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北京大学学报（医学版） ›› 2020, Vol. 52 ›› Issue (5): 815-820. doi: 10.19723/j.issn.1671-167X.2020.05.004

• 论著 • 上一篇    下一篇

WNT代谢通路相关基因与中国人群非综合征型唇腭裂发病风险的交互作用

王梦莹1,李文咏1,周仁1,王斯悦1,刘冬静1,郑鸿尘1,李静2,李楠3,周治波3,朱洪平3,吴涛1,∆(),胡永华1   

  1. 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,儿童口腔科 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.北京大学口腔医学院·口腔医院颌面外科,北京 100081
  • 收稿日期:2018-07-10 出版日期:2020-10-18 发布日期:2020-10-15
  • 通讯作者: 吴涛 E-mail:twu@bjmu.edu.cn
  • 基金资助:
    国家自然科学基金(81102178);国家自然科学基金(81573225);北京市自然科学基金(7172115)

Evaluating the effect of WNT pathway genes considering interactions on the risk of non-syndromic oral clefts among Chinese populations

Meng-ying WANG1,Wen-yong LI1,Ren ZHOU1,Si-yue WANG1,Dong-jing LIU1,Hong-chen ZHENG1,Jing LI2,Nan LI3,Zhi-bo ZHOU3,Hong-ping ZHU3,Tao WU1,∆(),Yong-hua HU1   

  1. 1. Department of Epidemiology and Biostatistics, Peking University School of Public Health, Beijing 100191, China
    2. Department of Pediatric Dentistry, 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
    3. Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing 100081, China
  • Received:2018-07-10 Online:2020-10-18 Published:2020-10-15
  • Contact: Tao WU E-mail:twu@bjmu.edu.cn
  • Supported by:
    National Natural Science Foundation of China(81102178);National Natural Science Foundation of China(81573225);Beijing Municipal Natural Science Foundation(7172115)

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摘要：

目的:利用全基因组关联研究(genome-wide association study,GWAS)数据,从基因-基因交互作用和基因-环境交互作用方面探索WNT代谢通路相关基因在中国人群非综合征型唇腭裂(non-syndromic oral clefts,NSOC)发生风险中的作用。方法:本研究样本来自“唇腭裂基因和交互作用的国际合作研究”项目在中国地区募集的806个非综合征型唇裂合并或不合并腭裂(non-syndromic cleft lip with or without cleft palate,NSCL/P)核心家系和202个非综合征型单纯腭裂(non-syndromic cleft palate,NSCP)核心家系。通过收集研究对象的DNA样本和问卷调查获得基因型数据和母亲孕期环境暴露信息,利用此GWAS数据,采用条件Logistic回归模型探讨基因-基因交互作用和基因-环境交互作用,由R软件中的trio软件包完成。经过Bonferroni多重检验校正后,统计学检验的显著性阈值均设为P<3.47×10-4。结果:经过数据质量控制后,NSCL/P核心家系和NSCP核心家系各纳入7个基因上的144个单核苷酸多态性(single nucleotide polymorphisms, SNPs)位点进入分析。在NSCL/P和NSCP家系中,分别有三对SNPs交互作用达到统计学显著性水平(P<3.47×10-4):rs7618735(WNT5A)与rs10848543(WNT5B),rs631948(WNT11)与rs556874(WNT5A)以及rs631948(WNT11)与rs472631(WNT5A);rs589149(WNT11)与rs4765834(WNT5B),rs1402704(WNT11)与rs358792(WNT5A)以及rs1402704(WNT11)与rs358793(WNT5A)。此外,基因-环境交互作用分析未发现显著结果。结论:未发现WNT代谢通路相关基因-环境交互作用在NSCL/P和NSCP发病风险中的作用,但WNT代谢通路相关基因可能通过基因-基因交互作用影响NSOC的发病风险。

关键词: 非综合征型唇腭裂, 全基因组关联研究, WNT信号通路

Abstract:

Objective: In this study, we used genome-wide association study (GWAS) data to explore whether WNT pathway genes were associated with non-syndromic oral clefts (NSOC) considering gene-gene interaction and gene-environment interaction. Methods: We conducted the analysis using 806 non-syndromic cleft lip with or without cleft palate (NSCL/P) case-parent trios and 202 non-syndromic cleft palate (NSCP) case-parent trios among Chinese populations selected from an international consortium established for a GWAS of non-syndromic oral clefts. Genotype data and maternal environmental exposures were collected through DNA samples and questionnaires. Conditional Logistic regression models were adopted to explore gene-gene interaction and gene-environment interaction using trio package in R software. The threshold of significance level was set as 3.47×10-4 using Bonferroni correction. Results: A total of 144 single nucleotide polymorphisms (SNPs) in seven genes passed the quality control process in NSCL/P trios and NSCP trios, respectively. Totally six pairs of SNPs interactions showed statistically significant SNP-SNP interaction (P<3.47×10-4) after Bonferroni correction, which were rs7618735 (WNT5A) and rs10848543 (WNT5B), rs631948 (WNT11) and rs556874 (WNT5A), and rs631948 (WNT11) and rs472631 (WNT5A) among NSCL/P trios; rs589149 (WNT11) and rs4765834 (WNT5B), rs1402704 (WNT11) and rs358792 (WNT5A), and rs1402704 (WNT11) and rs358793 (WNT5A) among NSCP trios, respectively. In addition, no significant result was found for gene-environment interaction analysis in both of the NSCL/P trios and NSCP trios. Conclusion: Though this study failed to detect significant association based on gene-environment interactions of seven WNT pathway genes and the risk of NSOC, WNT pathway genes may influence the risk of NSOC through potential gene-gene interaction.

