ACE gene and male infertility : a South Slavic case-control study and multi-omics data integration

Kunej, Tanja (author), Podgrajšek, Rebeka (author), Jaklič, Helena (author), Hodžić, Alenka (author), Štimpfel, Martin (author), Miljanović, Olivera (author), Ristanović, Momčilo (author), Novaković, Ivana (author), Plašeska Karanfilska, Dijana (author), Noveski, Predrag (author), Ostojić, Saša (author), Buretić-Tomljanović, Alena (author), Gršković, Antun (author), Peterlin, Borut (author)

Components of the renin-angiotensin system (RAS) are expressed in both female and male reproductive tracts, with angiotensin I converting enzyme (ACE) being an important component for male reproductive function, as shown in animal models. The most studied ACE polymorphism is the Alu insertion-deletion (I/D), which has been proposed to have a negative effect on male fertility. Given the conflicting evidence in the literature, we conducted a multicentric case-control study to investigate the association between the ACE Alu I/D polymorphism and impaired spermatogenesis. Using PCR amplification and agarose electrophoresis, we genotyped the ACE gene Alu I/D polymorphism in 745 South Slavic men. The study group consisted of 457 patients with impaired spermatogenesis, 239 with non-obstructive azoospermia (NOA) and 218 with oligoasthenoteratozoospermia (OAT) and a control group of 288 fertile men. No association was found between the Alu I/D polymorphism and these semen phenotypes, suggesting that it is not associated with NOA or severe OAT in this cohort. To provide a broader regulatory context, we also developed an integrative atlas of ACE regulatory elements by in silico multi-omics analysis using genomics databases and bioinformatics tools. Data integration revealed various regulatory mechanisms at multiple omics levels, including genomics, epigenomics, miRNAomics, transcriptomics, proteomics and epiproteomics. These include genomic variants with predicted deleterious effects, a CpG island, microRNAs (miRNAs) and post-translational modifications (PTMs). In addition, protein interaction analysis revealed that ACE is indirectly linked to several proteins previously associated with male infertility and is also targeted by miRNA previously associated with oligozoospermia. This comprehensive, multi-faceted approach, combining genetic association analysis with bioinformatics, provides insights into ACE regulation in its broader molecular context. These results emphasize the importance of further integrative multi-omics and systems biology research to better understand the role of ACE in male reproductive function.

• Language: English
• Keywords: angiotensin I converting enzyme, ACE, male infertility, azoospermia, oligozoospermia, multi-omics
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: BF - Biotechnical Faculty; MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2025
• Number of pages: Str. 524–537
• Numbering: Vol. 71, no. 1
• PID: 20.500.12556/RUL-174742
• UDC: 61:575
• ISSN on article: 1939-6376
• DOI: 10.1080/19396368.2025.2566747
• COBISS.SI-ID: 252402691
• Publication date in RUL: 09.10.2025

Record is a part of a journal

• Title: Systems biology in reproductive medicine
• Publisher: Taylor & Francis
• ISSN: 1939-6376
• COBISS.SI-ID: 522445593

Licences

• License: CC BY-NC-ND 4.0, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
• Link: http://creativecommons.org/licenses/by-nc-nd/4.0/
• Description: The most restrictive Creative Commons license. This only allows people to download and share the work for no commercial gain and for no other purposes.

Secondary language

• Language: Slovenian
• Keywords: genetika, geni, gen ACE, moška neplodnost, omike