Gene-gene interactions of cytokines and C-reactive protein in psoriasis in residents of Kemerovo region

Psoriasis is the most common inflammatory skin disease, affecting on average 2-4% of the world’s population. Currently, psoriasis is considered a multifactorial disease occurring in genetically predisposed individuals under the influence of various environmental factors that trigger a disrupted immune response via complex inflammatory cascades. The disease is initiated and maintained by the mutual interaction of cells of innate and adaptive immunity, primarily, dendritic cells, T lymphocytes and keratinocytes. Their leading role may alternate at different stages of the disease and proceeds, mainly, at the IL-23/Th17 pathway. To date, many gene polymorphisms (SNPs) associated with the development of psoriasis have been described. To understand the pathophysiology of psoriasis as a complex autoinflammatory disease, it seems interesting to study the intergenic interactions between polymorphic gene variants of cytokines and C-reactive protein related to the risk of psoriasis development. The aim of our study was to investigate intergenic interactions of polymorphic variants of IL1β (rs16944), IL6 (rs1554606), IL8 (rs2227306), IL10 (rs1800896), TNFα (rs361525), CRP (rs1205) genes associated with altered risk of psoriasis development among the Kemerovo Region residents. We examined 175 patients with ordinary papular plaque psoriasis of moderate severity, with progressive course of the disorder. The control group (n = 155) was recruited from conditionally healthy, age-matched donors. Genotyping was performed by PCR using TaqMan probes (Thermo Fisher Scientific, USA), by means of the detection amplifier ViiA^TM 7 Real-Time PCR System (Life Technologies, USA), for the following polymorphic variants of genes: IL1β (rs16944), IL6 (rs1554606), IL8 (rs2227306), IL10 (rs1800896), TNFα (rs361525), CRP (rs1205). Intergenic interactions were analyzed using Multifactor Dimensionality Reduction (MDR). The common papulosis-plaque psoriasis was found to be associated with individual polymorphic variants of cytokine and CRP genes as well as with gene-gene interactions. Concerning individual polymorphic gene variants, the association strength (% entropy) with common papulosis-plaque psoriasis was as follows: TNFα_ rs361525 (16.99% entropy), IL1β_rs16944 (6.40% entropy), CRP_rs1205 (2.55% entropy), IL6_rs1554606 (1.11% entropy), IL10_rs1800896 (0.57% entropy), IL8_rs2227306 (0.30% entropy). We have found that IL6 (rs1554606) and IL8 (rs2227306) showed marked synergism, as well as moderate synergism of CRP (rs1205) and IL10 (rs1800896), and pronounced antagonism of IL1β (rs16944) and TNFα (rs361525).

1. Maximova Yu.V., Svechnikova EV, Maximov VN, Kolesnik KN, Lykova SG Polymorphism -511C/T gene IL1B and atopic dermatitis. Immunopatologiya, allergologiya, infektologiya = Immunopathology, Allergology, Infectology, 2015, no. 2, pp. 35-38. (In Russ.)

2. Meniailo M.E., Malashchenko V.V., Shmarov V.A., Gasatova N.D., Melashchenko O.B., Goncharov A.G., Seledtsova G.V., Seledtsov V.I. A role for interleukin-8 in direct regulation of T cell functional activity. Meditsinskaya immunologiya = Medical Immunology (Russia), 2017, Vol. 19, no. 5, pp. 529-536. (In Russ.)

3. Nemchaninova O.B., Malchenko E.E., Maksimov V.N., Lykova S.G. Association of single nucleotide polymorphism-511C/T (rs16944) of IL-1b gene with psoriasis and eczema. Meditsinskiy almanakh = Medicine Almanac, 2018, Vol. 4, no 55, pp. 178-180. (In Russ.)

4. Ponomarenko I.V. Using the method of Multifactor Dimensionality Reduction (MDR) and its modifications for analysis of gene-gene and gene-environment interactions in genetic-epidemiological studies (review). Nauchnye rezultaty biomeditsinskikh issledovaniy = Research Results in Biomedicine, 2019, Vol. 5, no. 1, pp. 4-21. (In Russ.)

5. Shevchenko A.V., Golovanova O.V., Konenkov V.I., Voevoda M.I., Maksimov V.N. Polimorfizm promotornogo regiona gena IL-1β u pacientov s ostrym infarktom miokarda v anamneze. Meditsinskaya Immunologiya = Medical Immunology (Russia), 2010, Vol. 12, no. 3, pp. 219-226. (In Russ.)

6. Acikbas I., Sanlı B., Tepeli E., Ergin S., Aktan S., Bagci H. Vitamin D receptor gene polymorphisms and haplotypes (Apa I, Bsm I, Fok I, Taq I) in Turkish psoriasis patients. Med. Sci. Monit., 2012, Vol. 18, no. 11, pp. CR661CR 666.

