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Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels
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نویسنده
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thun g.a. ,imboden m. ,ferrarotti i. ,kumar a. ,obeidat m. ,zorzetto m. ,haun m. ,curjuric i. ,couto alves a. ,jackson v.e. ,albrecht e. ,ried j.s. ,teumer a. ,lopez l.m. ,huffman j.e. ,enroth s. ,bossé y. ,hao k. ,timens w. ,gyllensten u. ,polasek o. ,wilson j.f. ,rudan i. ,hayward c. ,sandford a.j. ,deary i.j. ,koch b. ,reischl e. ,schulz h. ,hui j. ,james a.l. ,rochat t. ,russi e.w. ,jarvelin m.-r. ,strachan d.p. ,hall i.p. ,tobin m.d. ,dahl m. ,fallgaard nielsen s. ,nordestgaard b.g. ,kronenberg f. ,luisetti m. ,probst-hensch n.m.
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منبع
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plos genetics - 2013 - دوره : 9 - شماره : 8
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چکیده
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Several infrequent genetic polymorphisms in the serpina1 gene are known to substantially reduce concentration of alpha1-antitrypsin (aat) in the blood. since low aat serum levels fail to protect pulmonary tissue from enzymatic degradation,these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (copd). the role of more common serpina1 single nucleotide polymorphisms (snps) in respiratory health remains poorly understood.we present here an agnostic investigation of genetic determinants of circulating aat levels in a general population sample by performing a genome-wide association study (gwas) in 1392 individuals of the sapaldia cohort.five common snps,defined by showing minor allele frequencies (mafs) >5%,reached genome-wide significance,all located in the serpina gene cluster at 14q32.13. the top-ranking genotyped snp rs4905179 was associated with an estimated effect of β = -0.068 g/l per minor allele (p = 1.20*10-12). but denser serpina1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis,as well as exon-sequencing in a subsample (n = 410),suggested that aat serum level is causally determined at this locus by rare (maf<1%) and low-frequent (maf 1-5%) variants only,in particular by the well-documented protein inhibitor s and z (pi s,pi z) variants. replication of the association of rs4905179 with aat serum levels in the copenhagen city heart study (n = 8273) was successful (p<0.0001),as was the replication of its synthetic nature (the effect disappeared after adjusting for pi s and z,p = 0.57). extending the analysis to lung function revealed a more complex situation. only in individuals with severely compromised pulmonary health (n = 397),associations of common snps at this locus with lung function were driven by rarer pi s or z variants. overall,our meta-analysis of lung function in ever-smokers does not support a functional role of common snps in the serpina gene cluster in the general population. © 2013 thun et al.
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آدرس
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swiss tropical and public health institute,basel,switzerland,university of basel,basel, Switzerland, swiss tropical and public health institute,basel,switzerland,university of basel,basel, Switzerland, center for diagnosis of inherited alpha1-antitrypsin deficiency,institute for respiratory disease,irccs san matteo hospital foundation,university of pavia,pavia, Italy, swiss tropical and public health institute,basel,switzerland,university of basel,basel,switzerland,wellcome trust centre for human genetics,university of oxford,oxford, United Kingdom, james hogg research centre,institute for heart and lung health,university of british columbia,vancouver, Canada, center for diagnosis of inherited alpha1-antitrypsin deficiency,institute for respiratory disease,irccs san matteo hospital foundation,university of pavia,pavia, Italy, division of genetic epidemiology,department of medical genetics,molecular and clinical pharmacology,innsbruck medical university,innsbruck, Austria, swiss tropical and public health institute,basel,switzerland,university of basel,basel, Switzerland, department of epidemiology and biostatistics,imperial college london,london, United Kingdom, departments of health sciences and genetics,university of leicester,leicester, United Kingdom, institute of genetic epidemiology,helmholtz zentrum münchen - german research center for environmental health,neuherberg, Germany, institute of genetic epidemiology,helmholtz zentrum münchen - german research center for environmental health,neuherberg, Germany, interfaculty institute for genetics and functional genomics,university medicine greifswald,greifswald, Germany, centre for cognitive ageing and cognitive epidemiology,department of psychology,university of edinburgh,edinburgh, United Kingdom, mrc human genetics,institute of genetics and molecular medicine,university of edinburgh,edinburgh, United Kingdom, department of immunology,genetics,and pathology,rudbeck laboratory,scilifelab,uppsala university,uppsala, Sweden, institut universitaire de cardiologie et de pneumologie de québec,department of molecular medicine,laval university,québec city, Canada, department of genetics and genomic sciences,icahn institute of genomics and multiscale biology,icahn school of medicine,mount sinai,ny, United States, department of pathology and medical biology,university medical center groningen,griac research institute,university of groningen,groningen, Netherlands, department of immunology,genetics,and pathology,rudbeck laboratory,scilifelab,uppsala university,uppsala, Sweden, department of public health,university of split,split, Croatia, centre for population health sciences,medical school,university of edinburgh,edinburgh, United Kingdom, centre for population health sciences,medical school,university of edinburgh,edinburgh, United Kingdom, mrc human genetics,institute of genetics and molecular medicine,university of edinburgh,edinburgh, United Kingdom, james hogg research centre,institute for heart and lung health,university of british columbia,vancouver, Canada, centre for cognitive ageing and cognitive epidemiology,department of psychology,university of edinburgh,edinburgh, United Kingdom, department of internal medicine b,university medicine greifswald,greifswald, Germany, research unit of molecular epidemiology,helmholtz zentrum münchen - german research center for environmental health,neuherberg, Germany, institute of epidemiology i,helmholtz zentrum münchen - german research center for environmental health,neuherberg, Germany, school of population health,university of western australia,perth,australia,pathology and laboratory medicine,university of western australia,perth,australia,busselton population medical research foundation,perth, Australia, west australian sleep disorders research institute,perth,australia,school of medicine and pharmacology,university of western australia,perth, Australia, division of pulmonary medicine,university hospital of geneva,geneva, Switzerland, pulmonary division,university hospital of zurich,zurich, Switzerland, department of epidemiology and biostatistics,imperial college london,london,united kingdom,institute of health sciences,university of oulu,oulu,finland,biocenter oulu,university of oulu,oulu,finland,unit of primary care,oulu university hospital,oulu,finland,department of children and young people and families,national institute for health and welfare,oulu, Finland, division of population health sciences and education,st george's,university of london,london, United Kingdom, division of therapeutics and molecular medicine,queen's medical centre,nottingham, United Kingdom, departments of health sciences and genetics,university of leicester,leicester, United Kingdom, department of clinical biochemistry,rigshospitalet,copenhagen university hospital,copenhagen, Denmark, department of clinical biochemistry,herlev hospital,copenhagen university hospital,herlev, Denmark, department of clinical biochemistry,herlev hospital,copenhagen university hospital,herlev, Denmark, division of genetic epidemiology,department of medical genetics,molecular and clinical pharmacology,innsbruck medical university,innsbruck, Austria, center for diagnosis of inherited alpha1-antitrypsin deficiency,institute for respiratory disease,irccs san matteo hospital foundation,university of pavia,pavia, Italy, swiss tropical and public health institute,basel,switzerland,university of basel,basel, Switzerland
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