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北京大学学报（医学版） ›› 2024, Vol. 56 ›› Issue (3): 384-389. doi: 10.19723/j.issn.1671-167X.2024.03.002

• 论著 • 上一篇    下一篇

转化生长因子β信号通路与非综合征型唇腭裂发病风险的基因-基因及基因-环境交互作用

侯天姣1,2,周治波3,王竹青1,王梦莹2,4,王斯悦1,2,彭和香1,2,郭煌达1,2,李奕昕1,2,章涵宇1,2,秦雪英1,2,武轶群1,2,郑鸿尘1,李静5,吴涛1,2,*(),朱洪平3,*()   

  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. 重大疾病流行病学教育部重点实验室(北京大学)，北京 100191
    3. 北京大学口腔医院·口腔医院口腔颌面外科，国家口腔医学中心，国家口腔疾病临床医学研究中心，口腔生物材料和数字诊疗装备国家工程研究中心，口腔数字医学北京市重点实验室，国家卫生健康委员会口腔医学计算机应用工程技术研究中心，国家药品监督管理局口腔材料重点实验室，北京 100081
    4. 北京大学公共卫生学院营养与食品卫生学系，北京 100191
    5. 北京大学口腔医院·口腔医院儿童口腔科，国家口腔医学中心，国家口腔疾病临床医学研究中心，口腔生物材料和数字诊疗装备国家工程研究中心，口腔数字医学北京市重点实验室，国家卫生健康委员会口腔医学计算机应用工程技术研究中心，国家药品监督管理局口腔材料重点实验室，北京 100081
  • 收稿日期:2024-02-18 出版日期:2024-06-18 发布日期:2024-06-12
  • 通讯作者: 吴涛,朱洪平 E-mail:twu@bjmu.edu.cn;zhuhongping@cndent.com
  • 基金资助:
    国家自然科学基金(81573225)

Gene-gene/gene-environment interaction of transforming growth factor-β signaling pathway and the risk of non-syndromic oral clefts

Tianjiao HOU1,2,Zhibo ZHOU3,Zhuqing WANG1,Mengying WANG2,4,Siyue WANG1,2,Hexiang PENG1,2,Huangda GUO1,2,Yixin LI1,2,Hanyu ZHANG1,2,Xueying QIN1,2,Yiqun WU1,2,Hongchen ZHENG1,Jing LI5,Tao WU1,2,*(),Hongping ZHU3,*()   

  1. 1. Department of Epidemiology and Biostatistics, Peking University School of Public Health, Beijing 100191, China
    2. Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education, Beijing 100191, China
    3. Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, NHC Research Center of Engineering and Technology for Computerized Dentistry, NMPA Key Laboratory for Dental Materials, Beijing 100081, China
    4. Department of Nutrition and Food Hygiene, Peking University School of Public Health, Beijing 100191, China
    5. Department of Pediatric Dentistry, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing Key Laboratory of Digital Stomatology, NHC Research Center of Engineering and Technology for Computerized Dentistry, NMPA Key Laboratory for Dental Materials, Beijing 100081, China
  • Received:2024-02-18 Online:2024-06-18 Published:2024-06-12
  • Contact: Tao WU,Hongping ZHU E-mail:twu@bjmu.edu.cn;zhuhongping@cndent.com
  • Supported by:
    Supported by the National Natural Science Foundation of China(81573225)

