Wang Siyue, Shi Jiayu, Liu Chunfang, Wang Ping, Wang Mengying, Li Wenyong, Zhou Ren, Zheng Hongchen, Jiang Jin, Li Nan, Li Jing, Zhou Zhibo, Zhu Hongping, Wu Yiqun, Jia Zhonglin, Wu Tao, Hu Yonghua, Beaty Terri H
Peking University Health Science Center, Beijing, China.
Division of Growth and Development and Section of Orthodontics, School of Dentistry, University of California, Los Angeles, USA.
Oral Dis. 2023 Apr;29(3):1080-1088. doi: 10.1111/odi.14068. Epub 2021 Nov 18.
The folate-mediated one-carbon metabolism pathway is thought to play an important role in the etiology of non-syndromic oral clefts (NSOFC), although none of the genes in this pathway has shown significant signals in genome-wide association studies (GWAS). Recent evidence indicated that enhanced understanding could be gained by aggregating multiple SNPs effect simultaneously into polygenic risk score (PRS) to assess its association with disease risks. This study is aimed to assess the association between the genetic effect of folate-mediated one-carbon metabolism pathway and NSOFC risks using PRS based on a case-parent trio design. A total of 297 SNPs mapped from 18 genes in the folate-mediated one-carbon metabolism pathway were aggregated from a GWAS of 2458 case-parent trios recruited from an international consortium. We found a PRS based on the folate-mediated one-carbon metabolism pathway was significant among all NSOFC trios (OR = 1.95, 95% CI: 1.66-2.28, p = 2.39 × 10 ), as well as two major subtypes, non-syndromic cleft lip with or without cleft palate (NSCL/P) trios (OR = 1.71, 95% CI: 1.50-1.96, p = 7.66 × 10 ) and non-syndromic cleft palate only (NSCPO) trios (OR = 1.51, 95% CI: 1.36-1.68, p = 2.1 × 10 ). Similar results were also observed in further subgroup analyses stratified into Asian and European trios. The averaged PRS of the folate-mediated one-carbon metabolism pathway varied between the NSOFC case group and its comparison group (p < 0.05) with higher average PRS in the cases. Moreover, the top 5% pathway PRS group had 2.25 (95% CI: 1.85-2.73) times increased NSOFC risk, also 3.09 (95% CI: 2.50-3.81) and 2.06 (95% CI: 1.39-3.02) times increased risk of NSCL/P and NSCPO compared to the remainder of the distribution. The results of our study confirmed the folate-mediated one-carbon metabolism pathway was important in controlling risk to NSOFC and this study enhanced evidence towards understanding the genetic risks of NSOFC.
叶酸介导的一碳代谢途径被认为在非综合征性口腔颌面部裂隙（NSOFC）的病因学中起重要作用，尽管该途径中的基因在全基因组关联研究（GWAS）中均未显示出显著信号。最近的证据表明，通过将多个单核苷酸多态性（SNP）效应同时汇总到多基因风险评分（PRS）中以评估其与疾病风险的关联，可以获得更深入的理解。本研究旨在基于病例-父母三联体设计，使用PRS评估叶酸介导的一碳代谢途径的遗传效应与NSOFC风险之间的关联。从一个国际财团招募的2458个病例-父母三联体的GWAS中汇总了叶酸介导的一碳代谢途径中18个基因的297个SNP。我们发现，基于叶酸介导的一碳代谢途径的PRS在所有NSOFC三联体中具有显著性（比值比[OR]=1.95，95%置信区间[CI]：1.66-2.28，p=2.39×10），在两种主要亚型中也具有显著性，即伴有或不伴有腭裂的非综合征性唇裂（NSCL/P）三联体（OR=1.71，95%CI：1.50-1.96，p=7.66×10）和仅非综合征性腭裂（NSCPO）三联体（OR=1.51，95%CI：1.36-1.68，p=2.1×10）。在进一步按亚洲和欧洲三联体分层的亚组分析中也观察到了类似结果。叶酸介导的一碳代谢途径的平均PRS在NSOFC病例组与其对照组之间存在差异（p<0.05），病例组的平均PRS更高。此外，PRS最高的5%途径组的NSOFC风险增加了2.25倍（95%CI：1.85-2.73），与分布的其余部分相比，NSCL/P和NSCPO的风险也分别增加了3.09倍（95%CI：2.50-3.81）和2.06倍（95%CI：1.39-3.02）。我们的研究结果证实了叶酸介导的一碳代谢途径在控制NSOFC风险方面很重要，并且本研究为理解NSOFC的遗传风险提供了更多证据。
