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Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis
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نویسنده
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kiryluk k. ,li y. ,sanna-cherchi s. ,rohanizadegan m. ,suzuki h. ,eitner f. ,snyder h.j. ,choi m. ,hou p. ,scolari f. ,izzi c. ,gigante m. ,gesualdo l. ,savoldi s. ,amoroso a. ,cusi d. ,zamboli p. ,julian b.a. ,novak j. ,wyatt r.j. ,mucha k. ,perola m. ,kristiansson k. ,viktorin a. ,magnusson p.k. ,thorleifsson g. ,thorsteinsdottir u. ,stefansson k. ,boland a. ,metzger m. ,thibaudin l. ,wanner c. ,jager k.j. ,goto s. ,maixnerova d. ,karnib h.h. ,nagy j. ,panzer u. ,xie j. ,chen n. ,tesar v. ,narita i. ,berthoux f. ,floege j. ,stengel b. ,zhang h. ,lifton r.p. ,gharavi a.g.
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منبع
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plos genetics - 2012 - دوره : 8 - شماره : 6
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چکیده
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Iga nephropathy (igan),major cause of kidney failure worldwide,is common in asians,moderately prevalent in europeans,and rare in africans. it is not known if these differences represent variation in genes,environment,or ascertainment. in a recent gwas,we localized five igan susceptibility loci on chr.6p21 (hla-dqb1/drb1,psmb9/tap1,and dpa1/dpb2 loci),chr.1q32 (cfhr3/r1 locus),and chr.22q12 (hormad2 locus). these igan loci are associated with risk of other immune-mediated disorders such as type i diabetes,multiple sclerosis,or inflammatory bowel disease. we tested association of these loci in eight new independent cohorts of asian,european,and african-american ancestry (n = 4,789),followed by meta-analysis with risk-score modeling in 12 cohorts (n = 10,755) and geospatial analysis in 85 world populations. four susceptibility loci robustly replicated and all five loci were genome-wide significant in the combined cohort (p = 5×10-32-3×10-10),with heterogeneity detected only at the psmb9/tap1 locus (i2 = 0.60). conditional analyses identified two new independent risk alleles within the hla-dqb1/drb1 locus,defining multiple risk and protective haplotypes within this interval. we also detected a significant genetic interaction,whereby the odds ratio for the hormad2 protective allele was reversed in homozygotes for a cfhr3/r1 deletion (p = 2.5×10-4). a seven-snp genetic risk score,which explained 4.7% of overall igan risk,increased sharply with eastward and northward distance from africa (r = 0.30,p = 3×10-128). this model paralleled the known east-west gradient in disease risk. moreover,the prediction of a south-north axis was confirmed by registry data showing that the prevalence of igan-attributable kidney failure is increased in northern europe,similar to multiple sclerosis and type i diabetes. variation at igan susceptibility loci correlates with differences in disease prevalence among world populations. these findings inform genetic,biological,and epidemiological investigations of igan and permit cross-comparison with other complex traits that share genetic risk loci and geographic patterns with igan. © 2012 kiryluk et al.
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آدرس
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department of medicine,college of physicians and surgeons,columbia university,new york,ny, United States, department of medicine,college of physicians and surgeons,columbia university,new york,ny, United States, department of medicine,college of physicians and surgeons,columbia university,new york,ny,united states,department of medicine,st. luke's-roosevelt hospital center,new york,ny, United States, department of medicine,college of physicians and surgeons,columbia university,new york,ny, United States, division of nephrology,department of internal medicine,juntendo university faculty of medicine,tokyo, Japan, department of nephrology,rwth university of aachen,aachen, Germany, department of medicine,college of physicians and surgeons,columbia university,new york,ny, United States, department of genetics,howard hughes medical institute,yale university school of medicine,new haven,ct, United States, renal division,peking university first hospital,peking university institute of nephrology,beijing, China, university of brescia and second division of nephrology,montichiari hospital,montichiari, Italy, university of brescia and second division of nephrology,montichiari hospital,montichiari, Italy, section of nephrology,department of emergency and organ transplantation,university of bari,bari, Italy, section of nephrology,department of emergency and organ transplantation,university of bari,bari, Italy, nephrology and dialysis unit,ciriè hospital,torino, Italy, department of genetics,biology,and biochemistry,university of torino,torino, Italy, renal division,dmco,san paolo hospital,school of medicine,university of milan,milan, Italy, department of nephrology,second university of naples,naples, Italy, departments of microbiology and medicine,university of alabama at birmingham,birmingham,al, United States, departments of microbiology and medicine,university of alabama at birmingham,birmingham,al, United States, children's foundation research center,le bonheur children's hospital,memphis,tn,united states,division of pediatric nephrology,university of tennessee health sciences center,memphis,tn, United States, department of immunology,transplantology,and internal medicine,warsaw medical university,warsaw, Poland, department of chronic disease prevention,national institute for health and welfare,helsinki,finland,institute for molecular medicine finland fimm,university of helsinki,helsinki,finland,the estonian genome center,university of tartu,tartu, Estonia, department of chronic disease prevention,national institute for health and welfare,helsinki, Finland, department of medical epidemiology and biostatistics,karolinska institutet,stockholm, Sweden, department of medical epidemiology and biostatistics,karolinska institutet,stockholm, Sweden, decode genetics,reykjavik,iceland,faculty of medicine,university of iceland,reykjavík, Iceland, decode genetics,reykjavik,iceland,faculty of medicine,university of iceland,reykjavík, Iceland, decode genetics,reykjavik,iceland,faculty of medicine,university of iceland,reykjavík, Iceland, centre national de génotypage,cea,institut de génomique,evry, France, inserm,centre for research in epidemiology and population health,villejuif, France, nephrology,dialysis,and renal transplantation department,university north hospital,saint etienne, France, department of medicine,division of nephrology,university hospital,würzburg, Germany, era-edta registry,department of medical informatics,academic medical center,university of amsterdam,amsterdam, Netherlands, division of clinical nephrology and rheumatology,niigata university,niigata, Japan, department of nephrology,1st faculty of medicine and general university hospital,charles university,prague, Czech Republic, clinical research center and division of nephrology,al rassoul al-aazam hospital,beirut, Lebanon, nephrology center and 2nd department of internal medicine,medical faculty,university of pécs,pécs, Hungary, iii medizinische klinik,universitätsklinikum hamburg-eppendorf,hamburg, Germany, department of nephrology,ruijin hospital,shanghai jiaotong university school of medicine,shanghai, China, department of nephrology,ruijin hospital,shanghai jiaotong university school of medicine,shanghai, China, department of nephrology,1st faculty of medicine and general university hospital,charles university,prague, Czech Republic, division of clinical nephrology and rheumatology,niigata university,niigata, Japan, nephrology,dialysis,and renal transplantation department,university north hospital,saint etienne, France, department of nephrology,rwth university of aachen,aachen, Germany, inserm,centre for research in epidemiology and population health,villejuif, France, renal division,peking university first hospital,peking university institute of nephrology,beijing, China, department of genetics,howard hughes medical institute,yale university school of medicine,new haven,ct, United States, department of medicine,college of physicians and surgeons,columbia university,new york,ny, United States
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Authors
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