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摘要：

目的: 探索亚裔人群中转化生长因子β(transforming growth factor-β，TGF-β)信号通路基因多态性与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)的关联及可能存在的基因-基因、基因-环境交互作用。方法: 选取1 038个NSCL/P核心家系作为研究对象。对TGF-β信号通路上的10个基因的343个单核苷酸多态性(single nucleotide polymorphism，SNP)位点进行了传递不平衡检验(transmission disequilibrium test，TDT)，采用条件Logistic回归模型进行基因-基因交互作用分析和基因-环境交互作用分析。研究收集的环境因素包括患儿母亲孕期吸烟、被动吸烟、乙醇摄入量以及维生素使用情况。由于患儿母亲孕期吸烟和饮酒暴露率较低(<3%)，因此，仅对母亲孕期被动吸烟及补充多种维生素这两个环境因素与基因之间的交互作用进行了分析。采用Bonferroni法对结果进行多重检验校正，显著性的阈值设置为P=1.46×10-4。结果: 共有4个基因的23个SNP位点与NSCL/P之间存在关联(P<0.05)，但经过Bonferroni多重检验校正后，这些关联均未达到统计学显著性水平。经过Bonferroni多重检验校正之后，6对SNP[rs4939874(SMAD2)与rs1864615(TGFBR2)，rs2796813(TGFB2)与rs2132298(TGFBR2)，rs4147358(SMAD3)与rs1346907(TGFBR2)，rs4939874(SMAD2)与rs1019855(TGFBR2)，rs4939874(SMAD2)与rs12490466(TGFBR2)，以及rs2009112(TGFB2)与rs4075748(TGFBR2)]存在显著的统计学交互作用(P<1.46×10-4)，基因-环境交互作用的分析没有达到多重检验校正阈值的显著结果。结论: 未发现TGF-β通路基因多态性与NSCL/P的关联，该通路上部分基因可能通过基因-基因交互作用影响NSCL/P的发病风险。未来仍需其他独立研究的证据支持，以进一步的探索其中潜在的生物学机制。

关键词: 非综合征型唇腭裂, 转化生长因子β信号通路, 全基因组关联研究, 核心家系

Abstract:

Objective: To explore the association between polymorphisms of transforming growth factor-β (TGF-β) signaling pathway and non-syndromic cleft lip with or without cleft palate (NSCL/P) among Asian populations, while considering gene-gene interaction and gene-environment interaction. Methods: A total of 1 038 Asian NSCL/P case-parent trios were ascertained from an international consortium, which conducted a genome-wide association study using a case-parent trio design to investigate the genes affec-ting risk to NSCL/P. After stringent quality control measures, 343 single nucleotide polymorphism (SNP) spanning across 10 pivotal genes in the TGF-β signaling pathway were selected from the original genome-wide association study(GWAS) dataset for further analysis. The transmission disequilibrium test (TDT) was used to test for SNP effects. The conditional Logistic regression models were used to test for gene-gene interaction and gene-environment interaction. Environmental factors collected for the study included smoking during pregnancy, passive smoking during pregnancy, alcohol intake during pregnancy, and vitamin use during pregnancy. Due to the low rates of exposure to smoking during pregnancy and alcohol consumption during pregnancy (<3%), only the interaction between maternal smoking during pregnancy and multivitamin supplementation during pregnancy was analyzed. The threshold for statistical significance was rigorously set at P =1.46×10-4, applying Bonferroni correction to account for multiple testing. Results: A total of 23 SNPs in 4 genes yielded nominal association with NSCL/P (P<0.05), but none of these associations was statistically significant after Bonferroni' s multiple test correction. However, there were 6 pairs of SNPs rs4939874 (SMAD2) and rs1864615 (TGFBR2), rs2796813 (TGFB2) and rs2132298 (TGFBR2), rs4147358 (SMAD3) and rs1346907 (TGFBR2), rs4939874 (SMAD2) and rs1019855 (TGFBR2), rs4939874 (SMAD2) and rs12490466 (TGFBR2), rs2009112 (TGFB2) and rs4075748 (TGFBR2) showed statistically significant SNP-SNP interaction (P<1.46×10-4). In contrast, the analysis of gene-environment interactions did not yield any significant results after being corrected by multiple testing. Conclusion: The comprehensive evaluation of SNP associations and interactions within the TGF-β signaling pathway did not yield any direct associations with NSCL/P risk in Asian populations. However, the significant gene-gene interactions identified suggest that the genetic architecture influencing NSCL/P risk may involve interactions between genes within the TGF-β signaling pathway. These findings underscore the necessity for further investigations to unravel these results and further explore the underlying biological mechanisms.