Key words: Non-syndromic oral clefts, Genome-wide association studies, WNT signaling pathway

中图分类号: 

  • R181.33

表1

中国人群NSOC核心家系数目分布情况"

Site Male Female Total
CL/P CP CL/P CP
Taiwan 139 29 94 50 312
Shandong 193 16 81 22 312
Hubei 132 19 55 26 232
Sichuan 75 18 37 22 152
Total 539 82 267 120 1 008

表2

NSOC家系中WNT家族基因信息"

Subtypes Gene Chromosome Number of SNPs
NSCL/P WNT3 17 7
WNT3A 1 8
WNT5A 3 45
WNT5B 12 28
WNT9A 1 13
WNT9B 17 9
WNT11 11 34
Total 144
NSCP WNT3 17 7
WNT3A 1 7
WNT5A 3 46
WNT5B 12 28
WNT9A 1 13
WNT9B 17 9
WNT11 11 34
Total 144

表3

基因-基因交互作用分析结果"

Subtypes Gene1 SNP1 MAF1 P1 Gene2 SNP2 MAF2 P2 Pinteraction RR Empirical P
NSCL/P WNT5A rs7618735 0.153 0.250 WNT5B rs10848543 0.268 0.355 2.66×10-4 1.01 2.00×10-4
WNT11 rs631948 0.360 0.601 WNT5A rs556874 0.318 0.540 3.10×10-4 1.06 3.00×10-4
WNT11 rs631948 0.360 0.601 WNT5A rs472631 0.321 0.441 3.42×10-4 1.07 4.00×10-4
NSCP WNT11 rs589149 0.444 0.940 WNT5B rs4765834 0.306 0.153 1.08×10-4 1.19 1.00×10-4
WNT11 rs1402704 0.434 0.178 WNT5A rs358792 0.273 0.502 1.37×10-4 1.10 1.00×10-4
WNT11 rs1402704 0.434 0.178 WNT5A rs358793 0.275 0.452 1.71×10-3 1.56 1.00×10-4
[1] Cooper ME, Ratay JS, Marazita ML. Asian oral-facial cleft birth prevalence[J]. Cleft Palate Craniofac J, 2006,43(5):580-589.
doi: 10.1597/05-167 pmid: 16986997
[2] Wang M, Yuan Y, Wang Z, et al. Prevalence of orofacial clefts among live births in China: A systematic review and meta-analysis[J]. Birth Defects Res, 2017,109(13):1011-1019.
pmid: 28635078
[3] Leslie EJ, Marazita ML. Genetics of cleft lip and cleft palate[J]. Am J Med Genet C Semin Med Genet, 2013,163C(4):246-258.
doi: 10.1002/ajmg.c.31381 pmid: 24124047
[4] Mangold E, Ludwig KU, Nothen MM, Breakthroughs in the gene-tics of orofacial clefting[J]. Trends Mol Med, 2011,17(12):725-733.
doi: 10.1016/j.molmed.2011.07.007 pmid: 21885341
[5] Beaty TH, Marazita ML, Leslie EJ. Genetic factors influencing risk to orofacial clefts: Today’s challenges and tomorrow’s opportunities[J]. F1000Res, 2016,5:2800.
doi: 10.12688/f1000research.9503.1 pmid: 27990279
[6] Leslie EJ, Carlson JC, Shaffer JR, et al. Association studies of low-frequency coding variants in nonsyndromic cleft lip with or without cleft palate[J]. Am J Med Genet A, 2017,173(6):1531-1538.
doi: 10.1002/ajmg.a.38210 pmid: 28425186
[7] Mani P, Jarrell A, Myers J, et al. Visualizing canonical Wnt signaling during mouse craniofacial development[J]. Dev Dyn, 2010,239(1):354-363.
doi: 10.1002/dvdy.22072 pmid: 19718763
[8] Lan Y, Ryan R, Zhang Z, et al. Expression of Wnt9b and activation of canonical Wnt signaling during midfacial morphogenesis in mice[J]. Dev Dyn, 2006,235(5):1448-1454.
doi: 10.1002/dvdy.20723 pmid: 16496313
[9] Chiquet BT, Blanton SH, Burt A, et al. Variation in WNT genes is associated with nonsyndromic cleft lip with or without cleft palate[J]. Hum Mol Genet, 2008,17(14):2212-2218.
doi: 10.1093/hmg/ddn121 pmid: 18413325
[10] Menezes R, Letra A, Kim AH, et al. Studies with Wnt genes and nonsyndromic cleft lip and palate[J]. Birth Defects Res A Clin Mol Teratol, 2010,88(11):995-1000.
doi: 10.1002/bdra.20720 pmid: 20890934
[11] 刘小俊, 周小平, 崔毓贵, 等. WNT5A基因rs566926多态性与中国苏皖地区部分人群非综合征性唇腭裂的相关性[J]. 江苏医药, 2010,36(13):1495-1498.
