rs1041740

Two-stage genetic study examining 28 SNPs in oxidative stress genes (SOD1, SOD2, SOD3, PON1, PON2, PON3) in relation to nonsyndromic cleft lip with or without cleft palate (NSCL/CP) in Brazilian population. Initial transmission disequilibrium test (TDT) on 325 trios identified gene-gene interactions, which were validated in case-control analysis (722 cases, 866 controls). PON1 rs2237583 C allele showed protective effect (OR=0.79, 95% CI 0.67-0.93, p=0.005), and multiple significant PON1-PON2-PON3 gene-gene interactions were detected after Bonferroni correction.

A candidate gene association study of 610 families (329 trios and 281 duos) from the US and Canada investigating 17 SNPs in SOD1 and SOD2 genes for association with nonsyndromic myelomeningocele (MM). Four SOD1 SNPs (rs202446, rs202447, rs4816405, rs2070424) and one SOD2 SNP (rs5746105) showed significant association with MM (p<0.05), with rare alleles appearing protective. Gene expression analysis in CEPH cell lines suggested associations with altered SOD1 and SOD2 mRNA levels.

This study demonstrates a genetic interaction between the RET enhancer polymorphism rs2435357 (C>T) on chromosome 10 and chromosome 21 dosage in Down syndrome and Hirschsprung disease. The RET +9.7 T allele showed significant association with HSCR in both transmission disequilibrium (P=0.0015) and case-control (P=0.0115) analyses, with allele frequencies of 0.26 in DS alone, 0.61 in HSCR alone, and 0.41 in DS+HSCR, representing the first reported genetic interaction between a common functional variant and chromosome 21 dosage in human developmental disorders.