Key words: Non-syndromic cleft lip with or without cleft palate, Transforming growth factor-β signaling pathway, Genome-wide association study, Case-parent trio

中图分类号: 

  • R195.4

表1

母亲孕期环境因素暴露情况"

Exposure factor Exposed, n Unexposed, n Missing information, n Exposure rate/%
Smoking during pregnancy 29 1 007 2 2.80
Passive smoking during pregnancy 355 564 119 34.20
Alcohol consumption during pregnancy 21 1 004 13 2.00
Multivitamin supplementation during pregnancy 149 734 155 14.40

表2

TGF-β信号通路基因-基因交互作用分析"

Gene1 ChrGene1 Gene2 ChrGene2 SNP1 SNP2 MAF1 MAF2 LR P value Empirical P
SMAD2 18 TGFBR2 3 rs4939874 rs1864615 0.48 0.39 24.10 7.62×10-5 <0.01
TGFB2 1 TGFBR2 3 rs2796813 rs2132298 0.24 0.21 23.54 9.88×10-5 <0.01
SMAD3 15 TGFBR2 3 rs4147358 rs1346907 0.41 0.34 23.25 1.13×10-4 <0.01
SMAD2 18 TGFBR2 3 rs4939874 rs1019855 0.48 0.38 23.02 1.25×10-4 <0.01
SMAD2 18 TGFBR2 3 rs4939874 rs12490466 0.48 0.38 23.02 1.25×10-4 <0.01
TGFB2 1 TGFBR2 3 rs2009112 rs4075748 0.14 0.37 22.77 1.40×10-4 <0.01

表3

TGF-β信号通路基因-环境交互作用分析结果"

Chromosome Gene SNP Position MAF χ2 P(TDT) LR (1df) P(LRT 1df) LR (2df) P(LRT 2df)
Passive smoking during pregnancy
18 SMAD2 rs3813071 43411179 0.27 4.14 0.04 12.75 3.57×10-4 16.86 2.18×10-4
18 SMAD2 rs8083993 43402114 0.27 4.48 0.03 11.82 5.87×10-4 16.65 2.40×10-4
15 SMAD3 rs16950543 65130135 0.16 1.38 0.24 11.68 6.30×10-4 12.92 1.56×10-3
18 SMAD2 rs10853557 43467495 0.26 5.04 0.02 11.64 6.40×10-4 16.72 2.30×10-4
3 TGFBR2 rs1461084 30724669 0.39 2.03 0.15 10.62 1.12×10-3 12.69 1.75×10-3
18 SMAD2 rs8089400 43417118 0.39 4.30 0.04 9.17 2.46×10-3 13.30 1.30×10-3
18 SMAD2 rs1995415 43429400 0.39 4.30 0.04 9.01 2.69×10-3 12.99 1.51×10-3
18 SMAD2 rs905313 43461891 0.34 3.72 0.05 7.88 4.99×10-3 12.44 1.98×10-3
15 SMAD3 rs2053295 65178793 0.12 0.00 0.96 7.86 5.04×10-3 7.94 1.88×10-2
3 TGFBR2 rs3773663 30705876 0.47 0.25 0.62 7.47 6.27×10-3 7.65 2.18×10-2
15 SMAD3 rs2053294 65186138 0.10 0.03 0.87 7.09 7.74×10-3 7.10 2.88×10-2
15 SMAD3 rs17293443 65224917 0.07 0.00 1.00 6.74 9.41×10-3 6.83 3.29×10-2
15 SMAD3 rs920293 65201479 0.08 0.38 0.54 5.13 2.35×10-2 6.04 4.88×10-2
12 DCN rs1389057 90251542 0.41 4.15 0.04 4.21 4.01×10-2 9.47 8.77×10-3
Multivitamin supplementation during pregnancy
12 DCN rs7960169 90360991 0.05 0.21 0.64 10.04 1.53×10-3 10.28 5.87×10-3
12 DCN rs7974879 90360968 0.05 0.29 0.59 9.81 1.73×10-3 10.13 6.31×10-3
10 BAMBI rs2065693 29035015 0.27 1.13 0.29 4.59 3.22×10-2 6.73 3.46×10-2
18 SMAD2 rs1792658 43636603 0.48 3.34 0.07 4.53 3.32×10-2 8.07 1.77×10-2
3 TGFBR2 rs13075948 30658510 0.04 1.71 0.19 4.22 4.00×10-2 6.06 4.84×10-2
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ISSN 1671-167X
CN 11-4691/R
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