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Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension
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نویسنده
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padmanabhan s. ,melander o. ,johnson t. ,di blasio a.m. ,lee w.k. ,gentilini d. ,hastie c.e. ,menni c. ,monti m.c. ,delles c. ,laing s. ,corso b. ,navis g. ,kwakernaak a.j. ,van der harst p. ,bochud m. ,maillard m. ,burnier m. ,hedner t. ,kjeldsen s. ,wahlstrand b. ,sjögren m. ,fava c. ,montagnana m. ,danese e. ,torffvit o. ,hedblad b. ,snieder h. ,connell j.m.c. ,brown m. ,samani n.j. ,farrall m. ,cesana g. ,mancia g. ,signorini s. ,grassi g. ,eyheramendy s. ,erich wichmann h. ,laan m. ,strachan d.p. ,sever p. ,shields d.c. ,stanton a. ,vollenweider p. ,teumer a. ,völzke h. ,rettig r. ,newton-cheh c. ,arora p. ,zhang f. ,soranzo n. ,spector t.d. ,lucas g. ,kathiresan s. ,siscovick d.s. ,luan j. ,loos r.j.f. ,wareham n.j. ,penninx b.w. ,nolte i.m. ,mcbride m. ,miller w.h. ,nicklin s.a. ,baker a.h. ,graham d. ,mcdonald r.a. ,pell j.p. ,sattar n. ,welsh p. ,munroe p. ,caulfield m.j. ,zanchetti a. ,dominiczak a.f.
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منبع
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plos genetics - 2010 - دوره : 6 - شماره : 10 - صفحه:1 -11
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چکیده
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Hypertension is a heritable and major contributor to the global burden of disease. the sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in bp and hypertension. this suggests the existence of more undiscovered common variants. we conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme casecontrol design. we identified a locus on chromosome 16 in the 59 region of uromodulin (umod; rs13333226,combined p value of 3.6×10-11). the minor g allele is associated with a lower risk of hypertension (or [95%ci]: 0.87 [0.84-0.91]),reduced urinary uromodulin excretion,better renal function; and each copy of the g allele is associated with a 7.7% reduction in risk of cvd events after adjusting for age,sex,bmi,and smoking status (h.r. = 0.923,95% ci 0.860-0.991; p = 0.027). in a subset of 13,446 individuals with estimated glomerular filtration rate (egfr) measurements,we show that rs13333226 is independently associated with hypertension (unadjusted for egfr: 0.89 [0.83-0.96],p = 0.004; after egfr adjustment: 0.89 [0.83-0.96],p = 0.003). in clinical functional studies,we also consistently show the minor g allele is associated with lower urinary uromodulin excretion. the exclusive expression of uromodulin in the thick portion of the ascending limb of henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. the newly discovered umod locus for hypertension has the potential to give new insights into the role of uromodulin in bp regulation and to identify novel drugable targets for reducing cardiovascular risk. © 2010 padmanabhan et al.
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آدرس
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institute of cardiovascular and medical sciences,college of medical veterinary and life sciences,university of glasgow,glasgow, United Kingdom, department of clinical sciences,hypertension and cardiovascular diseases,university hospital malmö,lund university,malmö, Sweden, clinical pharmacology and barts and the london genome centre,william harvey research institute,barts and the london school of medicine,queen mary university of london,london, United Kingdom, istituto auxologico italiano,milan, Italy, institute of cardiovascular and medical sciences,college of medical veterinary and life sciences,university of glasgow,glasgow, United Kingdom, istituto auxologico italiano,milan, Italy, institute of cardiovascular and medical sciences,college of medical veterinary and life sciences,university of glasgow,glasgow, United Kingdom, institute of cardiovascular and medical sciences,college of medical veterinary and life sciences,university of glasgow,glasgow,united kingdom,università milano-bicocca,dipartimento di medicina clinica e prevenzione,ospedale san gerardo,monza,milano, Italy, istituto auxologico italiano,milan,italy,department of health science,university of pavia,pavia, Italy, institute of cardiovascular and medical sciences,college of medical veterinary and life sciences,university of glasgow,glasgow, United Kingdom, institute of cardiovascular and medical sciences,college of medical veterinary and life sciences,university of glasgow,glasgow, United Kingdom, istituto auxologico italiano,milan,italy,department of health science,university of pavia,pavia, Italy, department of nephrology,university medical center groningen,university of groningen,groningen, Netherlands, department of nephrology,university medical center groningen,university of groningen,groningen, Netherlands, department of cardiology,university medical center groningen,university of groningen,groningen, Netherlands, university institute of social and preventive medicine,centre hospitalier universitaire vaudois and university of lausanne,lausanne, Switzerland, service of nephrology,centre hospitalier universitaire vaudois and university of lausanne,lausanne, Switzerland, service of nephrology,centre hospitalier universitaire vaudois and university of lausanne,lausanne, Switzerland, institute of medicine,the sahlgrenska academy,university of gothenburg,gothenburg, Sweden, department of cardiology,university of oslo,ullevaal hospital,oslo, Norway, institute of medicine,the sahlgrenska academy,university of gothenburg,gothenburg, Sweden, department of clinical sciences,hypertension and cardiovascular diseases,university hospital malmö,lund university,malmö, Sweden, department of clinical sciences,hypertension and cardiovascular diseases,university hospital malmö,lund university,malmö,sweden,department of medicine,section of internal medicine c,university of verona,verona, Italy, department of clinical sciences,hypertension and cardiovascular diseases,university hospital malmö,lund university,malmö,sweden,department of life and reproduction sciences,section of clinical chemistry,university of verona,verona, Italy, department of clinical sciences,hypertension and cardiovascular diseases,university hospital malmö,lund university,malmö,sweden,department of life and reproduction sciences,section