Podgrajsek R, et al. World J Mens Health. 2025 Jan;43:e1. https://doi.org/10.5534/wjmh.240149

Founder variants in sarcomere protein genes account for a significant proportion of disease-causing variants in patients with hypertrophic cardiomyopathy (HCM). However, information on founder variants in non-sarcomeric protein genes, such as FHOD3, which have only recently been associated with HCM, remains scarce. In this study, we conducted a retrospective analysis of exome sequencing data of 134 probands with HCM for recurrent pathogenic variants. We discovered a novel likely pathogenic variant c.1646+2T>C in FHOD3 in heterozygous state in eight probands with HCM and confirmed its presence in seven additional relatives. Individuals with this variant had a wide range of ages at onset of the disease (4–63 years). No adverse cardiac events were observed. Haplotype analysis revealed that the individuals with this variant shared a genomic region of approximately 5 Mbp surrounding the variant, confirming the founder effect of the variant. FHOD3 c.1646+2T>C is estimated to have arisen 58 generations ago (95% CI: 45–81) in a common ancestor living on the Balkans. A founder FHOD3 c.1646+2T>C variant is the second most common genetic variant in our cohort of patients with HCM, occurring in 16% of probands with a known genetic cause of HCM, which represents a substantially higher proportion than the currently estimated 0.5–2% for causal FHOD3 variants. Our study broadens the understanding of the genetic causes of HCM and may improve the diagnosis of this condition, particularly in patients from the Balkans.

The main goal of our study was to assess the potential effect of the polymorphism of the coagulation-related genes F2, F5, and F13A on the risk of venous thromboembolism (VTE) development. The study was conducted at the Clinical Center, Podgorica, Montenegro, and included 103 VTE patients and 106 sex- and age-matched healthy controls. Demographic, clinical, and laboratory data were obtained from the medical records and questionnaires. Genotyping for F2 19911A>G (rs3136516), F5 6665A>G (rs6027), and F13A 102G>T (rs5985) was performed by allele-specific PCR. Controlling for the effect of known risk factors, the presence of at least one variant F5 6665 G allele conferred a significantly higher risk of VTE among females [OR (95%CI): 64.06 (5.38; 763.61)], but not among males. In addition, thromboembolic events were associated with comorbidities [OR (95%CI): 197.10 (19.17; 2026.19)], overweight [OR (95%CI): 33.59 (2.47; 456.65)], and the presence of F2 20210G>A [OR (95%CI): 32.43 (4.21; 249.77)] and F5 1601G>A [OR (95%CI): 144.80 (13.59; 1542.63)] in females, as well as with comorbidities [OR (95%CI): 6.32 (1.90; 20.98)], family history of VTE [OR (95%CI): 8.10 (2.28; 28.83)], and the presence of F5 1601G>A [OR (95%CI): 20.10 (2.34; 173.02)] in males. Our study reports an association between the presence of at least one F5 6665G variant allele and an increased risk of VTE development in females. Our results indicate that F5 6665A>G, in combination with other confirmed factors of influence, such as comorbidities, overweight, F2 20210G>A, and F5 1601G>A, could contribute to VTE risk prediction in females.

Background: Recurrent pregnancy loss (RPL) affects up to 5% of pregnancies, but with no consensus on the definition. Inherited thrombophilia has been postulated as a risk factor for RPL. The aim of this study was to investigate the association of RPL with polymorphisms of five genes that influent the coagulation and fibrinolysis. Methods: This study was conducted on total of 224 women, 129 women with ≥2 early RPL or ≥1 late pregnancy loss, 95 women with at least two normal life births and no history of pregnancy loss. Five gene polymorphisms F2 20 210G>A (rs1799963), F5 1691G>A (rs6025), MTHFR 677C>T (rs1801133), SERPINE1 −675 4G/5G (rs1799762) and ACE I/D (rs1799752) were genotyped by PCR-based methods. Results: A significant relationship was found between SERPINE1 4G/4G and ACE D/D polymorphisms and RPL (pA, F5 1691G>A and MTHFR 677C>T polymorphisms and risk for RPL. A combination of hypofibrinolytic homozygotes SERPINE1 4G/4G+ACE D/D was observed as a highly associated with RPL (Cochran-Armitage test, p<0.001), and their strong independent association with RPL risk was confirmed by logistic regression analysis (both p values <0.001, OR 3.35 and 3.43, respectively). Conclusion: Our data have demonstrated that SERPINE1 and ACE gene polymorphisms, individually or in combination, appear to be a significant risk for RPL. This data may be useful in adding to the knowledge on inherited thrombophilia as an important contributor to RPL pathogenesis.

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.