Functional Haplotypes of the hTERT Gene, Leukocyte Telomere Length Shortening, and the Risk of Peripheral Arterial Disease 英文参考文献.docVIP

FunctionalHaplotypesofthehTERTGene,Leukocyte TelomereLengthShortening,andtheRiskofPeripheral ArterialDisease WeiliZhang1*,YuChen1,XiaominYang2,JingyaoFan1,XuenanMi1,JizhengWang1,ChannaZhang1, FrankB.Hu3,RutaiHui1 1Sino-GermanLaboratoryforMolecularMedicine,theStateKeyLaboratoryofCardiovascularDisease,FuWaiHospital,NationalCenterforCardiovascularDisease,Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, 2The Second Affiliated Hospital of Baotou Medical College, Baotou City, China, 3DepartmentofNutritionandEpidemiology,HarvardSchoolofPublicHealth,Boston,Massachusetts,UnitedStatesofAmerica Abstract Background: The developmentofperipheral arterialdisease(PAD) isheterogeneouseveninthepresenceofsimilar risk factors. Our aim was to determine whether inter-individual differences in leukocyte telomere length contribute to the susceptibilityofPAD. Methods:Atotalof485patientswithPAD(definedbytheankle-brachialindex)and970age-andgender-matchedcontrols were recruited from seven rural communities in Henan Province in China. The relative leukocyte telomere length was determinedbyaquantitativePCR-basedmethod.TwocommonpromotervariantsofthehTERTgeneweregenotypedto assess their effects on telomere length and the risk of PAD. In vivo luciferase assay was performed to study the transcriptionalactivity. Results: After adjustment for vascular risk factors and genetic variants in the hTERT gene, individuals in the lowest and middletertilesoftelomerelengthhadasignificantlyhigherriskofPADthandidthoseinthehighesttertile(oddsratio[OR] 1.73, 95% confidence interval [CI] 1.29–2.49 in the middle tertile; 3.15, 95%CI 2.31–4.29 in the lowest tertile). Haplotype analysisusingthe2variants(rs2735940andrs2853669)showedthatsubjectswiththeat-riskC-Chaplotypehadshorter telomerelengththanthoseindividualswiththeT-Thaplotypeandconsistentlyhad1.30-fold(OR1.30,95%CI1.06–1.58; P=0.005)increasedriskforPAD.TheC-Chaplotypehad43%loweredtranscriptionactivityofhTERTpromoter(P,0.