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Background: Nonsyndromic cleft lip with or without cleft palate (nsCL6P) and nonsyndromic cleft palate (nsCP) are caused by a combination of genetic and environmental risk factors. We investigated gene-environment and gene-gene joint effects in a large multicenter study of caseparent triads. Methods: The nsCL6P or nsCP triads were recruited in 11 European countries between 2001 and 2005. We collected DNA samples from infants and from their mothers and fathers, and mothers completed a questionnaire on exposures, including smoking and folic acid supplement use during pregnancy. We used log-linear regression to estimate relative risks (RRs) and 95% confidence intervals (CIs) for associations between nsCL6P or nsCP and variants in MTHFR, MTHFD1, TGFA, SATB2, and MSX1, stratifying by environmental or genetic factors. Results: We obtained genotype and exposure data for 728 nsCL6P triads and 292 nsCP triads. In male infants, there was no association between the mother抯 homozygous MSX1 p(CA) 4/ 4 genotype and nsCL6P (RR, 0.98; 95% CI, 0.63�54), but this maternal genotype resulted in a doubling of risk for female infants (RR, 2.21; 95% CI, 1.13�34). There was evidence suggestive of gene-gene joint-effects between MTHFR-TGFA for nsCP but not for nsCL6P. Conclusion: Although we chose the genes and their variants and putative joint effects based on associations previously reported in the literature, we replicated few associations. These results do not provide evidence supporting associations between these genes and oral clefts in European populations, although gene-environment and gene-gene interactions could play a role in oral cleft etiology. [ABSTRACT FROM AUTHOR]