Variants of developmental genes (TGFA, TGFB3, and MSX1) and their associations with orofacial clefts: A case‐parent triad analysis

Abstract

We selected 262 case-parent triads from a population-based study of orofacial clefts in Norway, and examined variants of developmental genes TGFA, TGFB3, and MSX1 in the etiology of orofacial clefts. One hundred seventy-four triads of cleft lip cases (CL+/-P) and 88 triads of cleft palate only cases (CPO) were analyzed. There was little evidence for an association of any of these genes with CL+/-P. The strongest association was a 1.7-fold risk with two copies of the TGFB3-CA variant (95% CI=0.9-3.0). Among CPO cases, there was a 3-fold risk with two copies of the TGFA TaqI A2 allele, and no increase with one copy. Assuming this to be a recessive effect, we estimated a 3.2-fold risk among babies homozygous for the variant (95% CI=1.1-9.2). Furthermore, there was strong evidence of gene-gene interaction. While there was only a weak association of the MSX1-CA variant with CPO, the risk was 9.7-fold (95% CI=2.9-32) among children homozygous for both the MSX1-CA A4 allele and the TGFA A2 allele. No association of CPO with the TGFA variant was seen among the other MSX1-CA genotypes. In conclusion, no strong associations were found between CL+/-P and variants at these three genes. There was a possible recessive effect of the TGFA TaqI variant on the risk of CPO, with a 3-fold risk among children homozygous for the variant. The effect of this TGFA genotype was even stronger among children homozygous for the MSX1-CA A4 allele, raising the possibility of interaction between these two genes.

Contribution of MSX1 variants to the risk of non-syndromic cleft lip and palate in a Malay population

“…8,11,19,20 In the present research, no transmission distortion was found in the transmission disequilibrium analysis for either MSX1-CA or TGFB3-CA intragenic markers, but TGFB3-CA exhibited a trend to excess maternal transmission. Our findings suggest that both the maternal and fetal RR results are in agreement for both TGFB3-CA alleles, as the 163-bp allele had a deleterious recessive effect, whereas the 165-bp allele had a protective recessive effect.…”

“…3,4 Their involvement is further supported by linkage and association studies in populations of different ethnic origin. [5][6][7][8] Although no deleterious mutation has been reported in TGFB3. 7,9 MSX1 has been suggested to function upstream of TGFB3 in the development of oral cleft.…”

Progress toward discerning the genetics of cleft lip

“…However, other studies have not been able to replicate this finding by either linkage or association [9,17,18]. Two meta-analyses, one looking at association studies [19] and a more recent study combining 13 genome scan studies [20•], reveal positive results, corroborating the hypothesis that TGFA is a modifier rather than necessary or sufficient to cause clefting.…”

Dentistry and Molecular Biology: A Promising Field for Tooth Agenesis Management

“…However, there is no consensus among authors concerning the interaction between MSX1 and TGFA. Some studies show no statistically significant evidence of interaction between these genes in human tooth agenesis (Vieira et al 2004), whereas others indicate strong correlation (Jugessur et al 2003) among individuals with clefts.…”