Association between Interleukin-32 and Interleukin-17A Single Nucleotide Polymorphisms and Serum Levels with Polycystic Ovary Syndrome
Polycystic ovary syndrome (PCOS) is correlated with low-grade chronic inflammation. Interleukin-17A (IL-17A) and Interleukin-32 (IL-32) are two members of the pro-inflammatory cytokines which act as significant components of the immune system during certain inflammatory diseases. Along with immunological processes, genetic factors play major roles in predisposition to PCOS. There are myriad single nucleotide polymorphisms (SNPs) within IL-17A and IL-32 genes that may affect their production and the susceptibility of individuals to PCOS. The objective of the present research was to investigate the association between IL-17A (rs2275913) and IL-32 (rs9927163, rs4786370) SNPs, and also their serum levels with susceptibility to PCOS in a group of Iranian women. In this case-control study, 150 PCOS patients (mean age of 29.1 years) and 150 healthy women (mean age of 26.1 years) were analyzed in terms of IL-17A and IL-32 SNPs via polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Furthermore, serum levels of IL-17A and IL-32 cytokines were measured through the use of ELISA method. There were significant differences between PCOS and healthy women regarding IL-17A rs2275913 alleles, genotypes frequencies (p=0.005, and 0.01, respectively) and the allelic distribution of IL-32 rs9927163 SNP (p=0.03). Additionally, significant differences were indicated between two groups concerning the AG genotype against AA+GG genotypes (p=0.009) and the GG genotype against AA+AG genotypes (p=0.006) in IL-17A rs2275913 SNP. In the matter of IL-32 gene SNPs, GC haplotype frequency was significantly different between patients and controls (p=0.05). Furthermore, IL-32 serum level was not significantly different between the two studied groups and the serum level of IL-17A was not detectable. In conclusion, IL-17A and IL-32 SNPs might be associated with predisposition to PCOS in Iranian women.
2. Azziz R, Kashar-Miller MD. Family history as a risk factor for the polycystic ovary syndrome. JPEM 2000; (13 Suppl 5):1303-6.
3. Lerchbaum E, Schwetz V, Giuliani A, Obermayer-Pietsch B. Influence of a positive family history of both type 2 diabetes and PCOS on metabolic and endocrine parameters in a large cohort of PCOS women. Eur J Endocrinol 2014; 170(5):727-39.
4. Franks S, McCarthy M. Genetics of ovarian disorders: polycystic ovary syndrome. Rev Endocr Metab Disord 2004; 5(1):69-76.
5. Shorakae S, Teede H, de Courten B, Lambert G, Boyle J, Moran LJ. The Emerging Role of Chronic Low-Grade Inflammation in the Pathophysiology of Polycystic Ovary Syndrome. Semin Reprod Med 2015; 33(4):257-69.
6. Duleba AJ, Dokras A. Is PCOS an inflammatory process? Fertil Steril 2012; 97(1):7-12.
7. Kelly CC, Lyall H, Petrie JR, Gould GW, Connell JM, Sattar N. Low grade chronic inflammation in women with polycystic ovarian syndrome. J Clin Endocrinol Metab 2001; 86(6):2453-5.
8. Samy N, Hashim M, Sayed M, Said M. Clinical significance of inflammatory markers in polycystic ovary syndrome: their relationship to insulin resistance and body mass index. Dis Markers 2009; 26(4):163-70.
9. Ozcaka O, Buduneli N, Ceyhan BO, Akcali A, Hannah V, Nile C, et al. Is interleukin-17 involved in the interaction between polycystic ovary syndrome and gingival inflammation? J Periodontol 2013; 84(12):1827-37.
10. Iwakura Y, Ishigame H. The IL-23/IL-17 axis in inflammation. J Clin Invest 2006; 116(5):1218-22.
11. Espinoza JL, Takami A, Nakata K, Onizuka M, Kawase T, Akiyama H, et al. A genetic variant in the IL-17 promoter is functionally associated with acute graft-versus-host disease after unrelated bone marrow transplantation. PloS one 2011; 6(10):e26229.
12. Yan N, Yu YL, Yang J, Qin Q, Zhu YF, Wang X, et al. Association of interleukin-17A and -17F gene single-nucleotide polymorphisms with autoimmune thyroid diseases. Autoimmunity 2012; 45(7):533-9.
13. Hayashi R, Tahara T, Shiroeda H, Saito T, Nakamura M, Tsutsumi M, et al. Influence of IL17A polymorphisms (rs2275913 and rs3748067) on the susceptibility to ulcerative colitis. Clin Exp Med 2013; 13(4):239-44.
14. Anvari F, Dabagh-Gorjani F, Soltani-Zangbar MS, et al. Investigating the Association of IL-17A and IL-17F with Susceptibility to Pre-eclampsia in Iranian Women. IJI 2015; 12(2):117-28.
15. Wang H, Guo M, Liu F, Wang J, Zhou Z, Ji J, et al. Role of IL-17 Variants in Preeclampsia in Chinese Han Women. PloS one 2015; 10(10).
