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A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple loci implicated in sex steroid hormone regulation
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نویسنده
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coviello a.d. ,haring r. ,wellons m. ,vaidya d. ,lehtimäki t. ,keildson s. ,lunetta k.l. ,he c. ,fornage m. ,lagou v. ,mangino m. ,onland-moret n.c. ,chen b. ,eriksson j. ,garcia m. ,liu y.m. ,koster a. ,lohman k. ,lyytikäinen l.-p. ,petersen a.-k. ,prescott j. ,stolk l. ,vandenput l. ,wood a.r. ,zhuang w.v. ,ruokonen a. ,hartikainen a.-l. ,pouta a. ,bandinelli s. ,biffar r. ,brabant g. ,cox d.g. ,chen y. ,cummings s. ,ferrucci l. ,gunter m.j. ,hankinson s.e. ,martikainen h. ,hofman a. ,homuth g. ,illig t. ,jansson j.-o. ,johnson a.d. ,karasik d. ,karlsson m. ,kettunen j. ,kiel d.p. ,kraft p. ,liu j. ,ljunggren ö. ,lorentzon m. ,maggio m. ,markus m.r.p. ,mellström d. ,miljkovic i. ,mirel d. ,nelson s. ,morin papunen l. ,peeters p.h.m. ,prokopenko i. ,raffel l. ,reincke m. ,reiner a.p. ,rexrode k. ,rivadeneira f. ,schwartz s.m. ,siscovick d. ,soranzo n. ,stöckl d. ,tworoger s. ,uitterlinden a.g. ,van gils c.h. ,vasan r.s. ,wichmann h.-e. ,zhai g. ,bhasin s. ,bidlingmaier m. ,chanock s.j. ,de vivo i. ,harris t.b. ,hunter d.j. ,kähönen m. ,liu s. ,ouyang p. ,spector t.d. ,van der schouw y.t. ,viikari j. ,wallaschofski h. ,mccarthy m.i. ,frayling t.m. ,murray a. ,franks s. ,järvelin m.-r. ,de jong f.h. ,raitakari o. ,teumer a. ,ohlsson c. ,murabito j.m. ,perry j.r.b.
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منبع
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plos genetics - 2012 - دوره : 8 - شماره : 7
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چکیده
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Sex hormone-binding globulin (shbg) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones,primarily testosterone and estradiol. shbg has been associated with chronic diseases including type 2 diabetes (t2d) and with hormone-sensitive cancers such as breast and prostate cancer. we performed a genome-wide association study (gwas) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. we identified twelve genomic regions (snps) associated with circulating shbg concentrations. loci near the identified snps included shbg (rs12150660,17p13.1,p = 1.8×10-106),prmt6 (rs17496332,1p13.3,p = 1.4×10-11),gckr (rs780093,2p23.3,p = 2.2×10-16),zbtb10 (rs440837,8q21.13,p = 3.4×10-09),jmjd1c (rs7910927,10q21.3,p = 6.1×10-35),slco1b1 (rs4149056,12p12.1,p = 1.9×10-08),nr2f2 (rs8023580,15q26.2,p = 8.3×10-12),znf652 (rs2411984,17q21.32,p = 3.5×10-14),tdgf3 (rs1573036,xq22.3,p = 4.1×10-14),lhcgr (rs10454142,2p16.3,p = 1.3×10-07),baiap2l1 (rs3779195,7q21.3,p = 2.7×10-08),and ugt2b15 (rs293428,4q13.2,p = 5.5×10-06). these genes encompass multiple biologic pathways,including hepatic function,lipid metabolism,carbohydrate metabolism and t2d,androgen and estrogen receptor function,epigenetic effects,and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. we found evidence of sex-differentiated genetic influences on shbg. in a sex-specific gwas,the loci 4q13.2-ugt2b15 was significant in men only (men p = 2.5×10-08,women p = 0.66,heterogeneity p = 0.003). additionally,three loci showed strong sex-differentiated effects: 17p13.1-shbg and xq22.3-tdgf3 were stronger in men,whereas 8q21.12-zbtb10 was stronger in women. conditional analyses identified additional signals at the shbg gene that together almost double the proportion of variance explained at the locus. using an independent study of 1,129 individuals,all snps identified in the overall or sex-differentiated or conditional analyses explained ~15.6% and ~8.4% of the genetic variation of shbg concentrations in men and women,respectively. the evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.
