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Journal of Peking University (Health Sciences) ›› 2024, Vol. 56 ›› Issue (3): 384-389. doi: 10.19723/j.issn.1671-167X.2024.03.002

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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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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

CLC Number: 

  • R195.4

Table 1

Exposure status among mothers of affected children during pregnancy"

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

Table 2

Gene-gene interaction analysis of TGF-β signaling pathway"

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

Table 3

Results of gene-environment interaction analysis of TGF-β signaling pathway"

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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