مکانیسم‌های مولکولی و ژن‌های درگیر در ناباروری مردان مبتلا به واریکوسل: مرور سیستماتیک

نوع مقاله : مروری

نویسندگان

1 دانشجوی دکتری ژنتیک مولکولی، پژوهشکده زیست فناوری صنعت و محیط زیست، پژوهشگاه ملی مهندسی ژنتیک و زیست فناوری، تهران، ایران.

2 دانشیار ژنتیک مولکولی، گروه زیستشناسی، پردیس علوم، دانشگاه یزد، یزد، ایران.

10.22038/ijogi.2022.20431

چکیده

مقدمه: یکی از شایع‌ترین دلایل ناباروری مردان، ناهنجاری واریوکسل است. مردان با سابقه خانوادگی واریکوسل بیشتر در معرض خطر ابتلاء به این ناهنجاری­­ها هستند. در نتیجه عوامل ژنتیکی و مولکولی ممکن است در بیماری‌زایی واریکوسل، مرتبط با ناباروری نقش مهمی ایفا ­کنند. لذا مطالعه مروری حاضر با هدف بررسی ژن­های کاندید و مکانیسم‌های مولکولی آنها و نقش ژنتیک در ابتلاء یا تشدید آن در واریکوسل انجام شد.
روش‌کار: در این مطالعه جهت یافتن مقالات مرتبط، پایگاه‌های اطلاعاتی لاتین (PubMed، Google Scholar) و فارسی (SID و Magiran) بدون محدودیت زمانی و با استفاده از کلمات کلیدی Varicocele،Male Infertility و Gene در بازه زمانی 4 ساله مورد جستجو قرار گرفتند.
یافته­ها: جهش یا پلی­مورفیسم­های ژن­های کاندید احتمالی از جمله NOS3، hoGG1، TNP1,2، GST، POLG، P53، MTHFR ACP1 اثرات متفاوتی بر اسپرم، اسپرماتوژنز و در کل واریکوسل دارند.
نتیجه‌گیری: تاکنون چندین ژن به‌عنوان کاندیدهای احتمالی برای وقوع و پیشرفت واریکوسل در جمعیت­های گوناگون جهان مورد بررسی قرار گرفته است که هرکدام اثرات متنوعی بر پاتوفیزیولوژی واریکوسل نشان داده است. بنابراین صحیح یا غلط بودن فرضیه (تأثیر ژنتیک بر واریکوسل) به‌دلیل نداشتن هماهنگی شواهد و اختلاف نظر هنوز مشخص نیست.

کلیدواژه‌ها


عنوان مقاله [English]

Molecular Mechanisms and Genes involved in Infertile Men with Varicocele: A Systematic Review

نویسندگان [English]

  • Seyede Nafiseh Tabatabaei 1
  • Mohammad Mehdi Heidari 2
1 PHD Student in Molecular Genetics, Institute of Industrial and Environmental Biotechnology (IIEB), National Institute for Genetic and Biotechnology (NIGEB), Tehran, Iran.
2 Associate Professor of Molecular Genetics, Department of Biology, School of Sciences, Yazd University, Yazd, Iran.
چکیده [English]

Introduction: One of the most common causes of male infertility is Varicocele abnormality. Men with a family history of varicocele are at higher risk for these disorders. As a result, genetic and molecular factors may play an important role in the pathogenesis of varicocele associated with infertility. Therefore, this review study was performed with aim to investigate the role of candidate genes and their molecular mechanisms and the role of genetics in the development or exacerbation of varicocele.
Methods: In this review article, to find the related studies, the Latin (PubMed, Google Scholar) and Persian (SID and Magiran) databases were searched without time limitation in a period of 4 years using the keywords of "Varicocele, Male Infertility and Gene".
Results: Mutations or polymorphisms of probable candidate genes including GST, TNP1,2, hoGG1, NOS3, MTHFR ACP1, P53 and POLG have different effects on sperm, spermatogenesis and varicocele in general.
Conclusion: So far, several genes have been investigated as possible candidates for the occurrence and progression of varicocele in different populations of the world, each of which has shown various effects on the pathophysiology of varicocele. Therefore, the correctness or wrongness of the hypothesis (the effect of genetics on varicocele) is still unclear due to the lack of coordination of evidence.
 