7. Akcılar R., Dizen Namdar N., Yükcü F., Arslan Utku S. TNF-α gene -238G>A polymorphism is associated with psoriasis patients. J. Cosmet. Dermatol., 2022, Vol. 21, no. 6, pp. 2662-2667.

8. AlBosale A.H., Mashkina E.V. Association between ТР53, MDM2 and NQO1 gene polymorphisms and viral load among women with human papillomavirus. Vavilovskii Zhurnal Genet. Selektsii, 2022, Vol. 26, no. 1, pp. 59-64.

9. Alharbi K.K., Syed R., Khan I.A. Association of interleukin-6 polymorphisms with obesity and metabolic alterations in young Saudi population. Mol. Biol. Rep., 2014, Vol. 41, no. 3, pp. 1519-1523.

10. Arican O., Aral M., Sasmaz S., Ciragil P. Serum levels of TNF-alpha, IFN-gamma, IL-6, IL-8, IL-12, IL-17, and IL-18 in patients with active psoriasis and correlation with disease severity. Mediators Inflamm., 2005, Vol. 5, pp. 273-279.

11. Cramer C., Link E., Horster M., Koletzko S., Bauer C.P., Berdel D., von Berg A., Lehmann I., Herbarth O., Borte M., Schaaf B., Behrendt H., Chen C.M., Sausenthaler S., Illig T., Wichmann H.E., Heinrich J., Krämer U.; LISAplus Study Group and the GINIplus Study Group. Elder siblings enhance the effect of filaggrin mutations on childhood eczema: results from the 2 birth cohort studies LISAplus and GINIplus. J. Allergy Clin. Immunol., 2010, Vol. 125, no. 6, pp. 1254-1260.e5.

12. Cui Y.X., Zhao H., Guo H.Q. Role of IL-8 rs4073 and rs2227306 polymorphisms in the development of primary gouty arthritis in a Chinese population. Genet. Mol. Res., 2016, Vol. 15, no. 4, gmr15048511. doi: 10.4238/gmr15048511.

13. Daprà V., Ponti R., Lo Curcio G., Archetti M., Dini M., Gavatorta M., Quaglino P., Fierro M.T., Bergallo M. Functional study of TNF-α as a promoter of polymorphisms in psoriasis. Ital. J. Dermatol. Venerol., 2022, Vol. 157, no. 2, pp. 146-153.

14. Emonts M., Hazes M.J.M.W., Houwing-Duistermaat J.J., van der Gaast-de Jongh C.E., de Vogel L., Han H.K.H., Wouters J.M.G.W., Laman J.D., Dolhain R.J.E.M. Polymorphisms in genes controlling inflammation and tissue repair in rheumatoid arthritis: A case control study. BMC Med. Genet., 2011, Vol. 12, 36. doi: 10.1186/1471-2350-12-36.

15. Galimova E., Rätsep R., Traks T., Kingo K., Escott-Price V., Kõks S. Interleukin-10 family cytokines pathway: genetic variants and psoriasis. Br. J. Dermatol., 2017, Vol. 176, no. 6, pp. 1577-1587.

16. Gola D., Mahachie John J.M., van Steen K., König I.R. A roadmap to multifactor dimensionality reduction methods. Brief. Bioinform., 2016, Vol. 17, no. 2, pp. 293-308.

17. Hagag M.M., Ghazy M.M., Elhelbawy N.G. Tumor necrosis factor-α gene promoter −308 and −238 polymorphisms and its serum level in psoriasis. Biochem. Biophysics Rep., 2021, Vol. 27, 101050. doi: 10.1016/j.bbrep.2021.101050.

18. Hahn L.W., Ritchie M.D., Moore J.H. Multifactor dimensionality reduction software for detecting genegene and gene-environment interactions. Bioinformatics, 2003, Vol. 19, no. 3, pp. 376-382.

19. Hébert H.L., Bowes J., Smith R.L., McHugh N.J., Barker J.N.W.N., Griffiths C.E.M., Barton A., Warren R.B. Polymorphisms in IL-1B distinguish between psoriasis of early and late onset. J. Invest. Dermatol., 2014, Vol. 134, no. 5, pp. 1459-1462.

20. Indhumathi S., Rajappa M., Chandrashekar L., Hariharan Ananthanarayanan P., Thappa D. M., Negi V. S. T helper-2 cytokine/regulatory T-cell gene polymorphisms and their relation with risk of psoriasis in a South Indian Tamil cohort. Hum. Immunol., 2017, Vol. 78, pp. 209-215.

21. Isac L., Jiquan S. Interleukin 10 promotor gene polymorphism in the pathogenesis of psoriasis. Acta Dermatovenerol. Alp. Pannonica Adriat., 2019, Vol. 28, no. 3, pp. 119-123.

22. Karam R.A., Zidan H.E., Khater M.H. Polymorphisms in the TNF-α and IL-10 gene promoters and risk of psoriasis and correlation with disease severity. Cytokine, 2014, Vol. 66, no. 2, pp. 101-105.

