Wang Yiru, Shi Jiayu, Zheng Qian, Shi Bing, Jia Zhonglin
State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, Department of Cleft Lip and Palate, West China Hospital of Stomatology, Sichuan University Chengdu, China.
Division of Growth, Development and Section of Orthodontics, School of Dentistry, University of California Los Angeles, USA.
Int J Clin Exp Pathol. 2020 Feb 1;13(2):295-301. eCollection 2020.
Genome-wide association studies (GWAS) have found more than 20 genes associated with a risk of non-syndromic cleft lip with or without cleft palate (NSCL/P). However, the interactions between these risk genes have been rarely reported.
Here we selected 47 Single Nucleotide Polymorphisms (SNP) from previous GWASs and tested for possible interactions among 302 NSCL/P case-parent trios from a western Han Chinese population to further explore the genetic etiology of NSCL/P. Conditional logistic regression models were performed including gene-gene (G×G) interaction.
Twenty pairwise interactions yielded significant -values. Most of the signals of interaction between the SNPs were detected at the same gene including v-maf musculoaponeurotic fibrosarcoma oncogene family, protein B (MAFB), netrin 1 (NTN1), and single nucleotide polymorphic marker within interferon regulatory factor 6 (IRF6). We found evidence of the interaction between rs17563 (bone morphogenetic protein 4, BMP4) and rs560426 (subfamily A member 4/Rho GTPase activating protein 29, ARHGAP29) (P=0.00093) in NSCLO trios.
Gene-gene interaction between markers in BMP4 and ARHGAP29 may influence the risk of NSCLO in western Han Chinese population, which might explain the missing heritability for NSCL/P.
全基因组关联研究（GWAS）已发现20多个与非综合征性唇裂伴或不伴腭裂（NSCL/P）风险相关的基因。然而，这些风险基因之间的相互作用鲜有报道。
我们从先前的GWAS中选取了47个单核苷酸多态性（SNP），并对来自西汉汉族人群的302个NSCL/P病例-亲代三联体进行了可能的相互作用测试，以进一步探索NSCL/P的遗传病因。进行了条件逻辑回归模型分析，包括基因-基因（G×G）相互作用。
20对相互作用产生了显著的P值。SNP之间的大多数相互作用信号在同一基因中被检测到，包括v-maf肌腱膜纤维肉瘤癌基因家族蛋白B（MAFB）、netrin 1（NTN1）以及干扰素调节因子6（IRF6）内的单核苷酸多态性标记。我们在NSCLO三联体中发现了rs17563（骨形态发生蛋白4，BMP4）和rs560426（A亚家族成员4/ Rho GTP酶激活蛋白29，ARHGAP29）之间相互作用的证据（P = 0.00093）。
BMP4和ARHGAP29中标记之间的基因-基因相互作用可能影响西汉汉族人群中NSCLO的风险，这可能解释了NSCL/P遗传度缺失的问题。
