Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología, Universidad de Chile, Sergio Livingstone #943, Santiago, Chile.
Departamento de Nutrición, Diabetes y Metabolismo, Escuela de Medicina, Pontificia Universidad Católica de Chile, Lira #44, Santiago, Chile.
Arch Oral Biol. 2018 Jul;91:91-95. doi: 10.1016/j.archoralbio.2018.04.009. Epub 2018 Apr 18.
Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a birth defect for which several genes susceptibility genes been proposed. Consequently, it has been suggested that many of these genes belong to common inter-related pathways during craniofacial development gene-gene interaction. We evaluated the presence of gene-gene interaction for single nucleotide polymorphisms within interferon regulatory factor 6 (IRF6), muscle segment homeobox 1 (MSX1), bone morphogenetic protein 4 (BMP4) and transforming growth factor 3 (TGFB3) genes in NSCL/P risk in Chilean case-parent trios.
From previous studies, we retrieved genotypes for 13 polymorphic variants within these four genes in 152 case-parent trios. Using the trio package (R) we evaluate the gene-gen interaction in genetic markers pairs applying a 1°-of-freedom test (1df) and a confirmatory 4°-of-freedom (4df) test for epistasis followed by both a permutation test and a Benjamini-Hochberg test for multiple comparisons adjustment.
We found evidence of gene-gene interaction for rs6446693 (MSX1) and rs2268625 (TGFB3) (4df p = 0.024; permutation p = 0.015, Benjamini-Hochberg p = 0.001).
A significant gene-gene interaction was detected for rs6446693 (MSX1) and rs2268625 (TGFB3). This finding is concordant with research in animal models showing that MSX1 and TGFB3 are expressed in common molecular pathways acting in an epistatic manner during maxillofacial development.
非综合征性唇裂伴或不伴腭裂（NSCL/P）是一种出生缺陷，已有多个易感基因被提出。因此，有人认为这些基因中的许多基因属于颅面发育过程中常见的相互关联的途径，存在基因-基因相互作用。我们评估了干扰素调节因子 6（IRF6）、肌肉节同源盒 1（MSX1）、骨形态发生蛋白 4（BMP4）和转化生长因子 3（TGFB3）基因内单核苷酸多态性在智利病例-父母三体型 NSCL/P 风险中的基因-基因相互作用。
从之前的研究中，我们在 152 个病例-父母三体型中检索了这四个基因中 13 个多态性变异的基因型。使用 trio 包（R），我们在遗传标记对中评估了基因-基因相互作用，应用自由度为 1 的检验（1df）和确认的自由度为 4 的检验（4df）进行上位性检验，然后进行置换检验和 Benjamini-Hochberg 检验进行多重比较调整。
我们发现 rs6446693（MSX1）和 rs2268625（TGFB3）存在基因-基因相互作用的证据（4df p=0.024；置换检验 p=0.015，Benjamini-Hochberg p=0.001）。
rs6446693（MSX1）和 rs2268625（TGFB3）存在显著的基因-基因相互作用。这一发现与动物模型的研究结果一致，表明 MSX1 和 TGFB3 表达在共同的分子途径中，在颌面发育过程中表现出上位性作用。