[12] Yao T, Yang L, Li PQ, et al. Association of Wnt3A gene variants with non-syndromic cleft lip with or without cleft palate in Chinese population[J]. Arch Oral Biol, 2011,56(1):73-78.
doi: 10.1016/j.archoralbio.2010.09.002
[13] Beaty TH, Murray JC, Marazita ML, et al. A genome-wide asso-ciation study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4[J]. Nat Genet, 2010,42(6):525-529.
doi: 10.1038/ng.580 pmid: 20436469
[14] Beaty TH, Ruczinski I, Murray JC, et al. Evidence for gene-environment interaction in a genome wide study of isolated, non-syndromic cleft palate[J]. Genet Epidemiol, 2011,35(6):469-478.
doi: 10.1002/gepi.20595
[15] Cordell HJ. Epistasis: What it means, what it doesn’t mean, and statistical methods to detect it in humans[J]. Hum Mol Genet, 2002,11(20):2463-2468.
doi: 10.1093/hmg/11.20.2463 pmid: 12351582
[16] Christensen K, Juel K, Herskind AM, et al. Long term follow up study of survival associated with cleft lip and palate at birth[J]. BMJ, 2004,328(7453):1405-1408.
doi: 10.1136/bmj.38106.559120.7C pmid: 15145797
[17] Zhu JL, Basso O, Hasle H, et al. Do parents of children with congenital malformations have a higher cancer risk? A nationwide study in Denmark[J]. Br J Cancer, 2002,87(5):524-528.
doi: 10.1038/sj.bjc.6600488 pmid: 12189550
[18] Mangold E, Ludwig KU, Birnbaum S, et al. Genome-wide association study identifies two susceptibility loci for nonsyndromic cleft lip with or without cleft palate[J]. Nat Genet, 2010,42(1):24-26.
doi: 10.1038/ng.506 pmid: 20023658
[19] Birnbaum S, Ludwig KU, Reutter H, et al. Key susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24[J]. Nat Genet, 2009,41(4):473-477.
doi: 10.1038/ng.333 pmid: 19270707
[20] Grant SF, Wang K, Zhang H, et al. A genome-wide association study identifies a locus for nonsyndromic cleft lip with or without cleft palate on 8q24[J]. J Pediatr, 2009,155(6):909-913.
doi: 10.1016/j.jpeds.2009.06.020 pmid: 19656524
[21] Sun Y, Huang Y, Yin A, et al. Genome-wide association study identifies a new susceptibility locus for cleft lip with or without a cleft palate[J]. Nat Commun, 2015(6):6414.
[22] Leslie EJ, Carlson JC, Shaffer JR, et al. A multi-ethnic genome-wide association study identifies novel loci for non-syndromic cleft lip with or without cleft palate on 2p24.2, 17q23 and 19q13[J]. Hum Mol Genet, 2016,25(13):2862-2872.
doi: 10.1093/hmg/ddw104 pmid: 27033726
[23] Yu Y, Zuo X, He M, et al. Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic hete-rogeneity[J]. Nat Commun, 2017(8):14364.
[24] Xiao Y, Taub MA, Ruczinski I, et al. Evidence for SNP-SNP interaction identified through targeted sequencing of cleft case-parent trios[J]. Genet Epidemiol, 2017,41(3):244-250.
doi: 10.1002/gepi.22023 pmid: 28019042
[25] Li Q, Kim Y, Suktitipat B, et al. Gene-gene interaction among Wnt genes for oral cleft in trios[J]. Genet Epidemiol, 2015,39(5):385-394.
doi: 10.1002/gepi.21888 pmid: 25663376
[26] Letra A, Fakhouri W, Fonseca RF, et al. Interaction between IRF6 and TGFA genes contribute to the risk of nonsyndromic cleft lip/palate[J]. PLoS One, 2012,7(9):e45441.
doi: 10.1371/journal.pone.0045441 pmid: 23029012
[27] 张玉. TGFα、Wnt3基因多态性和环境因素的交互作用与非综合征型唇腭裂的关系研究[D]. 武汉: 华中科技大学, 2013.
[28] 俞辉明, 程宏宇, 房进. 环境暴露和FGF18、WNT5A基因多态性与NSCL/P的关系[J]. 广东医学, 2011,32(5):588-590.
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