Contribution of 6p24 to non-syndromic cleft lip and palate in a Malay population: association of variants in OFC1

Abstract

Non-syndromic cleft lip, with or without cleft palate, is a heterogeneous, complex disease with a high incidence in the Asian population. Several association studies have been done on cleft candidate genes, but no reports have been published thus far on the Orofacial Cleft 1 (OFC1) genomic region in an Asian population. This study investigated the association between the OFC1 genomic region and non-syndromic cleft lip with or without cleft palate in 90 Malay father-mother-offspring trios. Results showed a preferential over-transmission of a 101-bp allele of marker D6S470 in the allele- and haplotype-based transmission disequilibrium test (TDT), as well as an excess of maternal transmission. However, no significant p-value was found for a maternal genotype effect in a log-linear model, although single and double doses of the 101-bp allele showed a slightly increased cleft risk (RR = 1.37, 95% CI, 0.527-3.4, p-value = 0.516). Carrying two copies of the 101-bp allele was significantly associated with an increased cleft risk (RR = 2.53, 95% CI, 1.06-6.12, p-value = 0.035). In conclusion, we report evidence of the contribution of the OFC1 genomic region to the etiology of clefts in a Malay population.

Figure.

The relative dose risk for D6S470 alleles with frequency > 1% for maternal and child genotypes. X indicates a single dose, whereas O indicates a double dose. Reciprocal reference has been used. Having one copy of the 101-bp allele showed a trend toward increasing the risk (RR = 1.92, 95% CI, 0.964-3.91, p-value = 0.067), while having 2 copies of the 101-bp allele was significantly associated with increased cleft risk (RR = 2.53, 95% CI, 1.06-6.12, p-value = 0.035), suggesting a recessive effect of this allele. Maternal single or double dose of the 101-bp allele showed slightly increased risk with a dominant effect (RR = 1.37, 95% CI, 0.527-3.4, p-value = 0.516 for double-dose effect), but the p-value is not statistically significant. There seemed to be a protective effect for mothers who are carrying either 2 copies of the 93-bp or 99-bp allele or a single copy of the 103-bp, 112-bp, or 106-bp allele. The alleles without a double-dose effect indicate that homozygotes are rare.