Association of rs13429458 and rs12478601 Single Nucleotide Polymorphisms of THADA Gene with Polycystic Ovary Syndrome

Document Type : Original Article


1 Department of Reproductive Biology, Academic Center for Education, Culture and Research, Qom Branch, Qom, Iran

2 Department of Biology, Faculty of Science, Islamic Azad University, Qom, Iran

3 Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research, Qom Branch, Qom, Iran


Background: It is thought that genetic factors are influential in the etiology of polycystic ovarian syndrome (PCOS),
the most frequent endocrinological disorder of females in their reproductive age. This study was carried out to elucidate
the association of rs13429458 and rs12478601 single nucleotide polymorphisms (SNPs) of the THADA gene and
the risk of the PCOS among a population of Iranian female patients.
Materials and Methods: This case-control study contains 66 infertile women with PCOS (patient group) and 44
healthy women without PCOS (control group) that referred to the IVF Unit of the Infertility Research Center of the
Academic Center for Education, Culture and Research (ACECR). The polymerase chain reaction (PCR) was utilized
to amplify genome DNA as well as direct sequencing to determine SNPs. The THADA rs12478601 and rs13429458
genotypes were consequently examined with amplification refractory mutation system-PCR (ARMS-PCR).
Results: In this study, we observed that rs13429458 polymorphism was not associated with PCOS risk in two groups (P=0.42). On the other hand, data analysis indicated that the rs12478601 genotype significantly increased the risk of PCOS in the case group (P=0.032) in compared with control group. We found that the “T” allele of rs12478601 in the THADA gene had a significant relation to PCOS in the case group (odds ratio [OR]: 2.574, 95% confidence interval [CI]: 1.439-4.604, P=0.001).
Conclusion: This study has presented further evidence that TT and CT genotype of THADA rs12478601 is associated
with a high risk of PCOS.


