School of Public Health, Peking University, Beijing, China.
Department of Statistics and Information, Beijing Center for Disease Prevention and Control & Beijing Research Center for Preventive Medicine, Beijing, China.
Oral Dis. 2018 Jul;24(5):820-828. doi: 10.1111/odi.12831. Epub 2018 Apr 24.
Little consistent evidence is available for the association between the risk of non-syndromic cleft lip with or without cleft palate (NSCL/P) and any of the individual genes in the folate/homocysteine metabolic pathway. We investigated the genes in the folate pathway to further clarify its potential influence on the risk of NSCL/P considering gene-gene (G×G) interaction.
We selected markers in 18 genes from the pathway and applied Cordell's method to test for G×G interaction using 1,908 NSCL/P case-parent trios ascertained in an international consortium where a genomewide association study (GWAS) of oral clefts was conducted.
We found intriguing signals among Asian and European ancestry groups for G×G interaction between markers in betaine-homocysteine methyltransferase gene (BHMT/BHMT2) and dimethylglycine dehydrogenase gene (DMGDH) attaining genomewide significance. In the pooled data, the top significant interaction was found between rs13158309 (BHMT) and rs10514154 (DMGDH, p = 1.45 × 10 ).
Our study illustrated the importance of taking into account potential G×G interaction for genetic association analysis in NSCL/P, and this study suggested both BHMT/BHMT2 and DMGDH should be considered as candidate genes for NSCL/P in future studies.
关于叶酸/同型半胱氨酸代谢途径中单个基因与非综合征性唇裂伴或不伴腭裂（NSCL/P）风险之间的关联，目前仅有少量一致性证据。我们研究了叶酸途径中的基因，以进一步阐明其对 NSCL/P 风险的潜在影响，同时考虑基因-基因（G×G）相互作用。
我们从该途径中选择了 18 个基因中的标记物，并应用 Cordell 方法，利用在一个国际联合组织中确定的 1908 个 NSCL/P 病例-父母三体型，来检测基因-基因（G×G）相互作用，该联合组织开展了口腔裂的全基因组关联研究（GWAS）。
我们在亚洲和欧洲血统群体中发现了有趣的信号，提示甜菜碱-同型半胱氨酸甲基转移酶基因（BHMT/BHMT2）和二甲基甘氨酸脱氢酶基因（DMGDH）中的标记物之间存在 G×G 相互作用，达到全基因组显著水平。在汇总数据中，发现 rs13158309（BHMT）和 rs10514154（DMGDH，p=1.45×10）之间存在最显著的相互作用。
我们的研究说明了在 NSCL/P 的遗传关联分析中考虑潜在 G×G 相互作用的重要性，本研究表明 BHMT/BHMT2 和 DMGDH 都应在未来的研究中被视为 NSCL/P 的候选基因。
