Risk Factors For Orofacial Clefts Research Articles

Maternal Smoking, Genetic Variation of Glutathione S-Transferases, and Risk for Orofacial Clefts

Maternal smoking is a known risk factor for orofacial clefts. We investigated whether risk is greater among offspring who lack the genetic capacity to produce glutathione S-transferase enzymes relevant to detoxification of chemicals in cigarette smoke. Using a population-based case-control design, we genotyped 423 California infants with an isolated cleft and 294 nonmalformed controls for null variants of the glutathione S-transferases GSTT1 and GSTM1. If a mother smoked during pregnancy and her fetus was homozygous null for GSTT1, the risk of isolated cleft lip with or without cleft palate was tripled (odds ratio = 2.9; 95% confidence interval = 1.2-7.2). For fetuses who were homozygous null for GSTM1 and whose mothers smoked >/=20 cigarettes per day, we found nearly a 7-fold increased risk (6.8; 0.82-57). Combined absence of GSTM1 and GSTT1 enzymes among the offspring of smoking mothers was associated with a nearly 6-fold increased risk for cleft lip (6.3; 1.3-42). A similar increased risk for cleft palate was associated with absence of GSTM1, but not for absence of GSTT1. Maternal smoking during pregnancy increases risks for clefts among fetuses lacking enzymes involved in the detoxification of tobacco-derived chemicals.

Socioeconomic status and orofacial clefts in Scotland, 1989 to 1998.

The purpose of this study was to investigate the association between socioeconomic status and orofacial clefts (OFC) in Scotland. Study of prevalence at birth over a 10-year period using an area-based measure of material deprivation. Population-based study throughout Scotland. Eight hundred thirty-four live births with OFC born between January 1, 1989, and December 31, 1998, ascertained from the nationwide register of the Cleft Service in Scotland, compared with the total 603,825 live births in Scotland in this period. There was a strong positive relationship whereby the prevalence of OFC at birth increased with increasing deprivation. This trend was statistically significant for cleft lip and/or palate (CL[P]: p =.016) but not for cleft palate (CP; p =.078). For each type of cleft, the relative risk among those resident in the most deprived areas, compared with those resident in the least deprived areas, was 2.33. The association between OFC and socioeconomic status is consistent with a report for an earlier period in a smaller part of Scotland. Unlike the earlier study, this pattern appears to be stronger for CL(P) than for CP. These observations do not appear to be an artifact of recording. It is possible that they reflect the association between deprivation and risk factors for OFC, most likely tobacco smoking during pregnancy. Because the relationship between OFC and socioeconomic status appears to have been virtually unstudied in other populations, it would be valuable to investigate this relationship elsewhere and determine whether known risk factors account for the relationship.

Exploring the effects of methylenetetrahydrofolate reductase gene variants C677T and A1298C on the risk of orofacial clefts in 261 Norwegian case-parent triads.

Folic acid and the methylenetetrahydrofolate reductase (MTHFR) gene have both been implicated in the etiology of orofacial clefts. The authors selected 261 case-parent triads (173 cases with cleft lip with or without cleft palate (CL/P) and 88 cases with cleft palate only (CPO)) from a Norwegian population-based study of orofacial clefts (May 1996-1998). A case-parent triad design was used to examine whether MTHFR variants C677T and A1298C, and their haplotypes, are risk factors for orofacial clefts. Among CL/P cases, the child's genotype at C677T or A1298C did not influence the risk. However, children of mothers carrying the C677T variant allele had a lower risk of CL/P. For CPO, children carrying the C677T variant allele had about a twofold increased risk, whereas the mother's genotypes did not contribute to the risk. The haplotype-based transmission/disequilibrium test showed that except for 677T/1298A (p = 0.06), none of the other haplotypes showed evidence of excess transmission to the offspring. The authors also explored interaction of C677T with maternal use of folic acid among children with CPO. Surprisingly, the risk associated with the child's carrying either CT or TT was higher (fourfold) when the mother used folic acid. These findings suggest a possible role of MTHFR and folic acid in the causation of orofacial clefts, but the strength and direction of these effects remain to be clarified.