rs1800734: matüration arrestine bağlı nonobstrüktif azoospermi için bir risk aleli

Abstract

Arka Plan: Erkek interfilitesi, önemli bir üreme sağlığı sorunu olmasının yanı sıra, genel erkek sağlık durumunun bir biyolojik belirteci olarak giderek daha fazla kabul görmektedir. Nonobstrüktif azoospermi (NOA) hastaları, en kötü sağlık durumunun ve kansere yakalanma riskinin en yüksek olduğu gruptur. Kanser duyarlılık geni olan MLH1’in, mayoz bölünme sırasında homolog rekombinasyonda rol oynadığı iyi bilinmektedir. Mlh1 mutant farelerde, mayoz arresti ile birlikte azoospermi görülmüştür. Amaç: Bu çalışmada MLH1 geninin erkek infertilitesiyle de ilişkili olup olmadığını daha ayrıntılı olarak araştırmak amacıyla, nonobstrüktif azoospermiye bağlı matürasyon arresti (MA) olan erkeklerde MLH1 genindeki risk alelerini saptamayı amaçladık. Olgular ve Metodlar: MA olan 42 hastada MLH1 varyantlarının genotipleri belirlendi. Önemi olan varyantlar daha sonra GnomAD v.3.1.2 (kanser dışı) erkek popülasyon veritabanı ve bir ulusal genetik hastalık değerlendirme merkezinin (UGHDM) ekzom veri deposu ile karşılaştırıldı. Bulgular: rs1800734 alel frekansı, GnomAD'a (p<0,001) kıyasla hasta grubunda anlamlı olarak daha yüksek saptandı (odds oranı (OR): 2,3 (1,5-3,5)) ve UGHDM 'nin ekzom verilerine (p=0,002) kıyasla OR: 2 (1,3-3,1) idi. Rs1800734 için homozigot genotip, GnomAD (p<0,001) OR: 5 (2,24-11) ve ekzom verilerine (p=0,010) kıyasla OR: 3,3 (1,4-7,5) ile hasta grubunda anlamlı olarak daha yüksek saptandı. Sonuç: Bu çalışmada, rs1800734'ün MA ile ilişkili NOA için bir risk aleli olduğu tespit edilmiştir. Rs1800734'ün MLH1 promoter hipermetilasyonu ile ilişkili olduğu bilinmektedir. MLH1 promoter hipermetilasyonunun oligozoospermili erkeklerde arttığı gösterilmiştir, bu nedenle rs1800734 açısından azoospermi için de karsinogenezde aynı mekanizma mevcut olabileceği düşünülmüştür.

Keywords

• rs1800734
• MLH1
• Nonobstrüktif azoospermi
• matürasyon arresti
• erkek infertilitesi

rs1800734: a risk allele for nonobstructive azoospermia related to maturation arrest

Abstract

Background: Male infertility is increasingly being conceived as a biomarker of general male health status other than being a significant reproductive health issue. Nonobstructive azoospermia (NOA) patients have the worst health status impairment as well as highest risk of developing cancer. It’s well known that cancer susceptibility gene, MLH1 have roles in homologous recombination during meiosis. Mlh1 mutant mice have azoospermia with meiotic arrest. Aim: We aimed to identify risk alleles in MLH1 gene in males with nonobstructive azoospermia related maturation arrest (MA) to investigate further whether this cancer susceptibility gene is also related to male infertility. Patients and Methods: MLH1 variants were genotyped in 42 patients with MA. The variants of interest then compared to GnomAD v.3.1.2 (non-cancer) male population database and to the repository exome data of a national genetic disease evaluation center (NGDEC). Results: rs1800734 allele frequencies were significantly higher in the patient group compared to GnomAD (p<0.001) with odds ratio (OR):2.3 (1.5-3.5), and to the exome data of NGDEC (p=0.002) with OR:2 (1.3-3.1). Homozygous genotype for rs1800734 was significantly higher in the patient group compared to the GnomAD (p<0.001) with OR: 5 (2.24-11) and to the exome data (p=0.010) with OR: 3.3 (1.4-7.5). Conclusion: In this study we found rs1800734 is a risk allele for NOA related to MA. It is known that rs1800734 is related to hypermethylation of MLH1 promoter. As MLH1 hypermethylation has been shown to be increased in oligozoospermic males, the same mechanism in carcinogenesis may also exist for azoospermia in the context of rs1800734.

Keywords

• rs1800734
• MLH1
• nonobstructive azoospermia
• maturation arrest
• male infertility

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