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Türk popülasyonunda azoospermik erkek infertilitesi için bir risk faktörü olarak LEP -2548G>A (rs7799039) ve LEPR Q223R (rs1137101) polimorfizmlerinin ikili etkisi

Year 2023, Volume: 48 Issue: 2, 369 - 376, 02.07.2023
https://doi.org/10.17826/cumj.1245822

Abstract

Amaç: İnfertilite, korunmasız cinsel ilişkiye rağmen en az bir yıl içerisinde gebelik elde edilememesi durumudur. Erkek kısırlığı, testislerde hiç sperm olmamasından (azospermi) sperm kalitesindeki gözle görülür değişikliklere kadar değişebilir. Leptin (LEP) geninde mutasyon olan hastaların infertil olduğu, Leptin Reseptör (LEPR) geninde mutasyon olan hastaların puberte gelişiminin olmadığı gösterilmiştir. Bu çalışma azospermik erkek infertilitesi ile LEP geni -2548G>A ve LEPR geni Q223R polimorfizmleri arasında bir ilişki olup olmadığını ortaya koymak amacıyla yapılmıştır.
Gereç ve Yöntem: Bu çalışmaya 137 azospermik infertil erkek ve 100 fertil erkek dahil edildi. Katılımcıların periferik kanlarından elde edilen DNA'lar, polimeraz zincir reaksiyonu (PCR) ile birlikte restriksiyon fragman uzunluk polimorfizmi (RFLP) teknikleri ile analiz edildi.
Bulgular: LEP -2548G>A (rs7799039) ve LEPR Q223R (rs1137101) polimorfizmleri açısından azospermik infertil ve fertil erkeklerin genotip ve alel dağılımlarında istatistiksel olarak dikkat çekici bir farklılık gözlenmedi. Kompozit genotip analizinde GGQR kompozit genotipinin azospermik infertil erkeklerde fertil erkeklere göre yaklaşık 9 kat daha fazla olduğu belirlendi (8.8% vs. 1.0%).
Sonuç: LEP -2548G>A ve LEPR Q223R polimorfizmlerinin azospermik erkek infertilitesinde ikili etkiye sahip olabileceği belirlendi. Bu çalışmaların daha geniş popülasyonlarda yapılmasıyla daha etkin ve kesin sonuçlara ulaşılabileceğine inanıyoruz.

