中国人群Hedgehog通路基因与非综合征型唇腭裂的亲源效应  

Exploring parent-of-origin effects for non-syndromic cleft lip with or without cleft palate on PTCH1,PTCH2,SHH,SMO genes in Chinese case-parent trios

作　　者：李文咏 王梦莹[1] 周仁 王斯悦 郑鸿尘 朱洪平[2] 周治波[2] 吴涛[1,3] 王红[1] 石冰[4] LI Wen-yong;WANG Meng-ying;ZHOU Ren;WANG Si-yue;ZHENG Hong-chen;ZHU Hong-ping;ZHOU Zhi-bo;WU Tao;WANG Hong;SHI Bing(Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China;Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing 100081, China;Key Laboratory of Reproductive Health, Ministry of Health, Beijing 100191, China;Department of Oral and Maxillofacial Surgery, State Key Laboratory of Oral Disease, West China College of Stomatology, Sichuan University, Chengdu 610041, China)

机构地区：[1]北京大学公共卫生学院流行病与卫生统计学系,北京100191 [2]北京大学口腔医学院·口腔医院,口腔颌面外科,国家口腔疾病临床医学研究中心,口腔数字化医疗技术和材料国家工程实验室,口腔数字医学北京市重点实验室,北京100081 [3]卫生部生育健康重点实验室,北京100191 [4]四川大学华西口腔医学院口腔颌面外科,口腔疾病研究国家重点实验室,成都610041

出　　处：《北京大学学报（医学版）》2020年第5期809-814,共6页Journal of Peking University:Health Sciences

基　　金：国家自然科学基金(81102178,81573225);北京市自然科学基金(7172115);北京大学医学交叉研究基金(BMU2017MX018)。

摘　　要：目的:探索非综合征型唇腭裂(non-syndromic cleft lip with or without cleft palate,NSCL/P)这一类常见出生缺陷的可能致病机制,在Hedgehog(HH)通路基因中(PTCH1、PTCH2、SHH、SMO)探索基因多态性对NSCL/P的关联关系以及亲源效应(parent-of-origin effects,PoO)对NSCL/P发病风险的影响。方法:纳入806个中国非综合征型唇腭裂核心家系,对HH通路基因(PTCH1、PTCH2、SHH、SMO)的83个单核苷酸多态性位点(single nucleotide polymorphisms,SNPs)进行传递不平衡检验(transmission disequilibrium test,TDT),并采用对数线性模型进行亲源效应分析。家系样本来自“唇腭裂基因和交互作用的国际合作研究”项目。采用Plink进行TDT检验;通过R软件中的Haplin v6.2.1软件包开展亲源效应分析。采用Bonferroni法进行多重检验校正。结果:经过质量控制,共纳入65个SNPs进行分析,Bonferroni显著性水平为7.7×10^-4(0.05/65)。未校正P值前,关联分析发现rs4448343与NSCL/P存在关联(P=0.023),6个单体型(rs10512249-rs4448343、rs1461208-rs7786445、rs10512249-rs4448343、rs16909865-rs10512249-rs4448343、rs1461208-rs7786445-rs12698335、rs288756-rs288758-rs1151790)与NSCL/P存在关联(P<0.05);6个单体型(rs288765-rs1233563、rs12537550-rs11765352、rs872723-rs288765-rs1233563、rs288765-rs1233563-rs288756、rs6459952-rs12537550-rs11765352、rs12537550-rs11765352-rs6971211)具有潜在的PoO效应(P<0.05)。以上结果经过多重检验校正,均无统计学意义(P>7.7×10^-4)。结论:未发现HH通路基因多态性与NSCL/P的关联,未发现HH通路基因通过PoO效应影响NSCL/P发病风险。Objective:Non-syndromic cleft lip with or without cleft palate(NSCL/P)is a common birth defect,affecting 1.4 per 1000 live births,and multiple genetic and environmental risk factors influencing its risk.All the known genetic risk factors accounted for a small proportion of the heritability.Several authors have suggested parent-of-origin effects(PoO)may play an important role in the etiology of this complex and heterogeneous malformation.To clarify the genetic association between PTCH1,PTCH2,SHH and SMO in hedgehog(HH)pathway and NSCL/P,as well as testing for potential PoO effects in Chinese case-parent trios.Methods:We tested for transmission disequilibrium tests(TDT)and PoO effects using 83 common single nucleotide polymorphic(SNP)markers of HH pathway genes from 806 NSCL/P case-parent trios.These trios were drawn from an international consortium established for a genome-wide association studies(GWAS)of non-syndromic oral clefts of multiple ethnicities.DNA samples were collected from each trio.Single marker and haplotype based analysis were performed both in TDT tests and PoO effects.SNPs were excluded if they(i)had a call rate of<95%,(ii)had a minor allele frequency(MAF)of<0.05,(iii)had Mendelian errors over all trios of>5%,(iv)had a genotype distribution in the parents that deviated from the Hardy-Weinberg equilibrium(HWE)(P<0.0001).The process was done using Plink(version 1.07,http://pngu.mgh.harvard.edu/~purcell/plink/data.shtml).TDT test was performed in Plink v1.07.A log-linear model was used to explore PoO effects using Haplin v6.2.1 as implemented in R package v3.4.2.Significance level was assessed using the Bonferroni correction.Results:A total of 18 SNPs were dropped due to low MAF,thus leaving 65 SNPs available for the analysis.Thus the Bonferroni threshold was 7.7×10^-4(0.05/65).Nominal significant association with NSCL/P was found at a SNP(rs4448343 in PTCH1,P=0.023)and six haplotypes(rs10512249-rs4448343,rs1461208-rs7786445,rs10512249-rs4448343,rs16909865-rs10512249-rs4448343,rs1461208-rs7786445-r

关 键 词：亲源效应 非综合征型唇腭裂 HH通路基因 

分 类 号：R394[医药卫生—医学遗传学]