Relationship between degree of methylation of sperm long interspersed nuclear element-1 (LINE-1) gene and alteration of sperm parameters and age: a meta-regression analysis
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Titel:
Relationship between degree of methylation of sperm long interspersed nuclear element-1 (LINE-1) gene and alteration of sperm parameters and age: a meta-regression analysis
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<jats:title>Abstract</jats:title><jats:sec>
<jats:title>Introduction</jats:title>
<jats:p>The <jats:italic>long interspersed nuclear element-1</jats:italic> (<jats:italic>LINE1</jats:italic>) gene is a retrotransposon whose methylation status appears to play a role in spermatogenesis, the outcome of assisted reproductive techniques (ART), and even in recurrent pregnancy loss (RPL). Advanced paternal age appears associated with altered sperm parameters, RPL, poor ART outcomes, and compromised offspring health. The methylation status of <jats:italic>LINE1</jats:italic> has been reported to be affected by age. The latest meta-analysis on the <jats:italic>LINE1</jats:italic> methylation pattern in spermatozoa found no significant differences in methylation levels between infertile patients and fertile controls. However, to the best of our knowledge, no updated meta-analysis on this topic has been published recently. Furthermore, no comprehensive meta-regression analysis was performed to investigate the association between sperm <jats:italic>LINE1</jats:italic> methylation pattern and age.</jats:p>
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<jats:title>Objectives</jats:title>
<jats:p>To provide an updated and comprehensive systematic review and meta-analysis on sperm <jats:italic>LINE1</jats:italic> gene methylation degree in patients with abnormal sperm parameters compared to men with normal sperm parameters and to probe the association between sperm <jats:italic>LINE1</jats:italic> methylation status and age and/or sperm concentration.</jats:p>
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<jats:title>Methods</jats:title>
<jats:p>This meta-analysis was registered in PROSPERO (registration n. CRD42023397056). It was performed according to the MOOSE guidelines for Meta-analyses and Systematic Reviews of Observational Studies and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P). Only original articles evaluating <jats:italic>LINE1</jats:italic> gene methylation in spermatozoa from patients with infertility or abnormalities in one or more sperm parameters compared to fertile or normozoospermic men were included.</jats:p>
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<jats:title>Results</jats:title>
<jats:p>Of 192 abstracts evaluated for eligibility, only 5 studies were included in the quantitative synthesis, involving a total of 340 patients and 150 controls. Our analysis showed no significant difference in <jats:italic>LINE1</jats:italic> gene methylation degree in patients with infertility and/or abnormal sperm parameters compared to fertile controls and/or men with normal sperm parameters, although there was significant heterogeneity across studies. No significant evidence of publication bias was found, and no study was sensitive enough to alter the results. In meta-regression analysis, we found that the results were independent of both ages and sperm concentration. A sub-analysis examining patients and controls separately was also conducted and we found a trend for a positive correlation between <jats:italic>LINE1</jats:italic> methylation and sperm concentration in the control group only.</jats:p>
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<jats:title>Conclusions</jats:title>
<jats:p>The results of this systematic review and meta-analysis do not suggest a determining role of sperm <jats:italic>LINE1</jats:italic> gene methylation degree in patients with infertility and/or abnormal sperm parameters. Therefore, we do not suggest including <jats:italic>LINE1</jats:italic> in the genetic panel of prospective studies aimed at identifying the most representative and cost-effective genes to be analyzed in couples undergoing ART cycles.</jats:p>
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