Association of STAT4 Polymorphism with Severe Renal Insufficiency in Lupus Nephritis.docVIP

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Association of STAT4 Polymorphism with Severe Renal Insufficiency in Lupus Nephritis.doc

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Association of STAT4 Polymorphism with Severe Renal Insufficiency in Lupus Nephritis

AssociationofSTAT4PolymorphismwithSevereRenal InsufficiencyinLupusNephritis KarinBolin1,JohannaK.Sandling2,AgnetaZickert3,AndreasJo¨nsen4,ChristopherSjo¨wall5, ElisabetSvenungsson3,AndersA.Bengtsson4,Maija-LeenaEloranta1,LarsRo¨nnblom1,6 ,Ann- ChristineSyva¨nen2,IvaGunnarsson3,GunnelNordmark1* 1SectionofRheumatology,DepartmentofMedicalSciences,UppsalaUniversity,Uppsala,Sweden,2MolecularMedicine,DepartmentofMedicalSciencesandSciencefor LifeLaboratory,UppsalaUniversity,Uppsala,Sweden,3RheumatologyUnit,DepartmentofMedicine,KarolinskaUniversityHospitalandKarolinskaInstitutet,Stockholm, Sweden, 4Section of Rheumatology, Department Clinical Sciences, Lund University, Lund, Sweden, 5Rheumatology/AIR, Department of Clinical and Experimental Medicine,Linko¨pingUniversity,Linko¨ping,Sweden,6ScienceforLifeLaboratory,UppsalaUniversity,Uppsala,Sweden Abstract Lupusnephritisisacauseofsignificantmorbidityinsystemiclupuserythematosus(SLE)anditsgeneticbackgroundhasnot been completely clarified. The aim of this investigation was to analyze single nucleotide polymorphisms (SNPs) for associationwithlupusnephritis,itssevereformproliferativenephritisandrenaloutcome,intwoSwedishcohorts.CohortI (n=567 SLE cases, n= 512 controls) was previously genotyped for 5676 SNPs and cohort II (n=145 SLE cases, n=619 controls) was genotyped for SNPs in STAT4, IRF5, TNIP1 and BLK. Case-control and case-only association analyses for patients with lupus nephritis, proliferative nephritis and severe renal insufficiency were performed. In the case-control analysisofcohortI,fourhighlylinkedSNPsinSTAT4wereassociatedwithlupusnephritiswithgenomewidesignificance withp=3.761029,OR2.20forthebestSNPrStrongsignalsofassociationbetweenIRF5andanHLA-DR3SNP markerwerealsodetectedinthelupusnephritiscaseversushealthycontrolanalysis(p,0.0001).Anadditionalsixgenes showedanassociationwithlupusnephritiswithp,0.001(PMS2,TNIP1,CARD11,ITGAM,BLKandIRAK1).Inthecase-only meta-analysis of the two cohorts, the STAT4 SNP rs7