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Genome-wide association analysis in asthma subjects identifies SPATS2L as a novel bronchodilator response gene
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نویسنده
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himes b.e. ,jiang x. ,hu r. ,wu a.c. ,lasky-su j.a. ,klanderman b.j. ,ziniti j. ,senter-sylvia j. ,lima j.j. ,irvin c.g. ,peters s.p. ,meyers d.a. ,bleecker e.r. ,kubo m. ,tamari m. ,nakamura y. ,szefler s.j. ,lemanske jr. r.f. ,zeiger r.s. ,strunk r.c. ,martinez f.d. ,hanrahan j.p. ,koppelman g.h. ,postma d.s. ,nieuwenhuis m.a.e. ,vonk j.m. ,panettieri jr. r.a. ,markezich a. ,israel e. ,carey v.j. ,tantisira k.g. ,litonjua a.a. ,lu q. ,weiss s.t.
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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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Bronchodilator response (bdr) is an important asthma phenotype that measures reversibility of airway obstruction by comparing lung function (i.e. fev1) before and after the administration of a short-acting β2-agonist,the most common rescue medications used for the treatment of asthma. bdr also serves as a test of β2-agonist efficacy. bdr is a complex trait that is partly under genetic control. a genome-wide association study (gwas) of bdr,quantified as percent change in baseline fev1 after administration of a β2-agonist,was performed with 1,644 non-hispanic white asthmatic subjects from six drug clinical trials: camp,loccs,lodo,a medication trial conducted by sepracor,care,and acrn. data for 469,884 single-nucleotide polymorphisms (snps) were used to measure the association of snps with bdr using a linear regression model,while adjusting for age,sex,and height. replication of primary p-values was attempted in 501 white subjects from sarp and 550 white subjects from dag. experimental evidence supporting the top gene was obtained via sirna knockdown and western blotting analyses. the lowest overall combined p-value was 9.7e-07 for snp rs295137,near the spats2l gene. among subjects in the primary analysis,those with rs295137 tt genotype had a median bdr of 16.0 (iqr = [6.2,32.4]),while those with cc or tc genotypes had a median bdr of 10.9 (iqr = [5.0,22.2]). spats2l mrna knockdown resulted in increased β2-adrenergic receptor levels. our results suggest that spats2l may be an important regulator of β2-adrenergic receptor down-regulation and that there is promise in gaining a better understanding of the biological mechanisms of differential response to β2-agonists through gwas. © 2012 himes et al.
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آدرس
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channing laboratory,brigham and women's hospital and harvard medical school,boston,ma,united states,children's hospital informatics program,boston,ma,united states,partners healthcare center for personalized genetic medicine,harvard medical school,boston,ma, United States, program in molecular and integrative physiological sciences,department of environmental health,harvard school of public health,boston,ma, United States, program in molecular and integrative physiological sciences,department of environmental health,harvard school of public health,boston,ma, United States, department of population medicine,harvard pilgrim health care and harvard medical school,boston,ma, United States, channing laboratory,brigham and women's hospital and harvard medical school,boston,ma, United States, partners healthcare center for personalized genetic medicine,harvard medical school,boston,ma, United States, channing laboratory,brigham and women's hospital and harvard medical school,boston,ma, United States, channing laboratory,brigham and women's hospital and harvard medical school,boston,ma, United States, nemours children's clinic,center for pharmacogenomics and translational research,jacksonville,fl, United States, vermont lung center,department of medicine and physiology,university of vermont,burlington,vt, United States, center for genomics and personalized medicine research,wake forest school of medicine,winston-salem,nc, United States, center for genomics and personalized medicine research,wake forest school of medicine,winston-salem,nc, United States, center for genomics and personalized medicine research,wake forest school of medicine,winston-salem,nc, United States, riken center for genomic medicine,kanagawa, Japan, riken center for genomic medicine,kanagawa, Japan, laboratory of molecular medicine,the institute of medical science,the university of tokyo,tokyo, Japan, national jewish health and university of colorado denver school of medicine,denver,co, United States, clinical science center,university of wisconsin,madison,wi, United States, kaiser permanente southern california region,san diego,ca, United States, washington university school of medicine,st. louis,mo, United States, arizona respiratory center,university of arizona,college of medicine,tucson,az, United States, pulmatrix,lexington,ma, United States, department of pediatric pulmonology and pediatric allergology,beatrix children's hospital,griac research institute,university of groningen,university medical center groningen, Netherlands, department of pulmonology and tuberculosis,griac research institute,university of groningen,university medical center groningen, Netherlands, department of pulmonology and tuberculosis,griac research institute,university of groningen,university medical center groningen, Netherlands, department of epidemiology,griac research institute,university of groningen,university medical center groningen, Netherlands, pulmonary,allergy,and critical care division,university of pennsylvania,philadelphia,pa, United States, overlake internal medicine associates,bellevue,wa, United States, pulmonary and critical care division,brigham and women's hospital and harvard medical school,boston,ma, United States, channing laboratory,brigham and women's hospital and harvard medical school,boston,ma, United States, channing laboratory,brigham and women's hospital and harvard medical school,boston,ma, United States, channing laboratory,brigham and women's hospital and harvard medical school,boston,ma, United States, program in molecular and integrative physiological sciences,department of environmental health,harvard school of public health,boston,ma, United States, channing laboratory,brigham and women's hospital and harvard medical school,boston,ma,united states,partners healthcare center for personalized genetic medicine,harvard medical school,boston,ma, United States
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Authors
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