Keywords: 

کلیدواژه‌ها [English]

  • Gene
  • Male Infertility
  • Single Nucleotid Polymorphism
  • Varicocele
  1. Rajeev K, Rupin SH. Varicocele and male infertility: current status; 2005.
  2. Moein MR, Soleimani M, Tabibnejad N. Reactive oxygen species (ROS) production in seminal fluid correlate with the severity of varicocele in infertile men. International Journal of Reproductive BioMedicine 2008; 6(3):65.
  3. Rao L, Babu A, Kanakavalli M, Padmalatha V, Singh A, Singh PK, et al. Chromosomal abnormalities and y chromosome microdeletions in infertile men with varicocele and idiopathic infertility of South Indian origin. Journal of andrology 2004; 25(1):147-53.
  4. Su JS, Farber NJ, Vij SC. Pathophysiology and treatment options of varicocele: An overview. Andrologia 2021; 53(1):e13576.
  5. Maheshwari A, Muneer A, Lucky M, Mathur R, McEleny K, British Association of Urological Surgeons and the British Fertility Society. A review of varicocele treatment and fertility outcomes. Human Fertility 2020: 1-8.
  6. Siegel D. Imaging and interventional therapy for varicoceles. Current urology reports 2014; 15(4):1-6.
  7. Miyaoka R, Esteves SC. A critical appraisal on the role of varicocele in male infertility. Advances in urology 2011; 2012.
  8. Weedin JW, Khera M, Lipshultz LI. Varicocele repair in patients with nonobstructive azoospermia: a meta-analysis. The Journal of urology 2010; 183(6):2309-15.
  9. Kantartzi PD, Goulis CD, Goulis GD, Papadimas I. Male infertility and varicocele: myths and reality. Hippokratia 2007; 11(3):99.
  10. Panner Selvam MK, Baskaran S, Agarwal A, Henkel R. Protein profiling in unlocking the basis of varicocele‐associated infertility. Andrologia 2021; 53(1):e13645.
  11. Sheehan MM, Ramasamy R, Lamb DJ. Molecular mechanisms involved in varicocele-associated infertility. Journal of assisted reproduction and genetics 2014; 31(5):521-6.
  12. Ata-Abadi NS, Mowla SJ, Aboutalebi F, Dormiani K, Kiani-Esfahani A, Tavalaee M, et al. Hypoxia-related long noncoding RNAs are associated with varicocele-related male infertility. PloS one 2020; 15(4):e0232357.
  13. Sandlow J. Pathogenesis and treatment of varicoceles. Bmj 2004; 328(7446):967-8.
  14. Esteves SC, Cho CL, Majzoub A, Agarwal A, editors. Varicocele and Male Infertility: A Complete Guide. Springer Nature; 2019.
  15. Santana VP, Esteves SC. Seeking the elusive genes associated with varicocele: a step forward. Fertility and Sterility 2021; 115(2):313-4.
  16. Santana VP, Miranda-Furtado CL, de Oliveira-Gennaro FG, Dos Reis RM. Genetics and epigenetics of varicocele pathophysiology: an overview. Journal of Assisted Reproduction and Genetics 2017; 34(7):839-47.
  17. Samanta L, Agarwal A, Swain N, Sharma R, Gopalan B, Esteves SC, et al. Proteomic signatures of sperm mitochondria in varicocele: clinical use as biomarkers of varicocele associated infertility. The Journal of urology 2018; 200(2):414-22.
  18. Santana VP, James ER, Miranda-Furtado CL, de Souza MF, Pompeu CP, Esteves SC, et al. Differential DNA methylation pattern and sperm quality in men with varicocele. Fertility and Sterility 2020; 114(4):770-8.
  19. Heidari MM, Khatami M, Danafar A, Dianat T, Farahmand G, Talebi AR. Mitochondrial genetic variation in Iranian infertile men with varicocele. International journal of fertility & sterility 2016; 10(3):303.
  20. de Sousa Filho EP, Christofolini DM, Barbosa CP, Glina S, Bianco B. Y chromosome microdeletions and varicocele as aetiological factors of male infertility: A cross‐sectional study. Andrologia 2018; 50(3):e12938.
  21. Jensen CF, Østergren P, Dupree JM, Ohl DA, Sønksen J, Fode M. Varicocele and male infertility. Nature Reviews Urology 2017; 14(9):523-33.
  22. Dong Q, Yang B, Ren ZJ. Genetic characteristics of varicocele: An almost unexplored area. Zhonghua nan ke xue= National Journal of Andrology 2018; 24(10):867-70.
  23. Dehghani M, Vahidi AR, Moin MR, Haghiroalsadat F, Sharafaldini M, Sheikhha MH. Investigating frequency of GSTT1 and GSTM1 genes null genotype in Men with varicocele and its association with the sperm parameters. SSU_Journals 2012; 20(3):350-60.
