Testing reported associations of genetic risk factors for oral clefts in a large Irish study population

Abstract

BACKGROUND Suggestive, but not conclusive, studies implicate many genetic variants in oral cleft etiology. We used a large, ethnically homogenous study population to test whether reported associations between nonsyndromic oral clefts and 12 genes (CLPTM1, CRISPLD2, FGFR2, GABRB3, GLI2, IRF6, PTCH1, RARA, RYK, SATB2, SUMO1, TGFA) could be confirmed. METHODS Thirty-one single nucleotide polymorphisms (SNPs) in exons, splice sites, and conserved non-coding regions were studied in 509 patients with cleft lip with or without cleft palate (CLP), 383 with cleft palate only (CP), 838 mothers and 719 fathers of patients with oral clefts, and 902 controls from Ireland. Case-control and family-based statistical tests were performed using isolated oral clefts for the main analyses. RESULTS In case-control comparisons, the minor allele of PTCH1 A562A (rs2066836) was associated with reduced odds of CLP (OR: 0.29, 95% CI: 0.13–0.64 for homozygotes) whereas the minor allele of PTCH1 L1315P (rs357564) was associated with increased odds of CLP (OR: 1.36, 95% CI: 1.07–1.74 for heterozygotes and OR: 1.56, 95% CI: 1.09–2.24 for homozygotes). The minor allele of one SUMO1 SNP, rs3769817 located in intron 2, was associated with increased odds of CP (OR: 1.45, 95% CI: 1.06–1.99 for heterozygotes). Transmission disequilibrium was observed for the minor allele of TGFA V159V (rs2166975) which was over-transmitted to CP cases (P=0.041). CONCLUSIONS For 10 of the 12 genes, this is the largest candidate gene study of nonsyndromic oral clefts to date. The findings provide further evidence that PTCH1, SUMO1, and TGFA contribute to nonsyndromic oral clefts.

The CRISPLD2 gene is involved in cleft lip and/or cleft palate in a Chinese population

“…However, other association studies yielded conflicting results in different populations (Carter et al, 2010;Girardi et al, 2011;Jugessur et al, 2009;Letra et al, 2010;Shi et al, 2010). It is unclear whether this association crosses ethnic barriers or whether it is anthropologic diversity.…”

Genetic Aspects of Cleft Lip and Palate ? A Review

“…The functional association has been ascribed to the fact that TGF-α is similar to Epidermal Growth Factor (EGF) and has similar effect on the cells of the bone marrow which is considered to be mitogenic and responsible for differentiation of osteoblasts. Thus, as per the work of Carter et al, it has been shown that TGF-α does not seem to have a direct role in CLP [27,28].…”

“…T-box genes encode numerous transcription factors that are involved in the regulating various developmental processes and is believed to play a major role in palatogenesis [28]. Most of the studies till date reveal that a mutation in TBX 22 results in CP and ankyloglossia, though there are studies that indicate mutation of TBX 22 can result in CP alone [30].…”

SATB2 gene variants in non-syndromic cleft lip with or without cleft palate in Indian population

“…17 Analysis of two intronic SNPs (rs4673313 and rs17199393) in Irish NSCL/P showed no significant association between NSCL/P and SATB2. 18 Both TRIMM and HAPLIN methods that were used to detect multimarker effects on oral clefts of Norway and Denmark showed significant maternal effects of SATB2 gene variants for isolated cleft palate in Danish but not in Norwegian samples. 19 The expression of SATB2 during mid-facial development and palatogenesis in mouse, chick and zebrafish is highly conserved, and suggests that the SATB2 gene is under extreme evolutionary pressure.…”