Supporting Institution

Yok

Project Number

Yok

Thanks

Bu çalışma, Yüksek Lisans tezinin bir raporudur

References

  • Mahat RK, Arora M, Bhale DV, Holkar S, Kumar S, Yadav T. Risk factors and causes of male infertility-a review. Biochem Anal Biochem. 2016;5:1-5.
  • Agarwal A, Mulgund A, Hamada A, Chyatte MR. A unique view on male infertility around the globe. Reprod Biol Endocrinol. 2015;13:1-9.
  • Krausz, C. Male infertility: pathogenesis and clinical diagnosis. Best Pract Res Clin Endocrinol Metab. 2011;25:271-85.
  • Tournaye H, Krausz C, Oates RD. Novel concepts in the aetiology of male reproductive impairment. Lancet Diabetes Endocrinol. 2017;5:544-53.
  • Sharlip ID, Jarow JP, Belker AM, Lipshultz LI, Sigman M, Thomas AJ et al. Best practice policies for male infertility. Fertil Steril. 2002;77:873–82.
  • Isse N, Ogawa Y, Tamura N, Masuzaki H, Mori K, Okazaki T et al. Structural organization and chromosomal assignment of the human obese gene. J Biol Chem. 1995;270:27728-33.
  • Gonzalez-Añover P, Encinas T, Torres-Rovira L, Sanz E, Pallares P, Ros J et al. Patterns of corpora lutea growth and progesterone secretion in sows with thrifty genotype and leptin resistance due to leptin receptor gene polymorphisms (Iberian pig). Reprod Domest Anim. 2011;46:1011–6.
  • Cunningham MJ, Clifton DK, Steiner RA. Leptin's actions on the reproductive axis: perspectives and mechanisms. Biol Reprod. 1999;60:216–22.
  • Ponzo OJ, Reynoso R, Rondina D, Szwarcfarb B, Carbone S, Scacchi P et al. Effect of leptin on LH levels and hypothalamic release of GnRH. Its relationship with the hypothalamic neurotransmitter amino acids system in adult male rats. Endocr Res. 2004;30:179–87.
  • Jahan S, Bibi R, Ahmed S, Kafeel S. Leptin levels in infertile males. J Coll Physicians Surg Pak. 2011;21:393–7.
  • Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet. 1998;18:213–5.
  • Hoffstedt J, Eriksson P, Mottagui-Tabar S, Arner P. A polymorphism in the leptin promoter region (-2548 G/A) influences gene expression and adipose tissue secretion of leptin. Horm Metab Res. 2002;34:355–9.
  • Su PH, Yang SF, Yu JS, Chen SJ, Chen JY. Study of leptin levels and gene polymorphisms in patients with central precocious puberty. Pediatr Res. 2012;71:361–7.
  • Khosropour S, Hamidi M, Fattahi A, Khodadadi I, Karami M, Fazilati M et al. Leptin and leptin-receptor polymorphisms in fertile and infertile men. Syst Biol Reprod Med. 2017;63:7-14.
  • Vaisse C, Halaas JL, Horvath CM, Darnell JE Jr, Stoffel M, Friedman JM. Leptin activation of Stat3 in the hypothalamus of wildtype and ob/ob mice but not in db/db mice. Nature Genet. 1996;14:95-100.
  • Winick JD, Stoffel M, Friedman JM. Identification of microsatellite markers linked to the human leptin receptor gene on chromosome 1. Genomics. 1996;36:221-2.
  • Ishikawa T, Fujioka H, Ishimura T, Takenaka A, Fujisawa M. Expression of leptin and leptin receptor in the testis of fertile and infertile patients. Andrologia. 2007;39:22–7.
  • Aquila S, Rago V, Guido C, Casaburi I, Zupo S, Carpino A. Leptin and leptin receptor in pig spermatozoa: evidence of their involvement in sperm capacitation and survival. Reproduction. 2008;136:23–32.
  • Clément K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature. 1998;392:398–401.
  • Yiannakouris N, Yannakoulia M, Melistas L, Chan JL, Klimis-Zacas D, Mantzoros CS. The Q223R polymorphism of the leptin receptor gene is significantly associated with obesity and predicts a small percentage of body weight and body composition variability. J Clin Endocrinol Metab. 2001;86:4434–9.
  • Akhter N, Carllee T, Syed MM, Odle AK, Cozart MA, Haney AC et al. Selective deletion of leptin receptors in gonadotropes reveals activin and GnRH-binding sites as leptin targets in support of fertility. Endocrinology. 2014;55:4027–42.
  • Hodžić A, Ristanović M, Zorn B, Tulić C, Maver A, Novaković I et al. Genetic variation in leptin and leptin receptor genes as a risk factor for idiopathic male infertility. Andrology. 2017;5:70-4.
  • Mammes O, Betoulle D, Aubert R, Herbeth B, Siest G, Fumeron F. Association of the G-2548A polymorphism in the 5′ region of the LEP gene with overweight. Ann Hum Genet. 2000;64:391–4.
  • Kargasheh FB, Ansaripour S, Borumandnia N, Moradi N, Zandieh Z, Maleki M et al. Association of leptin G2548A and leptin receptor Q223R polymorphisms and their serum levels with infertility and recurrent pregnancy loss in Iranian women with polycystic ovary syndrome. PLoS One. 2021;16:e0255920.
  • Peelman F, Iserentant H, De Smet AS, Vandekerckhove J, Zabeau L, Tavernier J. Mapping of binding site III in the leptin receptor and modeling of a hexameric leptin. leptin receptor complex. J Biol Chem. 2006;281:15496–504.
  • Saukko M, Kesäniemi YA, Ukkola O. Leptin receptor Lys109Arg and Gln223Arg polymorphisms are associated with early atherosclerosis. Metab Syndr Relat Disord. 2010;8:425–30.
  • Martins AD, Moreira AC, Sá R, Monteiro MP, Sousa M, Carvalho RA et al. Leptin modulates human Sertoli cells acetate production and glycolytic profile: a novel mechanism of obesity-induced male infertility? Biochim Biophys Acta. 2015;1852:1824–32.
  • Alves MG, Jesus TT, Sousa M, Goldberg E, Silva BM, Oliveira PF. Male fertility and obesity: are ghrelin, leptin and glucagon-like peptide-1 pharmacologically relevant? Curr Pharm. 2016;22:783–91.
  • Gandhi Muruganandhan S, Manian R. Computational and artificial neural network based study of functional SNPs of human LEPR protein associated with reproductive function. J Cell Biochem. 2019;120:18910-26.