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آدرس
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section of preventive medicine and epidemiology,boston university school of medicine,boston,ma,united states,section of endocrinology,diabetes,and nutrition,boston university school of medicine,boston,ma,united states,national heart,lung,and blood institute's the framingham heart study,framingham,ma, United States, institute for clinical chemistry and laboratory medicine,university medicine,ernst-moritz-arndt university of greifswald,greifswald, Germany, department of medicine and department of obstetrics and gynecology,the university of alabama at birmingham,birmingham,al, United States, department of medicine,johns hopkins university,baltimore,md, United States, department of clinical chemistry,fimlab laboratories,tampere university hospital and university of tampere school of medicine,tampere, Finland, wellcome trust centre for human genetics,university of oxford,oxford, United Kingdom, department of biostatistics,boston university school of public health,boston,ma, United States, department of public health,indiana university school of medicine,indianapolis,in,united states,melvin and bren simon cancer center,indiana university,indianapolis,in, United States, university of texas health sciences center at houston,houston,tx, 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, department of twin research and genetic epidemiology,king's college london,london, United Kingdom, julius center for health sciences and primary care,university medical center utrecht,utrecht, Netherlands, program on genomics and nutrition and the center for metabolic disease prevention,school of public health,university of california los angeles,los angeles,ca, United States, center for bone and arthritis research,institute of medicine,sahlgrenska academy,university of gothenburg,gothenburg, Sweden, laboratory of epidemiology,demography,and biometry,national institute on aging,bethesda,md, United States, wake forest university school of medicine,winston-salem,nc,united states,department of epidemiology and prevention,division of public health sciences,wake forest university health sciences,winston-salem,nc, United States, laboratory of epidemiology,demography,and biometry,national institute on aging,bethesda,md, United States, wake forest university school of medicine,winston-salem,nc, United States, department of clinical chemistry,fimlab laboratories,tampere university hospital and university of tampere school of medicine,tampere, Finland, laboratory of epidemiology,demography,and biometry,national institute on aging,bethesda,md, United States, institute of genetic epidemiology,helmholtz zentrum münchen,neuherberg,germany,channing laboratory,department of medicine,brigham and women's hospital,harvard medical school,boston,ma, United States, channing laboratory,department of medicine,brigham and women's hospital,harvard medical school,boston,ma,united states,netherlands consortium of healthy aging,rotterdam, Netherlands, center for bone and arthritis research,institute of medicine,sahlgrenska academy,university of gothenburg,gothenburg, Sweden, netherlands consortium of healthy aging,rotterdam, Netherlands, department of biostatistics,boston university school of public health,boston,ma, United States, genetics of complex traits,peninsula medical school,university of exeter,exeter, United Kingdom, institute of diagnostics,university of oulu,oulu, Finland, department of obstetrics and gynecology,university hospital of oulu,oulu, Finland, national institute for health and welfare and institute of health sciences,university of oulu,oulu, Finland, geriatric unit,azienda sanitaria di firenze,florence, Italy, department of prosthetic dentistry,gerostomatology,and dental materials,university of greifswald,greifswald, Germany, experimental and clinical endocrinology,university of lübeck,lübeck,germany,department of epidemiology and biostatistics,school of public health,imperial college,london, United Kingdom, wellcome trust centre for human genetics,university of oxford,oxford, United Kingdom, california pacific medical center,san francisco,ca, United States, longitudinal studies section,clinical research branch,national institute on aging,baltimore,md, United States, cancer research center of lyon,inserm u1052,lyon, France, program in molecular and genetic epidemiology,department of epidemiology,harvard school of public health,boston,ma,united states,division of biostatistics and epidemiology,university of massachusetts,amherst,ma,united states,department of epidemiology,harvard school of public health,boston,ma, United States, institute of diagnostics,university of oulu,oulu, Finland, department of internal medicine,erasmus mc,rotterdam,netherlands,department of epidemiology,erasmus mc,rotterdam, Netherlands, interfaculty institute for genetics and functional genomics,university of greifswald,greifswald, Germany, research unit of molecular epidemiology,helmholtz zentrum münchen,neuherberg,germany,hannover unified biobank,hannover medical school,hannover, Germany, center for bone and arthritis research,institute of medicine,sahlgrenska academy,university of gothenburg,gothenburg, Sweden, national heart,lung,and blood institute's the framingham heart study,framingham,ma, United States, hebrew seniorlife institute for aging research and harvard medical school,boston,ma, United States, clinical and molecular osteoporosis research unit,department of clinical sciences and department of orthopaedics,lund university,malmö, Sweden, institute for molecular medicine finland (fimm),university of helsinki,helsinki,finland,department of chronic disease prevention,national institute for health and welfare,helsinki, Finland, hannover unified biobank,hannover medical school,hannover, Germany, institute of genetic epidemiology,helmholtz zentrum münchen,neuherberg, Germany, department of chronic disease prevention,national institute for health and welfare,helsinki, Finland, program in molecular and genetic epidemiology,department of epidemiology,harvard school of public health,boston,ma, United States, center for bone and arthritis research,institute of medicine,sahlgrenska academy,university of gothenburg,gothenburg, Sweden, women's health initiative clinical coordinating center,division of public health sciences,fred hutchinson cancer research