The study of association of variants in genes PRMT6, PEX10, SOX5, MIR27A and MIR146A with male infertility risk among men from North Macedonia

[S. Rajovski]

84 str.

Biologija - Biohemija i molekularna biologija / Biology - Biochemistry and molecular biology

Posle malignih tumora i vaskularnih bolesti, Svetska zdravstvena organizacija neplodnost definiše kao treću najčešću bolest ljudi sa preko 190 miliona neplodnih osoba širom sveta. Klinička neplodnost ili sterilitet definiše se kao nemogućnost začeća kod para koji ima redovne seksualne odnose u vremenskom periodu od godinu dana. Terminološki „muška neplodnost“ ne predstavlja jasno definisan klinički sindrom, već obuhvata skup različitih urođenih ili stečenih stanja heterogene etiologije. Kod skoro trećine parova za problemom začeća odgovorna je muška neplodnost. Muška neplodnosti bez jasne etiologije naziva se idiopatska neplodnost. Među brojnim faktorima koji uzrokuju razvoj idiopatske neplodnosti kod muškaraca, dominantni uzročnici su genetičke i epigenetičke promene. Kada je neplodnost muškaraca u pitanju, rezultati prve GWAS pokazale su statistički značajnu asocijaciju tri varijante u genima za proteine: PRMT6 (rs12097821), PEX10 (rs2477686) i SOX5 (rs10842262) sa rizikom za pojavu neplodnosti kod muškaraca poreklom iz Kine. Jedan od ciljeva ove disertacije bila je da se ispita da li se rezultati ove GWAS odnose i na muškarace iz Severne Makedonije. Nakon sprovedene studije slučajeva i kontola, cilj ove disertacije bila je i meta-analiza ove i drugih studija slučajeva i kontrola koje su za temu imale moguću asocijaciju ove tri genetičke varijante sa rizikom za razvoj idiopatske neplodnosti. Grupa slučajeva u kojoj je ispitivana asocijacija genetičkih varijanti rs12097821, rs2477686 i rs10842262 sa pojavom idioptske neplodnosti uključivala je 137 muškaraca sa kliničkom dijagnozom idiopatske neplodnosti, dok je kontrolnu grupu činilo 130 zdravih dobrovoljaca odgovarajućeg uzrasta koji su imali najmanje jedno dete. Genetičke varijante rs12097821, rs2477686 i rs10842262 nisu pokazale statistički značajnu povezanost sa rizikom za razvoj idiopatske neplodnosti kod muškaraca iz Severne Makedonije. Učestalost alela G genetičke varijante rs10842262 je značajno povećana u grupi neplodnih muškaraca sa niskim volumenom ejakulata, u poređenju sa fertilnim muškarcima, dok je učestalost genotipa GG genetičke varijante rs10842262 kod muškaraca sa oligospermijom oko dva puta bila veća u odnosu na onu utvrđenu kod fertilnih muškaraca. Rezultati meta-analize ukazuju na povezanost između manje učestalog alela G genetičke varijante rs10842262 i muške idiopatske neplodnosti. Nakon stratifikacije prema etničkoj pripadnosti učesnika, rs10842262 je ostao statistički značajno povezan sa neplodnošću kod muškaraca Azijskog porekla. Za drugu testiranu varijantu rs2477686, rezultati kvantitativne sinteze podataka nisu bili statistički značajni. Na kraju, rezultati meta-analize ukazuju na povezanost između genetičke varijante rs12097821 i idiopatske neplodnosti muškaraca. Mikro RNK su mali nekodirajući molekuli RNK koji regulišu ekspresiju gena na postranskripcionom nivou i učestvuju u kontroli širokog spektra ćelijskih procesa. Postoje eksperimentalni podaci da promena u ekspresiji molekula miR-27a i miR-146a imaju uticaj na odvijanje procesa spermatogeneze i posledičan ukupan broj spermatozoida u ejakulatu. Prekomerna ekspresija miR-27a detektovana je u biološkim uzorcima muškaraca sa kliničkom dijagnozom neobstruktivne azoospermije. Ekspresija miR-146a je značajno smanjena u uzorcima muškaraca sa azoospermijom, dok je povišena u uzorcima muškaraca sa astenozoospermijom...