16. Zidan HE, Rezk NA, Alnemr AA, Moniem MI. Interleukin-17 and leptin genes polymorphisms and their levels in relation to recurrent pregnancy loss in Egyptian females. Immunogenetics 2015; 67(11-12):665-73.
17. Najafi S, Hadinedoushan H, Eslami G, Aflatoonian A. Association of IL-17A and IL-17 F gene polymorphisms with recurrent pregnancy loss in Iranian women. J Assist Reprod Genet 2014; 31(11):1491-6.
18. Heinhuis B, Netea MG, van den Berg WB, Dinarello CA, Joosten LAB. Interleukin-32: A predominantly intracellular proinflammatory mediator that controls cell activation and cell death. Cytokine 2012; 60(2):321-7.
19. Kim S. Interleukin-32 in inflammatory autoimmune diseases. Immune Netw 2014; 14(3):123-7.
20. Hong JT, Son DJ, Lee CK, Yoon DY, Lee DH, Park MH. Interleukin 32, inflammation and cancer. Pharmacol Ther 2017; 174:127-37.
21. Damen M, Schraa K, Tweehuysen L, den Broeder AA, Netea MG, Popa CD, et al. Genetic variant in IL-32 is associated with the ex vivo cytokine production of anti-TNF treated PBMCs from rheumatoid arthritis patients.
Sci Rep 2018; 8(1):e14050.
22. Arcaroli JJ, Liu N, Yi N, Abraham E. Association between IL-32 genotypes and outcome in infection-associated acute lung injury. Crit Care 2011; 15(3):R138.
23. Damen M, Popa CD, Netea MG, Dinarello CA, Joosten LAB. Interleukin-32 in chronic inflammatory conditions is associated with a higher risk of cardiovascular diseases. Atherosclerosis 2017; 264:83-91.
24. Damen MSMA, Agca R, Holewijn S, de Graaf J, Dos Santos JC, van Riel PL, et al. IL-32 promoter SNP rs4786370 predisposes to modified lipoprotein profiles in patients with rheumatoid arthritis. Sci Rep 2017; 7:41629.
25. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004; 81(1):19-25.
26. Yoo J, Lee Y, Kim Y, Rha SY, Kim Y. SNPAnalyzer 2.0: a web-based integrated workbench for linkage disequilibrium analysis and association analysis. BMC bioinformatics 2008; 9:290.
27. Zafari Zangeneh F, Naghizadeh MM, Masoumi M. Polycystic ovary syndrome and circulating inflammatory markers. Int J Reprod Biomed 2017; 15(6):375-82.
28. Rolandelli A, Hernández Del Pino RE, Pellegrini JM, Tateosian NL, Amiano NO, de la Barrera S, et al. The IL-17A rs2275913 single nucleotide polymorphism is associated with protection to tuberculosis but related to higher disease severity in Argentina. Sci Rep 2017; 7:40666.
29. Holster A, Terasjarvi J, Lauhkonen E, Tormanen S, Helminen M, Koponen P, et al. IL-17A gene polymorphism rs2275913 is associated with the development of asthma after bronchiolitis in infancy. Allergol Int 2018; 67(1):109-13.
30. Quan Y, Zhou B, Wang Y, Duan R, Wang K, Gao Q, et al. Association between IL17 Polymorphisms and Risk of Cervical Cancer in Chinese Women. Clin Dev Immunol 2012; 2012:258293.
31. Bahadori M, Zarei S, Zarnani AH, Zarei O, Idali F, Hadavi R, et al. IL-6, IL-10 and IL-17 gene polymorphisms in Iranian women with recurrent miscarriage. Iran J Immunol 2014; 11(2):97-104.
32. Zhang M, Xu J, Bao X, Niu W, Wang L, Du L, et al. Association between Genetic Polymorphisms in Interleukin Genes and Recurrent Pregnancy Loss - A Systematic Review and Meta-Analysis. PloS one 2017; 12(1):e0169891.
33. Ha YJ, Park JS, Kang MI, Lee SK, Park YB, Lee SW. Increased serum interleukin-32 levels in patients with Behcet's disease. Int J Rheum Dis (In Press) 2017.
34. Shamoun L, Kolodziej B, Andersson RE, Dimberg J. Protein Expression and Genetic Variation of IL32 and Association with Colorectal Cancer in Swedish Patients. Anticancer Res 2018; 38(1):321-8.
35. Simundic T, Jelakovic B, Dzumhur A, Turk T, Sahinovic I, Dobrosevic B, et al. Interleukin 17A and Toll-like Receptor 4 in Patients with Arterial Hypertension. Kidney Blood Press Res 2017; 42(1):99-108.
36. Hoffmann SC, Stanley EM, Cox ED, DiMercurio BS, Koziol DE, Harlan DM, et al. Ethnicity greatly influences cytokine gene polymorphism distribution. Am J Transplant 2002; 2(6):560-7.