  24. Safarinejad MR, Shafiei N, Safarinejad S. The association of glutathione-S-transferase gene polymorphisms (GSTM1, GSTT1, GSTP1) with idiopathic male infertility. Journal of Human Genetics 2010; 55(9):565-70.
  25. Zhu B, Yin L, Zhang JY. Glutathione S-transferase polymorphisms in varicocele patients: a meta-analysis. Genetics and Molecular Research 2015; 14(4):18851-8.
  26. Chen SS, Chang LS, Chen HW, Wei YH. Polymorphisms of glutathione S-transferase M1 and male infertility in Taiwanese patients with varicocele. Human Reproduction 2002; 17(3):718-25.
  27. Wu Q, Xing J, Xue W, Sun J, Wang X, Jin X. Influence of polymorphism of glutathione S-transferase T1 on Chinese infertile patients with varicocele. Fertility and sterility 2009; 91(3):960-2.
  28. Tang K, Xue W, Xing Y, Xu S, Wu Q, Liu R, et al. Genetic polymorphisms of glutathione S‐transferase M1, T1, and P1, and the assessment of oxidative damage in infertile men with varicoceles from northwestern China. Journal of andrology 2012; 33(2):257-63.
  29. Acar H, Kılınç M, Guven S, Inan Z. Glutathione S‐transferase M1 and T1 polymorphisms in Turkish patients with varicocele. Andrologia 2012; 44(1):34-7.
  30. Ichioka K, Nagahama K, Okubo K, Soda T, Ogawa O, Nishiyama H. Genetic polymorphisms in glutathione S-transferase T1 affect the surgical outcome of varicocelectomies in infertile patients. Asian journal of andrology 2009; 11(3):333.
  31. Hu WG, Pan RJ, Cai W, Wang ZT, Zhu ZG. Lack of association between the hOGG1 gene Ser326Cys polymorphism and gastric cancer risk: evidence from a case-control study and a meta-analysis. Genet Mol Res 2015; 14:14670-9.
  32. Chen SS, Chiu LP. The hOGG1 Ser326Cys polymorphism and male subfertility in Taiwanese patients with varicocele. Andrologia 2018; 50(5):e13007.
  33. Heidari MM, Khatami M, Talebi AR, Moezzi F. Mutation analysis of TNP1 gene in infertile men with varicocele. Iranian journal of reproductive medicine 2014; 12(4):257.
  34. Heidari MM, Danafar A, Moezzi F, Khatami M, Talebi AR. The association between TNP2 gene polymorphisms and Iranian infertile men with varicocele: A case-control study. International Journal of Reproductive BioMedicine 2019; 17(8):557.
  35. Kahraman CY, Tasdemir S, Sahin I, Marzioglu Ozdemir E, Yaralı O, Ziypak T, et al. The relationship between endothelial nitric oxide synthase Gene (NOS3) polymorphisms, NOS3 expression, and varicocele. Genetic testing and molecular biomarkers 2016; 20(4):191-6.
  36. Tabatabaei SN, Heidari MM, Khatami M. The Study of Nitric Oxide Synthase 3 (NOS3) T-786C and 4a4b Gene Polymorphism in Iranian Men with Varicocele. Qom University of Medical Sciences Journal 2020; 13(12):45-54.
  37. Ucar VB, Nami B, Acar H, Kılınç M. Is methylenetetrahydrofolate reductase (MTHFR) gene A 1298 C polymorphism related with varicocele risk?. Andrologia 2015; 47(1):42-6.
  38. Gentile V, Nicotra M, Scaravelli G, Antonini G, Ambrosi S, Saccucci P, et al. ACP 1 genetic polymorphism and spermatic parameters in men with varicocele. Andrologia 2014; 46(2):147-50.
  39. Gentile V, Nicotra M, Minucci S, Ambrosi S, Saccucci P, Gloria‐Bottini F, et al. The relationship between p53 codon 72 genetic polymorphism and sperm parameters. A study of men with varicocele. Reproductive medicine and biology 2015; 14(1):11-5.
  40. Heidari MM, Khatami M, Talebi AR. The POLG gene polymorphism in Iranian varicocele-associated infertility patients. Iranian journal of basic medical sciences 2012; 15(2):739.
  41. Nayeri M, Talebi AR, Heidari MM, Seifati SM, Tabibnejad N. Polymorphisms of sperm protamine genes and CMA3 staining in infertile men with varicocele. Revista internacional de andrologia 2020; 18(1):7-13.
  42. Meistrich ML, Mohapatra B, Shirley CR, Zhao M. Roles of transition nuclear proteins in spermiogenesis. Chromosoma 2003; 111(8):483-8.
