We investigated the association of tumor necrosis factor-alpha (TNFalpha) gene polymorphisms with idiopathic recurrent miscarriage (RM). TNFalpha -1031T/C, -863C/A, -857C/T, -376G/A, -308G/A, -238G/A, and +488G/A single nucleotide polymorphisms (SNPs) were investigated in 204 RM women and 248 age-matched parous women by PCR-restriction fragment length polymorphism. Significantly higher frequencies of -1031C and -376A alleles were seen in RM patients; significant differences were also noted in the distribution of -1031T/C, -376G/A, and -238G/A genotypes between case and control subjects. Haploview analysis revealed high linkage disequilibrium between -857C/T and +488G/A SNPs, but was lower between the other polymorphisms. Of the possible 52 seven-locus haplotypes constructed, 10 were common, and were included in subsequent analysis. Increased frequency of CCCGGGG and CCCGGAA haplotypes, and reduced frequency of TCCGGGG and TCCGGGA haplotypes were seen in RM patients than in controls. When the Bonferroni correction was applied, differences were significant for the CCCGGAA haplotype, which was higher (OR=4.14; 95% CI=1.84-8.95), and the TCCGGGA haplotype, which were lower among RM cases (OR=0.09; 95% CI=0.02-0.68), thereby conferring RM susceptibility and protection to these haplotypes, respectively. Multivariate analysis confirmed the positive association of only CCCGGAA haplotype with RM (P=0.010; aOR=2.03; 95% CI=1.18-4.47), after controlling for a number of covariates. These results demonstrate that the TNFalpha polymorphisms, in particular the -1031T/C variant, are significantly associated with idiopathic RM. Additional replication studies on other racial groups are needed to confirm our findings.
Copyright 2010. Published by Elsevier Ireland Ltd.