genetics,university of oxford,oxford,united kingdom,oxford centre for diabetes,endocrinology,and metabolism,university of oxford,oxford,united kingdom,oxford nihr biomedical research centre,churchill hospital,oxford, United Kingdom, cnrs umr 8199,genomics of metabolic diseases,lille,france,department of genomics of common diseases,hammersmith hospital,imperial college london,london, United Kingdom, biomedical research institute,ninewells hospital and medical school,university of dundee,dundee, United Kingdom, mrc epidemiology unit,medical research council,cambridge, United Kingdom, diabetes and endocrinology research unit,department of clinical sciences,lund university,malmoe, Sweden, genetics of complex traits,peninsula medical school,university of exeter,exeter, United Kingdom, cnrs umr 8199,genomics of metabolic diseases,lille, France
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Authors
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