Laouar Rania, Chellat-Rezgoune Djalila, Horchi Meroua, Achou Rayene, Djoudi Brahim, Touabti Souhem, Benhizia Yacine, Sifi Karima
Laboratory of Molecular and Cellular Biology, Department of Animal Biology, Faculty of Natural and Life Science, University of Mentouri Constantine 1, Constantine, Algeria.
LIRE Laboratory, Department of Biochemistry, University of Mentouri Constantine 1, Constantine, Algeria.
Turk J Pediatr. 2025 Jul 6;67(3):398-409. doi: 10.24953/turkjpediatr.2025.6049.
Hypospadias, a congenital condition characterized by the urethral opening being on the underside of the penis, has received limited attention in its association with the MTHFR C677T variant. Given the crucial role of folate metabolism in embryonic development, and the involvement of the MTHFR C677T polymorphism in folate metabolism, this study aims to investigate whether this variant contributes to the risk of hypospadias in an Algerian population.
This case-control study included 105 patients with hypospadias and 125 controls. Genotyping of the MTHFR gene C677T variant was performed using polymerase chain reaction-restriction fragment length polymorphism.
A statistically significant difference in the genotype distribution of the MTHFR C677T variant between patients with hypospadias and controls was revealed. The significance was observed in the codominant genetic model CT vs. CC (p=0.034, odds ratio [OR]: 1.89, 95% CI: 1.04-3.44) and TT vs. CC (p=0.042, OR: 2.15, 95% CI: 1.02-4.53), as well as in the dominant model CC vs. CT+TT (p=0.010, OR: 1.98, 95% CI: 1.17-3.35). Maternal periconceptional folic acid supplement intake showed a significant association with the anatomical types of hypospadias in relation to the MTHFR C677T genotypes when folic acid was taken (p=0.006). Furthermore, a significant association was observed with the TT genotype in isolated hypospadias cases (p=0.038, OR=3.47, 95% CI: 1.03-11.68), suggesting a potential role of folic acid in modifying hypospadias risk. Multiple logistic regression analysis identified intrauterine growth restriction, gestational hypertension, residency, and the MTHFR C677T variant as independent potential risk factors for hypospadias development (p-values: 0.030, 0.016, 0.040, and 0.045, respectively).
This study reports, for the first time, an association between the MTHFR gene C677T variant and hypospadias in the Algerian population. The findings suggest a strong association between the MTHFR C677T variant and susceptibility to hypospadias. Identified risk factors such as intrauterine growth restriction, gestational hypertension, rural residency, and the MTHFR C677T variant contribute valuable insights into the multifaceted etiology of hypospadias in this population.
尿道下裂是一种先天性疾病，其特征为尿道开口位于阴茎腹侧，而关于它与亚甲基四氢叶酸还原酶（MTHFR）C677T变异体之间的关联，目前受到的关注有限。鉴于叶酸代谢在胚胎发育中起关键作用，且MTHFR C677T多态性参与叶酸代谢，本研究旨在调查该变异体是否会增加阿尔及利亚人群患尿道下裂的风险。
本病例对照研究纳入了105例尿道下裂患者和125例对照。采用聚合酶链反应-限制性片段长度多态性方法对MTHFR基因C677T变异体进行基因分型。
尿道下裂患者与对照之间，MTHFR C677T变异体的基因型分布存在统计学显著差异。在共显性遗传模型中，CT与CC相比（p = 0.034，比值比[OR]：1.89，95%置信区间[CI]：1.04 - 3.44）以及TT与CC相比（p = 0.042，OR：2.15，95% CI：1.02 - 4.53）具有显著性，在显性模型CC与CT + TT相比时也具有显著性（p = 0.010，OR：1.98，95% CI：1.17 - 3.35）。母亲围孕期补充叶酸摄入与MTHFR C677T基因型相关的尿道下裂解剖类型之间存在显著关联（p = 0.006）。此外，在单纯尿道下裂病例中观察到与TT基因型存在显著关联（p = 0.038，OR = 3.47，95% CI：1.03 - 11.68），这表明叶酸在改变尿道下裂风险方面可能发挥作用。多因素逻辑回归分析确定宫内生长受限、妊娠期高血压、居住地以及MTHFR C677T变异体为尿道下裂发生的独立潜在风险因素（p值分别为0.030、0.016、0.040和0.045）。
本研究首次报道了阿尔及利亚人群中MTHFR基因C677T变异体与尿道下裂之间的关联。研究结果表明MTHFR C677T变异体与尿道下裂易感性之间存在密切关联。所确定的风险因素，如宫内生长受限、妊娠期高血压、农村居住地以及MTHFR C677T变异体，为该人群尿道下裂的多方面病因提供了有价值的见解。