center,seattle,wa, United States, department of medical sciences,university of uppsala,uppsala, Sweden, center for bone and arthritis research,institute of medicine,sahlgrenska academy,university of gothenburg,gothenburg, Sweden, department of internal medicine and biomedical sciences,section of geriatrics,university of parma,parma, Italy, institute for community medicine,university of greifswald,greifswald, Germany, university of pittsburgh,pittsburgh,pa, United States, institute of diagnostics,university of oulu,oulu, Finland, julius center for health sciences and primary care,university medical center utrecht,utrecht, Netherlands, 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, gene environment initiative,program in medical and population genetics,broad institute of harvard and mit,boston,ma, United States, medizinische klinik and poliklinik iv,ludwig-maximilians university,munich, Germany, medical genetics institute,cedars-sinai medical center,los angeles,ca, United States, brigham and women's hospital,harvard medical school,boston,ma, United States, channing laboratory,department of medicine,brigham and women's hospital,harvard medical school,boston,ma,united states,netherlands consortium of healthy aging,rotterdam, Netherlands, cardiovascular health research unit,department of epidemiology,university of washington,seattle,wa, United States, division of public health sciences,fred hutchinson cancer research center,seattle,wa, United States, department of twin research and genetic epidemiology,king's college london,london,united kingdom,human genetics,wellcome trust sanger institute,hinxton, United Kingdom, institute of epidemiology ii,helmholtz zentrum münchen,neuherberg,germany,department of obstetrics and gynaecology,ludwig-maximilians-university,munich, Germany, program in molecular and genetic epidemiology,department of epidemiology,harvard school of public health,boston,ma,united states,department of epidemiology,harvard school of public health,boston,ma, United States, channing laboratory,department of medicine,brigham and women's hospital,harvard medical school,boston,ma,united states,netherlands consortium of healthy aging,rotterdam,netherlands,department of epidemiology,erasmus mc,rotterdam, Netherlands, julius center for health sciences and primary care,university medical center utrecht,utrecht, Netherlands, section of preventive medicine and epidemiology,boston university school of medicine,boston,ma,united states,national heart,lung,and blood institute's the framingham heart study,framingham,ma, United States, institute of epidemiology i,helmholtz zentrum münchen,neuherberg,germany,institute of medical informatics,biometry,and epidemiology,ludwig-maximilians-universität,munich,germany,klinikum großhadern,munich, Germany, department of twin research and genetic epidemiology,king's college london,london,united kingdom,discipline of genetics,faculty of medicine,memorial university of newfoundland,st. john's,nl, Canada, section of endocrinology,diabetes,and nutrition,boston university school of medicine,boston,ma, United States, department of biostatistics,university of washington,seattle,wa, United States, division of cancer epidemiology and genetics,national cancer institute,national institutes of health,bethesda,md, United States, institute of genetic epidemiology,helmholtz zentrum münchen,neuherberg,germany,channing laboratory,department of medicine,brigham and women's hospital,harvard medical school,boston,ma, United States, laboratory of epidemiology,demography,and biometry,national institute on aging,bethesda,md, United States, institute of genetic epidemiology,helmholtz zentrum münchen,neuherberg,germany,channing laboratory,department of medicine,brigham and women's hospital,harvard medical school,boston,ma, United States, department of clinical physiology,tampere university hospital and university of tampere school of medicine,tampere, Finland, program on genomics and nutrition,department of epidemiology,university of california los angeles,los angeles,ca, United States, division of cardiology,johns hopkins bayview medical center,baltimore,md, United States, department of twin research and genetic epidemiology,king's college london,london, United Kingdom, julius center for health sciences and primary care,university medical center utrecht,utrecht, Netherlands, department of medicine,turku university hospital and university of turku,turku, Finland, institute for clinical chemistry and laboratory medicine,university medicine,ernst-moritz-arndt university of greifswald,greifswald, Germany, wellcome trust centre for human genetics,university of oxford,oxford,united kingdom,oxford centre for diabetes,endocrinology,and metabolism,university of oxford,churchill hospital,oxford,united kingdom,oxford nihr biomedical research centre,churchill hospital,oxford, United Kingdom, netherlands consortium of healthy aging,rotterdam, Netherlands, netherlands consortium of healthy aging,rotterdam, Netherlands, institute of reproductive and developmental biology,imperial college london,london, United Kingdom, department of biostatistics and epidemiology,school of public health,mrc-hpa centre for environment and health,faculty of medicine,imperial college london,london,united kingdom,institute of health sciences,university of oulu,oulu,finland,biocenter oulu,university of oulu,oulu,finland,national institute of health and welfare,university of oulu,oulu, Finland, channing laboratory,department of medicine,brigham and women's hospital,harvard medical school,boston,ma, United States, department of clinical physiology and nuclear medicine,turku university hospital and research centre of applied and preventive cardiovascular medicine,university of turku,turku, Finland, department of epidemiology,erasmus mc,rotterdam, Netherlands, center for bone and arthritis research,institute of medicine,sahlgrenska academy,university of gothenburg,gothenburg, Sweden, national heart,lung,and blood institute's the framingham heart study,framingham,ma,united states,section of general internal medicine,boston university school of medicine,boston,ma, United States, 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,genetics of complex traits,peninsula medical school,university of exeter,exeter, United Kingdom
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Authors
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