Dual effect of LEP -2548G>A (rs7799039) and LEPR Q223R (rs1137101) polymorphisms as a risk factor for azoospermic male infertility in Turkish population

Year 2023, Volume: 48 Issue: 2, 369 - 376, 02.07.2023
https://doi.org/10.17826/cumj.1245822

Abstract

Purpose: Infertility is the situation in which pregnancy cannot be achieved despite unprotected sexual intercourse within at least one year. Male infertility can range from the entire absence of spermatozoa in the testicles (azoospermia) to noticeable variations in sperm quality. The patients with a mutation in the leptin (LEP) gene have been reported to be infertile and the patients with a mutation in the Leptin Receptor (LEPR) gene were shown to lack pubertal development. This study was performed to state if there is a relationship between azoospermic male infertility and LEP gene -2548G>A and LEPR gene Q223R polymorphisms.
Materials and Methods: One hundred thirty-seven azoospermic infertile men and a hundred fertile men were included in this study. DNAs obtained from peripheral blood of participants were analyzed by polymerase chain reaction (PCR) along with restriction fragment length polymorphism (RFLP) technics..
Results: In terms of LEP -2548G>A (rs7799039) and LEPR Q223R (rs1137101) polymorphisms, no statistically remarkable distinction was observed in the genotype and allele distributions of azoospermic infertile and fertile men. In the composite genotype analysis, it was determined that the GGQR composite genotype was approximately 9 times more common in azoospermic infertile men than in fertile men (8.8% vs. 1.0%).
Conclusion: It has been determined that LEP -2548G>A and LEPR Q223R polymorphisms may have a dual effect in azoospermic male infertility. We believe that more efficient and precise results can be obtained by conducting these studies in larger populations.

