Association of Two Variants in SMAD7 with the Risk of Congenital Heart Disease in the Han Chinese Population.docVIP

AssociationofTwoVariantsinSMAD7withtheRiskof CongenitalHeartDiseaseintheHanChinesePopulation ErliWang1,2.,WenfeiJin1.,WenyuanDuan3.,BinQiao3,ShunaSun4,GuoyingHuang4,KaihuShi5, LiJin1,2*,HongyanWang2,6 * 1Chinese Academy of Sciences and Max Planck Society (CAS-MPG) Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China, 2The State Key Laboratory of Genetic Engineering and Ministry of Education (MOE) Key Laboratory of Contemporary Anthropology,SchoolofLifeSciences,FudanUniversity,Shanghai,China,3InstituteofCardiovascularDisease,GeneralHospitalofJinanMilitaryRegion,Jinan,China, 4Children’sHospitalofFudanUniversity,Shanghai,China,5SecondHospitalofAnhuiMedicalUniversity,Hefei,China,6TheInstitutesofBiomedicalSciences,Fudan University,Shanghai,China Abstract SMAD7isageneralantagonistofTGF-bsignalingandhasbeenfoundtobeinvolvedincardiogenesisinmousemodels,but itsroleinhumancongenitalheartdisease(CHD)hasyettobeinvestigated.ToexamineifSMAD7isassociatedwithCHD,we conductedacase-controlstudyintheHanChinesepopulation.Exon1andexon4ofSMAD7,whichencodethefunctional MH1andMH2domains,weredirectlysequencedin1,201sporadicCHDpatientsand1,116controlindividuals.Atotalof18 sequencevariationswereidentified.Twocommonvariantsrs3809922andrs3809923arelocatedatexon4ofSMAD7,and werefoundinstronglinkagedisequilibriumwitheachother(r2=0.93).Weanalyzedtheassociationofthesetwolociwith CHDin3independentsubgroupcase-controlstudies,andfoundthatinsomesubgroups,rs3809922andrs3809923were significantly associated with CHD through genetic model analysis. In the combined data set, TT genotype in rs3809922 significantlyincreasedtheriskofCHDcomparedwithCCandCT,whileGGgenotypeinrs3809923significantlyincreased theriskofCHDcomparedwithCCandCG,particularlyintherecessivemodel.Inaddition,haplotypeanalysesshowedthat haplotypeTGsignificantlyincreasedtheriskofCHD(P=6.961026);thisfindingsupportstheresultsfromtheanalysesbased onsinglelocus.Acc