Following malignant tumors and vascular diseases, the World Health Organization ranks infertility as the third most prevalent human health condition, affecting over 190 million individuals globally. Clinically, infertility is defined as the inability to conceive after one year of regular, unprotected intercourse in a couple. "Male infertility" does not represent a well-defined clinical syndrome but rather encompasses a variety of congenital and acquired conditions with heterogeneous etiologies. In approximately one-third of infertile couples, male infertility is identified as the primary cause of impaired conception. When no clear cause is identified, the condition is termed idiopathic infertility. Among the various factors contributing to idiopathic male infertility, genetic and epigenetic alterations are predominant. The first genome-wide association study (GWAS) has identified significant associations between male infertility and three genetic variants: PRMT6 (rs12097821), PEX10 (rs2477686), and SOX5 (rs10842262) in Chinese men. One of the goals of this dissertation was to examine whether the results of this GWAS also apply to men from North Macedonia. After conducting a case-control study, the goal of this dissertation was a meta-analysis of this and other case-control studies that had as their topic the possible association of these three genetic variants with the risk for the development of idiopathic infertility. The case group comprised 137 men with clinically diagnosed idiopathic infertility, while the control group included 130 healthy volunteers of comparable age, all of whom had fathered at least one child. The results of the case-control study revealed no statistically significant association between the variants rs12097821, rs2477686, and rs10842262 and the risk of developing idiopathic infertility in men from North Macedonia. However, the frequency of the G allele of rs10842262 was significantly higher in infertile men with low ejaculate volume compared to their fertile counterparts. Additionally, the GG genotype of rs10842262 was found to be approximately twice as frequent in men with oligospermia relative to fertile men. The meta-analysis provided further insight, showing an association between the minor G allele of rs10842262 and male idiopathic infertility. Notably, this association remained statistically significant in Asian populations. Conversely, the rs2477686 variant did not show a significant association in the meta-analysis. In contrast, rs12097821 was found to be associated with male idiopathic infertility. MicroRNAs are small noncoding RNA molecules that function broadly as negative regulators of gene expression to control a wide range of cellular processes. Further examination of the molecular mechanisms underlying male infertility revealed that alterations in the expression of microRNAs, such as miR-27a and miR-146a, play a crucial role in spermatogenesis and sperm quality. Overexpression of miR-27a has been observed in men with non-obstructive azoospermia, while miR-146a expression was significantly decreased in azoospermic men but elevated in men with asthenozoospermia. The genetic variant rs2910164, located in the "seed" region of miR-146a, causes a G:U base pair substitution that affects miR-146a maturation. Similarly, the variant rs895819, situated within the pri-miRNA gene cluster for miR-23a, miR-24a, and miR-27a, alters the secondary structure of the miR-27a precursor. To date, no studies have explored the associations of the rs2910164 and rs895819 variants with idiopathic infertility in Slavic populations. In this study, 158 men from North Macedonia with clinical diagnoses of idiopathic infertility were examined for these genetic variants. The results did not indicate a significant association between either rs2910164 or rs895819 and the risk of idiopathic infertility. However, a closer look at subtypes of idiopathic infertility revealed that the C allele of rs2910164 was significantly more frequent in men with asthenoteratozoospermia compared to other infertility subtypes...

muška neplodnost, studija slučajeva i kontrola, meta-analiza, PRMT6, PEX10, SOX5, MIR27A i MIR146A

male infertility, case-control study, meta-analysis, PRMT6, PEX10, SOX5, MIR27A and MIR146A

577.2:616.697(497.7)(043.3) 612.61(497.7)(043.3)

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