  43. Yu YE, Zhang Y, Unni E, Shirley CR, Deng JM, Russell LD, et al. Abnormal spermatogenesis and reduced fertility in transition nuclear protein 1-deficient mice. Proceedings of the National Academy of Sciences 2000; 97(9):4683-8.
  44. Noblanc A, Kocer A, Drevet JR. Recent knowledge concerning mammalian sperm chromatin organization and its potential weaknesses when facing oxidative challenge. Basic and clinical andrology 2014; 24(1):1-12.
  45. Zhao M, Shirley CR, Hayashi S, Marcon L, Mohapatra B, Suganuma R, et al. Transition nuclear proteins are required for normal chromatin condensation and functional sperm development. Genesis 2004; 38(4):200-13.
  46. Miyagawa Y, Nishimura H, Tsujimura A, Matsuoka Y, Matsumiya K, Okuyama A, et al. Single‐nucleotide polymorphisms and mutation analyses of the TNP1 and TNP2 genes of fertile and infertile human male populations. Journal of andrology 2005; 26(6):779-86.
  47. Agarwal A, Hamada A, Esteves SC. Insight into oxidative stress in varicocele-associated male infertility: part 1. Nature Reviews Urology 2012; 9(12):678-90.
  48. Visioli F, Hagen TM. Antioxidants to enhance fertility: role of eNOS and potential benefits. Pharmacological research 2011; 64(5):431-7.
  49. Wattanapitayakul SK, Mihm MJ, Young AP, Bauer JA. Therapeutic implications of human endothelial nitric oxide synthase gene polymorphism. Trends in pharmacological sciences 2001; 22(7):361-8.
  50. Shin SJ, Lee HH, Cha SH, Kim JH, Shim SH, Choi DH, et al. Endothelial nitric oxide synthase gene polymorphisms (− 786T> C, 4a4b, 894G> T) and haplotypes in Korean patients with recurrent spontaneous abortion. European Journal of Obstetrics & Gynecology and Reproductive Biology 2010; 152(1):64-7.
  51. Botto LD, Yang Q. 5, 10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. American journal of epidemiology 2000; 151(9):862-77.
  52. Schwahn B, Rozen R. Polymorphisms in the methylenetetrahydrofolate reductase gene. American journal of pharmacogenomics 2001; 1(3):189-201.
  53. Neri A, Banci M, Pietropolli A, Gloria-Bottini F, Magrini A. Smoking, ACP 1 and Infertility in Subjects with Varicocele. Health 2019; 11(10):1331.
  54. Jin Q, Wang B, Wang J, Liu T, Yu X, Jia C, et al. Association between TP53 gene Arg72Pro polymorphism and idiopathic infertility in southeast Chinese Han males. Systems biology in reproductive medicine 2013; 59(6):342-6.
  55. Mashayekhi F, Hadiyan SP. A single‐nucleotide polymorphism in TP53 may be a genetic risk factor for Iranian patients with idiopathic male infertility. Andrologia 2012; 44:560-4.
  56. Jeong BS, Hu W, Belyi V, Rabadan R, Levine AJ. Differential levels of transcription of p53‐regulated genes by the arginine/proline polymorphism: p53 with arginine at codon 72 favors apoptosis. The FASEB Journal 2010; 24(5):1347-53.
  57. Gashti NG, Salehi Z, Madani AH, Dalivandan ST. 4977‐bp mitochondrial DNA deletion in infertile patients with varicocele. Andrologia 2014; 46(3):258-62.
  58. Ferlin A, Raicu F, Gatta V, Zuccarello D, Palka G, Foresta C. Male infertility: role of genetic background. Reproductive biomedicine online 2007; 14(6):734-45.
  59. Krausz C, Guarducci E, Becherini L, Degl’Innocenti S, Gerace L, Balercia G, et al. The clinical significance of the POLG gene polymorphism in male infertility. The Journal of Clinical Endocrinology & Metabolism 2004; 89(9):4292-7.
  60. Oliva R. Protamines and male infertility. Human reproduction update 2006; 12(4):417-35.
  61. Steger K, Balhorn R. Sperm nuclear protamines: A checkpoint to control sperm chromatin quality. Anatomia, histologia, embryologia 2018; 47(4):273-9.
  62. Balhorn R. The protamine family of sperm nuclear proteins. Genome biology 2007; 8(9):1-8.
  63. Rahimi H, Fateh F, Sheidanik S, Tabatabaei SN, Arefnezhad R, Khorrami N, et al. Genetics of Human Infertility. 1nd Tehran: jame-e-Negar; 1399.
  64. Yang B, Yang Y, Liu Y, Li H, Ren S, Peng Z, et al. Molecular characteristics of varicocele: integration of whole-exome and transcriptome sequencing. Fertility and Sterility 2021; 115(2):363-72.