Background: We are carrying out a population-based case-control study of facial clefts in Norway, where the rate of cleft lip and palate is one of the highest in the world. This study, which began in 1996 and will run through 2002, attempts to enroll all babies born in Norway with a cleft lip or palate. Mothers provide detailed information on occupational and other exposures to potentially toxic substances, as well as nutrition, personal habits and medical history. Control infants are selected randomly from all live births. In order to investigate possible genetic susceptibility to teratogens, biological samples (blood or cheek swabs) are collected from cases, controls, and their biological parents. When completed, this will be one of the largest and most comprehensive studies of this common birth defect ever conducted. Summary: Developmental Genes. We selected 262 complete case-parent triads from a population-based study of facial clefts in Norway and examined variants of developmental genes TGFA, TGFB3, and MSX1 in the etiology of facial clefts. Analyses were performed separately for 174 triads of cleft lip cases (CL+/-P) and 88 triads of cases who had cleft palate without cleft lip (CPO). There was little evidence for an association of any of these genes with the risk of CL+/-P. The strongest association was a 1.7-fold risk with two copies of the variant TGFB3-CA). In the CPO subtype, there was a 3-fold risk when the child had two copies of the TGFA TaqI A2 allele, and no increased risk with one copy of the variant. Under the assumption of a recessive effect, we estimated a 3.2-fold risk among babies homozygous for the variant. Furthermore, there was strong evidence of gene-gene interaction. While there was only a weak association of the MSX1-CA A4 allele with CPO, the risk of CPO was 9.7-fold among children homozygous for both the MSX1-CA A4 allele and the TGFA TaqI A2 allele. No association of CPO with the TGFA TaqI variant was seen among the other MSX1-CA genotypes. We did not find strong associations between CL+/-P and any of the variant alleles of three developmental genes. There was the suggestion of a recessive effect of TGFA Taql variant on the risk of cleft palate alone, with a three-fold risk among children who are homozygous for the variant. The effect of the TGFA TaqI variant was strongest among children homozygous for the A4 allele of MSXI-CA. Birthweight. We presented evidence that suggests the link between birthweight and health outcomes may not be causal. Methods of analysis that assume causality are unreliable at best, and biased at worst. The category of 'low birthweight' in particular is uninformative and seldom justified. The main utility of the birthweight distribution is to provide an estimate of the proportion of small preterm births in a population (although even this requires special analytical methods). While the ordinary approaches to birthweight are not well grounded, the links between birthweight and a range of health outcomes may nonetheless reflect the workings of biological mechanisms with implications for human health. Prenatal PCB Exposure. (see Longnecker 49016) Using Collaborative Perinatal Project samplese examined maternal DDE level during pregnancy in relation to adjusted odds of cryptorchidism, hypospadias, and polythelia [extra nipples] among their male offspring. Compared with those whose mother?s recovery-adjusted serum DDE level was < 21.4 ug/L, those with levels 85.6+ mg/L had an adjusted odds ratio for cryptorchidism of 1.3, for hypospadias of 1.2, and for polythelia of 1.9. For cryptorchidism and polythelia the results were consistent with a modest-to-moderate association, but in no instance was the estimate very precise. The results were inconclusive.
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