Gene-gene interaction for nonsyndromic cleft lip with or without cleft palate in chilean case-parent trios

Abstract

Objective: 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.

Design: 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 degrees-of-freedom test (1df) and a confirmatory 4 degrees-of-freedom (4df) test for epistasis followed by both a permutation test and a Benjamini-Hochberg test for multiple comparisons adjustment.

Results: We found evidence of gene-gene interaction for rs6446693 (MSXI) and rs2268625 (TGFB3) (4df p = 0.024; permutation p = 0.015, Benjamini-Hochberg p = 0.001).

Conclusions: 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.