Risk factors for oral clefts: a population-based case-control study in Shenyang, China

Shenyang in Northern China has one of the highest reported prevalence rates of oral clefts in the world. To explore the risk factors for oral clefts in Shenyang, we carried out a population-based case-control study. A total of 360 990 births in 2000 to 2007 were screened for oral clefts; the overall prevalence was 1.76 per 1000. The ratio of cleft lip with or without cleft palate (CL ± P) : cleft palate only (CP) was 5.60:1. The overall male : female ratio was 2.02:1. CLP and CL were more common in males than in females with a sex ratio (SR) of 2.88:1 and 1.86:1 respectively, whereas CP was more common in females with an SR of 0.71:1.
Using a multivariable conditional logistic regression model, 586 oral clefts cases were compared with 1172 control mothers. Maternal factors significantly associated with increased risk for oral clefts were history of a fever or cold (adjusted OR 2.34, 95% CI 1.06, 5.60); use of analgesic and antipyretic drugs (adjusted OR 3.10, 95% CI 1.41, 6.86); poor ventilation during heating (adjusted OR 2.25, 95% CI 1.10, 4.60); and consumption of pickled vegetables >6 per week (adjusted OR 3.86, 95% CI 1.11, 13.47) during pregnancy. Factors which appeared to be protective were meat consumption ≥4 times per week (adjusted OR 0.43, 95% CI 0.28, 0.67); and legume consumption >6 times per week (adjusted OR 0.60, 95% CI 0.41, 0.89). Differences in risk were found between the two most common phenotypes, CL ± P and CP only. Most of the environmental factors had stronger associations with risk for CL ± P rather than CP, whereas history of oral clefts, as well as legume consumption, were more strongly associated with the risk for CP than for CL ± P. The findings suggest that aetiological heterogeneity may exist between CL ± P and CP.     

Evidence that BCL3 plays a role in the etiology of nonsyndromic oral clefts in Brazilian families

The BCL3 gene has been considered a susceptibility locus for nonsyndromic cleft lip with or without cleft palate (NSCL/P), based on association and linkage studies in some populations. We evaluated an intragenic marker at the BCL3 gene and the microsatellite D19S178 (1.1 cM distant from the BCL3 gene) among 98 infants born with NSCL/P and their parents, using the transmission disequilibrium test (TDT) and a method for haplotype analysis. Our analysis, based on BCL3 alleles, revealed the existence of a marginal association of allele 135pb of the BCL3 gene with NSCL/P (chi(2)=3.60; P=0.058; 1 df), with a major effect in female (chi(2)=5.77; P=0.016; 1 df) and in familial cases (chi(2)=3.79; P=0.051; 1 df). However, the haplotype analysis detected no significant segregation distortion, even if the alleles of the D19S178 were grouped into two classes. These findings support previous findings that BCL3 plays a role in the etiology of NSCL/P as an allele of low penetrance or as a modifier locus. We hypothesize that there might be more than one mutation in this gene associated with NSCL/P, or alternatively, that more than one mutation has arisen associated with the 135-bp allele. Genet. Epidemiol. 23:364-374, 2002 Copyright 2002 Wiley-Liss, Inc.     

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

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.