Abnormal Methylation of Imprinted Genes and Cigarette Smoking: Assessment of Their Association With the Risk of Male Infertility

Male infertility is a complicated disease with causes generally split into 2 broad categories: genetic factors and environmental factors. The present study was designed to investigate the association between the methylation patterns of H19 and SNRPN imprinting control region (ICR) and male infertility and to assess the gene-environment interactions between environmental factors and methylation patterns. A total of 205 DNA samples from 48 oligozoospermia (OZ), 52 asthenozoospermia (AZ), 55 teratozoospermia (TZ) patients, and 50 normozoospermia (NZ) men were analyzed. The mean methylation level of H19-ICR in OZ (80.40% +/- 12.74%) and AZ patients (81.17% +/- 13.18%) was significantly lower than methylation in men with NZ (88.51% +/- 10.54%, P<.001, P<.001, respectively). The mean methylation level of SNRPN-ICR in AZ patients (7.74% +/- 5.71%) and TZ patients (9.33% +/- 5.48%) was significantly higher than in NZ men (6.32% +/- 3.54%, P<.001, P<.001, respectively). Among environmental factors, smoking was correlated with OZ (odds ratio [OR] = 5.12, 95% CI: 2.05-12.83), AZ (OR = 5.65, 95% CI: 2.13-14.99), and TZ (OR = 5.54, 95% CI: 2.21-13.89). Gene-environment interaction analysis revealed that hypomethylation of H19-ICR in OZ patients and hypermethylation of SNRPN-ICR in AZ and TZ patients were significantly associated with an increased the risk of infertility in men who were smokers (OR = 15.30, 95% CI: 1.13-207.97; OR = 13.20, 95% CI: 1.21-143.57; OR = 10.59, 95% CI: 1.04-107.39, respectively). This study demonstrated that hypomethylation of H19-ICR and hypermethylation of SNRPN-ICR are associated with male infertility, and the risk is potentiated by smoking.