Association of polymorphic markers in innate immunity receptor genes with the risk of primary adrenal insufficiency

Primary adrenal insufficiency is a disease resulting from bilateral destruction of the adrenal cortex. The most common etiological factors are autoimmune disorders and infectious diseases, which indicates the key role of the immune system in the development of this pathology. Activation of innate immune receptors leads to transcription of genes for pro-inflammatory cytokines and type I interferons, which contributes to the further development of the inflammatory process, activating both adaptive and innate immunity. The role of pattern recognition receptors and type I interferons has been previously shown in many autoimmune pathologies, but their significance in primary adrenal insufficiency is still not well understood. To gain a broader understanding of the occurring processes, innate immune receptors are being studied at both the molecular and genetic levels. Thus, the purpose of our work was to study polymorphic markers in the genes of interferon, NOD- and RIG-like receptors and their association with the risk of developing primary adrenal insufficiency. The biomaterial was collected from patients with primary adrenal insufficiency and from healthy individuals and was examined using real-time polymerase chain reaction. It was found that among the six polymorphic markers (rs2257167 in the IFNAR1 gene, rs2229207 in the IFNAR2 gene, rs2075822 in the NOD1 gene, rs8057341 and rs3135499 in the NOD2 gene and rs1990760 in the IFIH1 gene), there are only two sufficient predictors of the risk of developing primary adrenal gland disease: rs2257167 (IFNAR1) and rs2229207 (IFNAR2). The association of heterozygous genotypes of the polymorphic markers rs2257167 (IFNAR1) and rs2229207 (IFNAR2) with the risk of developing pathology, as well as the protective role of the CC genotype of the polymorphic marker rs2257167 (IFNAR1) was shown. The results obtained can be used for early diagnostics of the disease. These data can contribute to a better understanding of the pathogenesis of primary adrenal insufficiency and serve as the basis for further research in the field of personalized medicine. These markers can also be studied in connection with the severity of primary adrenal insufficiency, complications, as well as in connection with the effectiveness of the therapy.

1. Gankovskaya L.V., Khelminskaya N.M., Molchanova E.A., Svitich O.A. Role of innate immunity factors in periodontitis pathogenesis. Zhurnal mikrobiologii, epidemiologii i immunobiologii = Journal of Microbiology, Epidemiology, Immunobiology, 2016, no. 2, pp. 100-107. (In Russ.)

2. Melnichenko G.A., Fadeev V.V., Buziashvili I.I. Etiological aspects of primary chronic adrenal insufficiency. Problemy endokrinologii = Problems of Endocrinology, 1998, Vol. 44, no. 4, pp. 46-51. (In Russ.)

3. Svitich O.A., Gankovskaya L.V., Rakhmanova I.V., Zaytseva I.A., Gankovskiy V.A. The association of polymorphic markers in the 5’-untranslated region of the Defb1 gene with adenoid hypertrophy vegetations. Vestnik Rossiyskogo gosudarstvennogo meditsinskogo universiteta = Bulletin of Russian State Medical University, 2012, no. 3, pp. 59-62. (In Russ.)

4. Yukina M.Y., Nuralieva N.F., Troshina E.A. Analysis of prevalence and incidence of adrenal insufficiency in the world. Ateroscleroz = Atherosclerosis, 2022, Vol. 18, no. 4, pp. 426-429. (In Russ.)

5. Buonocore F., Achermann J.C Primary adrenal insufficiency: New genetic causes and their long-term consequences. Clin. Endocrinol., 2020, Vol. 92, no. 1, pp. 11-20.

6. Chen L., Cao S.Q., Lin Z.M., He S.J., Zuo J.P. NOD-like receptors in autoimmune diseases. Acta Pharmacol. Sin., 2021, Vol. 42, no. 11, pp. 1742-1756.

7. Ehtesham N., Alani B., Mortazavi D., Azhdari S., Kenarangi T., Esmaeilzadeh E., Pakzad B. Association of rs3135500 and rs3135499 Polymorphisms in the MicroRna-binding Site of Nucleotide-binding Oligomerization Domain 2 (NOD2) Gene with Susceptibility to Rheumatoid Arthritis. Iran. J. Allergy Asthma Immunol., 2021, Vol. 20, no. 2, pp. 178-187.

8. Esmaeilzadeh E., Saghi M., Hassani M., Davar S., Alani B., Pakzad B., Ghobakhloo S., Khosravi S., Sabet M.N. Strong association of common variants in the miRNA-binding site of NOD2 gene with clinicopathological characteristics and disease activity of systemic lupus erythematosus. Clin. Rheumatol., 2021, Vol. 40, no. 11, pp. 4559-4567.

9. Ivashkiv L.B., Donlin L.T. Regulation of type I interferon responses. Nat. Rev. Immunol., 2014, Vol. 14, no. 1, pp. 36-49.

10. Jiang J., Zhao M., Chang C., Wu H., Lu Q. Type I interferons in the pathogenesis and treatment of autoimmune diseases. Clin. Rev. Allergy Immunol., 2020, Vol. 59, no. 2 pp. 248-272.

11. Penna-Martinez M., Ramos-Lopez E., Robbers I., Kahles H., Hahner S., Willenberg H., Reisch N., Seidl C., Segni M., Badenhoop K. The rs1990760 polymorphism within the IFIH1 locus is not associated with Graves’ disease, Hashimoto’s thyroiditis and Addison’s disease. BMC Med. Genet., 2009, Vol. 4, no. 10, 126. doi:10.1186/1471-2350- 10-126.

12. Takeuchi O., Akira S. Pattern recognition receptors and inflammation. Cell, 2010, Vol. 140, no. 6, pp. 805-820.

13. Weidinger S., Klopp N., Rummler L., Wagenpfeil S., Novak N., Baurecht H.J., Groer W., Darsow U., Heinrich J., Gauger A., Schafer T., Jakob T., Behrendt H., Wichmann H.E., Ring J., Illig T. Association of NOD1 polymorphisms with atopic eczema and related phenotypes. J. Allergy Clin. Immunol., 2005, Vol. 116, no. 1, pp. 177-184.

14. Zhang Y., Liu J., Wang C., Liu J., Lu W. Toll-like receptors gene polymorphisms in autoimmune disease. Front. Immunol., 2021, no. 12, 672346. doi: 10.3389/fimmu.2021.672346.

15. Zurawek M., Fichna M., Januszkiewicz D., Fichna P., Nowak J. Polymorphisms in the interferon-induced helicase (IFIH1) locus and susceptibility to Addison’s disease. Clin. Endocrinol., 2013, Vol. 78, no. 2, pp. 191-196.