Impairment of sperm <scp>DNA</scp> methylation in male infertility: a meta‐analytic study

<jats:title>Summary</jats:title><jats:p>Considering the widespread use of assisted reproductive techniques (<jats:styled-content style="fixed-case">ART</jats:styled-content>), <jats:styled-content style="fixed-case">DNA</jats:styled-content> methylation of specific genes involved in spermatogenesis achieves increasingly clinical relevance, representing a possible explanation of increased incidence of syndromes related to genomic imprinting in medically assisted pregnancies. Several trials suggested a relationship between male sub‐fertility and sperm <jats:styled-content style="fixed-case">DNA</jats:styled-content> methylation, although its weight on seminal parameters alteration is still a matter of debate. To evaluate whether aberrant sperm <jats:styled-content style="fixed-case">DNA</jats:styled-content> methylation of imprinted genes is associated with impaired sperm parameters. Meta‐analysis of controlled clinical trials evaluating imprinted genes sperm <jats:styled-content style="fixed-case">DNA</jats:styled-content> methylation comparing men with idiopathic infertility to fertile controls. Twenty‐four studies were included, allowing a meta‐analytic evaluation for <jats:italic>H19</jats:italic>,<jats:italic> <jats:styled-content style="fixed-case">MEST</jats:styled-content></jats:italic>,<jats:italic> <jats:styled-content style="fixed-case">SNRPN</jats:styled-content></jats:italic>, and <jats:italic><jats:styled-content style="fixed-case">LINE</jats:styled-content>‐1</jats:italic>. When a high heterogeneity of the results was demonstrated, the random effect model was used. <jats:italic>H19</jats:italic> methylation levels resulted significantly lower in 879 infertile compared with 562 fertile men (7.53%, 95% <jats:styled-content style="fixed-case">CI</jats:styled-content>: 5.14–9.93%, <jats:italic>p</jats:italic> < 0.001), suggesting a 9.91‐fold higher risk ratio to show aberrant sperm <jats:styled-content style="fixed-case">DNA</jats:styled-content> methylation (95% <jats:styled-content style="fixed-case">CI</jats:styled-content>: 5.55–17.70, <jats:italic>p</jats:italic> < 0.001, I<jats:sup>2 </jats:sup>= 19%) in infertile men. The mean <jats:italic><jats:styled-content style="fixed-case">MEST</jats:styled-content></jats:italic> methylation level was significantly higher in 846 infertile compared with 353 fertile men (3.35%, 95% <jats:styled-content style="fixed-case">CI</jats:styled-content>: 1.41–5.29%, <jats:italic>p</jats:italic> < 0.001), as well as for <jats:italic><jats:styled-content style="fixed-case">SNRPN</jats:styled-content></jats:italic> comparing 301 infertile men with 124 controls (3.23%, 95% <jats:styled-content style="fixed-case">CI</jats:styled-content>: 0.75–5.72%, <jats:italic>p</jats:italic> < 0.001). <jats:italic><jats:styled-content style="fixed-case">LINE</jats:styled-content>‐1</jats:italic> methylation levels did not differ between 291 infertile men and 198 controls (0.44%, 95% <jats:styled-content style="fixed-case">CI</jats:styled-content>: −2.04–1.16%, <jats:italic>p</jats:italic> = 0.63). The meta‐analytic approach demonstrated that male infertility is associated with altered sperm methylation at <jats:italic>H19, <jats:styled-content style="fixed-case">MEST</jats:styled-content></jats:italic>, and <jats:italic><jats:styled-content style="fixed-case">SNRPN</jats:styled-content></jats:italic>. Although its role in infertility remains unclear, sperm <jats:styled-content style="fixed-case">DNA</jats:styled-content> methylation could be associated with the epigenetic risk in <jats:styled-content style="fixed-case">ART</jats:styled-content>. In this setting, before proposing this analysis in clinical practice, an accurate identification of the most representative genes and a cost‐effectiveness evaluation should be assessed in ad hoc prospective studies.</jats:p>