23. Lin N., Lu H., Cheng X., Zhao Y., Wan Q., Luo Y., Miao Y., Bai X., Liu D., Wang C. Association between the interleukin-1B polymorphism at rs16944 T>C and diabetic retinopathy. Int. J. Immunogenet., 2023, Vol. 50, no. 1, pp. 34-40.

24. Ogawa E., Sato Y., Minagawa A., Okuyama R. Pathogenesis of psoriasis and development of treatment. J. Dermatol., 2018, Vol. 45, no. 3, pp. 264-272.

25. Park M., Jeong H.B., Lee J.H., Park T. Spatial rank-based multifactor dimensionality reduction to detect gene-gene interactions for multivariate phenotypes. BMC Bioinformatics, 2021, Vol. 22, no. 1, 480. doi: 10.1186/s12859-021-04395-y.

26. Pușcaș A.D., Morar I.I., Vesa Ș.C., Cătană A., Pușcaș C., Ilieș R.F., Orasan R.-I. Association between IL-17F, IL-17RA gene polymorphisms and response to biological drugs in psoriasis and beyond. Genes, 2023, Vol. 14, no. 5, 1123. doi: 10.3390/genes14051123.

27. Qiao J., Jia Q.-N., Jin H.-Z. Lack of association of the IL-1RN and IL-10 polymorphisms with risk of psoriasis: A meta-analysis. Mol. Genet. Genomic Med., 2019, Vol. 7, no. 1, e00512. doi.org/10.1002/mgg3.512.

28. Sadafi S., Ebrahimi A., Sadeghi M., Emami Aleagha O. Association between tumor necrosis factoralpha polymorphisms (rs361525, rs1800629, rs1799724, 1800630, and rs1799964) and risk of psoriasis in studies following Hardy-Weinberg equilibrium: A systematic review and meta-analysis. Heliyon, 2023, Vol. 9, no. 7, e17552. doi: 10.1016/j.heliyon.2023.e17552.

29. Shen C.,Wang H., Song Q., Zhang B., Liu X., Li J. Tumor Necrosis Factor-α 308 G/A polymorphism and psoriasis risk: a pooled analysis in different populations. Medicine, 2020, Vol. 99, no. 47, e22339. doi: 10.1097/MD.0000000000022339.

30. Silva B.R.D., Cirelli T., Nepomuceno R., Theodoro L.H., Orrico S.R.P., Cirelli J.A., Barros S.P., ScarelCaminaga R.M. Functional haplotype in the Interleukin8 (CXCL8) gene is associated with type 2 Diabetes Mellitus and Periodontitis in Brazilian population. Diabetes Metab. Syndr., 2020, Vol. 14, no. 6, pp.1665-1672.

31. Sudhesan A., Rajappa M., Chandrashekar L., Ananthanarayanan P.H., Thappa D.M., Satheesh S., Chandrasekaran A., Devaraju P. Association of C-reactive protein (rs1205) gene polymorphism with susceptibility to psoriasis in south indian tamils. J. Clin. Diagn. Res., 2016, Vol. 10, no. 10, pp. GC01-GC04.

32. Suleman S., Chhabra G., Raza R., Hamid A., Qureshi J.A., Ahmad N. Association of CARD14 SingleNucleotide Polymorphisms with Psoriasis. Int. J. Mol. Sci. 2022, Vol. 23, no. 16, 9336. doi: 10.3390/ ijms23169336.

33. Traks T., Keermann M., Prans E., Karelson M., Loite U., Kõks G., Silm H., Kõks S., Kingo K. Polymorphisms in IL36G gene are associated with plaque psoriasis. BMC Med. Genet., 2019, Vol. 20, no. 1, 10. doi: 10.1186/s12881-018-0742-2.

34. Vičić M., Kaštelan M., Brajac I., Sotošek V., Massari L.P. Current concepts of psoriasis immunopathogenesis. Int. J. Mol. Sci., 2021, Vol. 22, no. 21, 11574. doi: 10.3390/ijms222111574.

35. Wongpiyabovorn J., Hirankarn N., Ruchusatsawat K., Yooyongsatit S., Asawanonda P., Poovorawan Y. Association of the interleukin-10 distal promoter (-2763A/C) polymorphism with late-onset psoriasis. Clin. Exp. Dermatol., 2008, Vol. 23, no. 2, pp. 186-189.

36. Wu M., Dai C., Zeng F. Cellular mechanisms of psoriasis pathogenesis: a systemic review. Clin. Cosmet. Investig. Dermatol., 2023, Vol. 16, pp. 2503-2515.

37. Wu X., Zhao Z. Associations between ERAP1 gene polymorphisms and psoriasis susceptibility: a metaanalysis of case-control studies. Biomed Res. Int., 2021, Vol. 2021, 5515868. doi: 10.1155/2021/5515868.