of clinical chemistry,university of verona,verona, Italy, department of nephrology,institution of clinical sciences,university hospital of lund,lund, Sweden, department of clinical sciences,hypertension and cardiovascular diseases,university hospital malmö,lund university,malmö, Sweden, unit of genetic epidemiology and bioinformatics,department of epidemiology,university medical center groningen,university of groningen,groningen, Netherlands, college of medicine,dentistry and nursing,ninewells hospital,university of dundee,dundee, United Kingdom, clinical pharmacology unit,university of cambridge,addenbrookes hospital,cambridge, United Kingdom, department of cardiovascular sciences,university of leicester,glenfield hospital,leicester, United Kingdom, department of cardiovascular medicine,wellcome trust centre for human genetics,oxford, United Kingdom, università milano-bicocca,dipartimento di medicina clinica e prevenzione,ospedale san gerardo,monza,milano, Italy, università milano-bicocca,dipartimento di medicina clinica e prevenzione,ospedale san gerardo,monza,milano, Italy, azienda ospedaliera di desio e vimercate,milano, Italy, università milano-bicocca,dipartimento di medicina clinica e prevenzione,ospedale san gerardo,monza,milano, Italy, department of statistics,pontificia universidad catolica de chile,santiago, Chile, institute of epidemiology,helmholtz zentrum münchen,german research center for environmental health,neuherberg,germany,institute of medical informatics,biometry and epidemiology,chair of epidemiology,ludwig-maximilians-universität,munich, Germany, institute of molecular and cell biology,university of tartu,tartu, Estonia, division of community health sciences,st george's,university of london,london, United Kingdom, international centre for circulatory health national heart and lung institute,imperial college,london, United Kingdom, conway institute of biomolecular and biomedical research,university college dublin,dublin, Ireland, molecular and cellular therapeutics,royal college of surgeons in ireland,dublin, Ireland, department of internal medicine,centre hospitalier universitaire vaudois,university of lausanne,lausanne, Switzerland, interfaculty institute for genetics and functional genomics,university of greifswald,greifswald, Germany, institute for community medicine,university of greifswald,greifswald, Germany, institute of physiology,university of greifswald,greifswald, Germany, center for human genetic research and cardiovascular research center,massachusetts general hospital,harvard medical school,boston,ma,united states,program in medical and population genetics,broad institute,cambridge,ma, United States, center for human genetic research and cardiovascular research center,massachusetts general hospital,harvard medical school,boston,ma,united states,program in medical and population genetics,broad institute,cambridge,ma, United States, department of twin research and genetic epidemiology,king's college london,london, United Kingdom, department of twin research and genetic epidemiology,king's college london,london,united kingdom,wellcome trust sanger institute,genome campus,hinxton, United Kingdom, department of twin research and genetic epidemiology,king's college london,london, United Kingdom, cardiovascular epidemiology and genetics group,institut municipal d'investigacio medica,barcelona, Spain, center for human genetic research and cardiovascular research center,massachusetts general hospital,harvard medical school,boston,ma,united states,program in medical and population genetics,broad institute,cambridge,ma, United States, cardiovascular health research unit,departments of medicine and epidemiology,university of washington,seattle,wa, United States, mrc epidemiology unit,institute of metabolic science,cambridge, United Kingdom, mrc epidemiology unit,institute of metabolic science,cambridge, United Kingdom, mrc epidemiology unit,institute of metabolic science,cambridge, United Kingdom, department of psychiatry/emgo institute,neuroscience campus,vu university medical center,amsterdam,netherlands,department of psychiatry,leiden university medical center,leiden,netherlands,department of psychiatry,university medical center groningen,university of groningen,groningen, Netherlands, unit of genetic epidemiology and bioinformatics,department of epidemiology,university medical center groningen,university of groningen,groningen, Netherlands, institute of cardiovascular and medical sciences,college of medical veterinary and life sciences,university of glasgow,glasgow, United Kingdom, institute of cardiovascular and medical sciences,college of medical veterinary and life sciences,university of glasgow,glasgow, United Kingdom, institute of cardiovascular and medical sciences,college of medical veterinary and life sciences,university of glasgow,glasgow, United Kingdom, institute of cardiovascular and medical sciences,college of medical veterinary and life sciences,university of glasgow,glasgow, United Kingdom, institute of cardiovascular and medical sciences,college of medical veterinary and life sciences,university of glasgow,glasgow, United Kingdom, institute of cardiovascular and medical sciences,college of medical veterinary and life sciences,university of glasgow,glasgow, United Kingdom, public health and health policy section,university of glasgow,glasgo, United Kingdom, institute of cardiovascular and medical sciences,college of medical veterinary and life sciences,university of glasgow,glasgow, United Kingdom, institute of cardiovascular and medical sciences,college of medical veterinary and life sciences,university of glasgow,glasgow, United Kingdom, clinical pharmacology and barts and the london genome centre,william harvey research institute,barts and the london school of medicine,queen mary university of london,london, United Kingdom, clinical pharmacology and barts and the london genome centre,william harvey research institute,barts and the london school of medicine,queen mary university of london,london, United Kingdom, istituto auxologico italiano,milan,italy,university of milano,milano, Italy, institute of cardiovascular and medical sciences,college of medical veterinary and life sciences,university of glasgow,glasgow, United Kingdom
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Authors
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