Background: The mismatch repair proteins MSH5 and MLH3 play a crucial role in spermatogenesis. We tested this hypothesis by examining the contribution of functional polymorphisms in MSH5 C85T and MLH3 C2531T to the risk of male infertility.
Methods: We investigated Chinese patients, including 162 infertile individuals with idiopathic azoospermia or severe oligozoospermia, and 160 fertile men as controls.
Results: We observed an increased risk of male infertility associated with the MSH5 (CT+TT) (OR, 2.51; 95% CI, 1.43-4.40; P<0.001) or MLH3 (CT+TT) (OR, 1.98; 95% CI, 1.23-3.17; P<0.001) genotype, compared to the MSH5 CC or MLH3 CC genotype, respectively. Interactions between these MSH5 and MLH3 polymorphisms increased the risk of male infertility in a multiplicative manner, with the OR being 6.78 (95% CI, 2.12-21.68) for subjects carrying both MSH5 (CT+TT) and MLH3 (CT+TT) genotypes.
Conclusions: There is an association of polymorphism C85T in MSH5 or C2531T in MLH3 with male infertility, specifically azoospermia or severe oligozoospermia, and interaction between these MSH5 and MLH3 polymorphisms increased the risk of developing male infertility. Therefore, the MSH5 and MLH3 polymorphisms may be genetic determinants for human spermatogenesis impairment.