Project Number

Yok

References

  • Mahat RK, Arora M, Bhale DV, Holkar S, Kumar S, Yadav T. Risk factors and causes of male infertility-a review. Biochem Anal Biochem. 2016;5:1-5.
  • Agarwal A, Mulgund A, Hamada A, Chyatte MR. A unique view on male infertility around the globe. Reprod Biol Endocrinol. 2015;13:1-9.
  • Krausz, C. Male infertility: pathogenesis and clinical diagnosis. Best Pract Res Clin Endocrinol Metab. 2011;25:271-85.
  • Tournaye H, Krausz C, Oates RD. Novel concepts in the aetiology of male reproductive impairment. Lancet Diabetes Endocrinol. 2017;5:544-53.
  • Sharlip ID, Jarow JP, Belker AM, Lipshultz LI, Sigman M, Thomas AJ et al. Best practice policies for male infertility. Fertil Steril. 2002;77:873–82.
  • Isse N, Ogawa Y, Tamura N, Masuzaki H, Mori K, Okazaki T et al. Structural organization and chromosomal assignment of the human obese gene. J Biol Chem. 1995;270:27728-33.
  • Gonzalez-Añover P, Encinas T, Torres-Rovira L, Sanz E, Pallares P, Ros J et al. Patterns of corpora lutea growth and progesterone secretion in sows with thrifty genotype and leptin resistance due to leptin receptor gene polymorphisms (Iberian pig). Reprod Domest Anim. 2011;46:1011–6.
  • Cunningham MJ, Clifton DK, Steiner RA. Leptin's actions on the reproductive axis: perspectives and mechanisms. Biol Reprod. 1999;60:216–22.
  • Ponzo OJ, Reynoso R, Rondina D, Szwarcfarb B, Carbone S, Scacchi P et al. Effect of leptin on LH levels and hypothalamic release of GnRH. Its relationship with the hypothalamic neurotransmitter amino acids system in adult male rats. Endocr Res. 2004;30:179–87.
  • Jahan S, Bibi R, Ahmed S, Kafeel S. Leptin levels in infertile males. J Coll Physicians Surg Pak. 2011;21:393–7.
  • Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet. 1998;18:213–5.
  • Hoffstedt J, Eriksson P, Mottagui-Tabar S, Arner P. A polymorphism in the leptin promoter region (-2548 G/A) influences gene expression and adipose tissue secretion of leptin. Horm Metab Res. 2002;34:355–9.
  • Su PH, Yang SF, Yu JS, Chen SJ, Chen JY. Study of leptin levels and gene polymorphisms in patients with central precocious puberty. Pediatr Res. 2012;71:361–7.
  • Khosropour S, Hamidi M, Fattahi A, Khodadadi I, Karami M, Fazilati M et al. Leptin and leptin-receptor polymorphisms in fertile and infertile men. Syst Biol Reprod Med. 2017;63:7-14.
  • Vaisse C, Halaas JL, Horvath CM, Darnell JE Jr, Stoffel M, Friedman JM. Leptin activation of Stat3 in the hypothalamus of wildtype and ob/ob mice but not in db/db mice. Nature Genet. 1996;14:95-100.
  • Winick JD, Stoffel M, Friedman JM. Identification of microsatellite markers linked to the human leptin receptor gene on chromosome 1. Genomics. 1996;36:221-2.
  • Ishikawa T, Fujioka H, Ishimura T, Takenaka A, Fujisawa M. Expression of leptin and leptin receptor in the testis of fertile and infertile patients. Andrologia. 2007;39:22–7.
  • Aquila S, Rago V, Guido C, Casaburi I, Zupo S, Carpino A. Leptin and leptin receptor in pig spermatozoa: evidence of their involvement in sperm capacitation and survival. Reproduction. 2008;136:23–32.
  • Clément K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature. 1998;392:398–401.
  • Yiannakouris N, Yannakoulia M, Melistas L, Chan JL, Klimis-Zacas D, Mantzoros CS. The Q223R polymorphism of the leptin receptor gene is significantly associated with obesity and predicts a small percentage of body weight and body composition variability. J Clin Endocrinol Metab. 2001;86:4434–9.
  • Akhter N, Carllee T, Syed MM, Odle AK, Cozart MA, Haney AC et al. Selective deletion of leptin receptors in gonadotropes reveals activin and GnRH-binding sites as leptin targets in support of fertility. Endocrinology. 2014;55:4027–42.
  • Hodžić A, Ristanović M, Zorn B, Tulić C, Maver A, Novaković I et al. Genetic variation in leptin and leptin receptor genes as a risk factor for idiopathic male infertility. Andrology. 2017;5:70-4.
  • Mammes O, Betoulle D, Aubert R, Herbeth B, Siest G, Fumeron F. Association of the G-2548A polymorphism in the 5′ region of the LEP gene with overweight. Ann Hum Genet. 2000;64:391–4.
  • Kargasheh FB, Ansaripour S, Borumandnia N, Moradi N, Zandieh Z, Maleki M et al. Association of leptin G2548A and leptin receptor Q223R polymorphisms and their serum levels with infertility and recurrent pregnancy loss in Iranian women with polycystic ovary syndrome. PLoS One. 2021;16:e0255920.
  • Peelman F, Iserentant H, De Smet AS, Vandekerckhove J, Zabeau L, Tavernier J. Mapping of binding site III in the leptin receptor and modeling of a hexameric leptin. leptin receptor complex. J Biol Chem. 2006;281:15496–504.
  • Saukko M, Kesäniemi YA, Ukkola O. Leptin receptor Lys109Arg and Gln223Arg polymorphisms are associated with early atherosclerosis. Metab Syndr Relat Disord. 2010;8:425–30.
  • Martins AD, Moreira AC, Sá R, Monteiro MP, Sousa M, Carvalho RA et al. Leptin modulates human Sertoli cells acetate production and glycolytic profile: a novel mechanism of obesity-induced male infertility? Biochim Biophys Acta. 2015;1852:1824–32.
  • Alves MG, Jesus TT, Sousa M, Goldberg E, Silva BM, Oliveira PF. Male fertility and obesity: are ghrelin, leptin and glucagon-like peptide-1 pharmacologically relevant? Curr Pharm. 2016;22:783–91.
  • Gandhi Muruganandhan S, Manian R. Computational and artificial neural network based study of functional SNPs of human LEPR protein associated with reproductive function. J Cell Biochem. 2019;120:18910-26.
There are 29 citations in total.

Details

Primary Language English
Subjects Clinical Sciences
Journal Section Research
Authors

Merve Akman 0000-0002-1009-195X

Nevin Karakuş 0000-0002-1916-7471

Hüsniye Rüstemoğlu 0000-0002-3143-5475

Project Number Yok
Early Pub Date July 9, 2023
Publication Date July 2, 2023
Acceptance Date April 8, 2023
Published in Issue Year 2023 Volume: 48 Issue: 2

Cite

MLA Akman, Merve et al. “Dual Effect of LEP -2548G>A (rs7799039) and LEPR Q223R (rs1137101) Polymorphisms As a Risk Factor for Azoospermic Male Infertility in Turkish Population”. Cukurova Medical Journal, vol. 48, no. 2, 2023, pp. 369-76, doi:10.17826/cumj.1245822.