  1. Albaghdadi AJH, Kan FWK. Therapeutic potentials of low-dose tacrolimus for aberrant endometrial features in polycystic ovary syndrome. Int J Mol Sci. 2021; 22(6): 2872.
  2. Zhang FF, Zhang Q, Wang YL, Wang FF, Hardiman PJ, Qu F. Intergenerational influences between maternal polycystic ovary syndrome and offspring: an updated overview. J Pediatr. 2021; 232: 272-281.
  3. Crespo RP, Bachega TASS, Mendonça BB, Gomes LG. An update of genetic basis of PCOS pathogenesis. Arch Endocrinol Metab. 2018; 62(3): 352-361.
  4. Højlund K. Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance. Dan Med J. 2014; 61(7): B4890.
  5. Mykhalchenko K, Lizneva D, Trofimova T, Walker W, Suturina L, Diamond MP, et al. Genetics of polycystic ovary syndrome. Expert Rev Mol Diagn. 2017; 17(7): 723-733.
  6. Xia JY, Tian W, Yin GH, Yan H. Association of Rs13405728, Rs12478601, and Rs2479106 single nucleotide polymorphisms and in vitro fertilization and embryo transfer efficacy in patients with polycystic ovarian syndrome: a case control genome-wide association study. Kaohsiung J Med Sci. 2019; 35(1): 49-55.
  7. Dumesic DA, Hoyos LR, Chazenbalk GD, Naik R, Padmanabhan V, Abbott DH. Mechanisms of intergenerational transmission of polycystic ovary syndrome. Reproduction. 2020; 159(1): R1-R13.
  8. Khan MJ, Ullah A, Basit S. Genetic basis of polycystic ovary syndrome (PCOS): current perspectives. Appl Clin Genet. 2019; 12: 249-260.
  9. Rippe V, Drieschner N, Meiboom M, Escobar HM, Bonk U, Belge G, et al. Identification of a gene rearranged by 2p21 aberrations in thyroid adenomas. Oncogene. 2003; 22(38): 6111-6114.
  10. Goodarzi MO, Jones MR, Li X, Chua AK, Garcia OA, Chen YDI, et al. Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts. J Med Genet. 2012; 49(2): 90-95.
  11. Gao J, Xue JD, Li ZC, Zhou L, Chen C. The association of DENND1A gene polymorphisms and polycystic ovary syndrome risk: a systematic review and meta-analysis. Arch Gynecol Obstet. 2016; 294(5): 1073-1080.
  12. Ha L, Shi Y, Zhao J, Li T, Chen ZJ. Association study between polycystic ovarian syndrome and the susceptibility genes polymorphisms in Hui Chinese women. PLoS One. 2015; 10(5): e0126505.
  13. Bao S, Ren YC, Chen ZS, Yang SY, Yi YP, Li JJ, et al. THADA gene variants and polycystic ovary syndrome in a Hainan Chinese population. Int J Clin Exp Pathol. 2016; 9(11): 11883-11889.
  14. Wang R, Mol BWJ. The rotterdam criteria for polycystic ovary syndrome: evidence-based criteria? Hum Reprod. 2017; 32(2): 261-264.
  15. Naserpoor L, Berjis K, Jannatifar R. Evaluation of the pregnancy rate of freezing embryo transfer in the presence or absence of GnRH agonist. J Arak Univ Med Sci. 2020; 23(6): 818-827.
  16. Pesole G, Liuni S, Grillo G, Licciulli F, Mignone F, Gissi C, et al. UTRdb and UTRsite: specialized databases of sequences and functional elements of 5′ and 3′ untranslated regions of eukaryotic mRNAs. Update 2002. Nucleic Acids Res. 2002; 30(1): 335-340.
  17. Frixione E, Ruiz-Zamarripa L. The “scientific catastrophe” in nucleic acids research that boosted molecular biology. J Biol Chem. 2019; 294(7): 2249-2255.
  18. Maleki A, Bashirian S, Soltanian AR, Jenabi E, Farhadinasab A. Association between polycystic ovary syndrome and risk of attention-deficit/hyperactivity disorder in offspring: a meta-analysis. Clin Exp Pediatr. 2021; 37(8): 716-720.
  19. Dadachanji R, Sawant D, Patil A, Mukherjee S. Replication study of THADA rs13429458 variant with PCOS susceptibility and its related traits in Indian women. Gynecol Endocrinol. 2021; 37(8): 716-720.
  20. Arikoglu H, Erkoc-Kaya D, Ipekci SH, Gokturk F, Iscioglu F, Korez MK, et al. Type 2 diabetes is associated with the MTNR1B gene, a genetic bridge between circadian rhythm and glucose metabolism, in a Turkish population. Mol Biol Rep. 2021; 48(5): 4181-4189.
  21. Carnesecchi J, Pinto PB, Lohmann I. Hox transcription factors: an overview of multi-step regulators of gene expression. Int J Dev Biol. 2018; 62(11-12): 723-732.
  22. Artini PG, Obino MER, Micelli E, Malacarne E, Vacca C, Papini F, et al. Effect of d-chiro-inositol and alpha-lipoic acid combination on COH outcomes in overweight/obese PCOS women. Gynecol Endocrinol. 2020; 36(9): 755-759.
  23. Friedenreich CM, Ryder-Burbidge C, McNeil J. Physical activity, obesity and sedentary behavior in cancer etiology: epidemiologic evidence and biologic mechanisms. Mol Oncol. 2021; 15(3): 790-800.
  24. Miazgowski T, Martopullo I, Widecka J, Miazgowski B, Brodowska A. National and regional trends in the prevalence of polycystic ovary syndrome since 1990 within Europe: the modeled estimates from the Global Burden of Disease Study 2016. Arch Med Sci. 2019; 17(2): 343-351.
  25. Li H, He YL, Li R, Wong C, Sy B, Lam CW, et al. Age-specific reference ranges of serum anti-müllerian hormone in healthy women and its application in diagnosis of polycystic ovary syndrome: a population study. BJOG. 2020; 127(6): 720-728.
  26. Skiba MA, Bell RJ, Herbert D, Garcia AM, Islam RM, Davis SR. Use of community-based reference ranges to estimate the prevalence of polycystic ovary syndrome by the recognised diagnostic criteria, a cross-sectional study. Hum Reprod. 2021; 36(6): 1611-1620.
  27. Ali AH, Abbas HJ, Naser NA. Preptin and adropin levels as new predictor in women with polycystic ovary syndrome. J Pharm Sci Res. 2018; 10(11): 3005-3008.
  28. Kahal H, Kyrou I, Uthman OA, Brown A, Johnson S, Wall PDH, et al. The prevalence of obstructive sleep apnoea in women with polycystic ovary syndrome: a systematic review and meta-analysis. Sleep Breath. 2020; 24(1): 339-350.
  29. Pani A, Gironi I, Vieste GD, Mion E, Bertuzzi F, Pintaudi B. From prediabetes to type 2 diabetes mellitus in women with polycystic ovary syndrome: lifestyle and pharmacological management. Int J Endocrinol. 2020; 2020: 6276187.