Associations of the APEX1 T444G DNA repair gene with the gout development

   Objective. To study the frequencies of alleles and genotypes of the polymorphic locus T444G rs1130409 of the APEX1 DNA repair gene in patients with gout and to evaluate their association with the gout development in the Russian population in the Trans-Baikal Territory.

   Materials and methods. 80 patients (69 men and 11 women) with gout were examined. The diagnosis of gout was made in accordance with the ACR/EULAR classification criteria, 2015. The control group consisted of 46 persons of the appropriate age. According to nationality all the subjects were Russians, born and living in the territory of the Trans-Baikal Territory. The material for the study was DNA isolated from whole peripheral blood leukocytes using the DNA-Express Blood kit (Litech, Russia). All patients were genotyped to determine the polymorphism of the T444G rs1130409 locus of the APEX1 gene. Statistical data processing was carried out using the Statistica 10.0 software registry. The correspondence of genotype distribution to the Hardy-Weinberg equilibrium was checked by χ² criterion. Differences in the frequency of alleles and genotypes between groups were assessed by Pearson's χ² test. To assess the association of genotypes and alleles with gout, high odds ratios (Odds Ratio, OR) were calculated with a 95 % confidence interval (Confidence Interval, CI).

   Results. In the study of T444G polymorphism of the APEX1 gene in patients with gout a statistically significant increase in the frequency of the homozygous genotype G/G (27.5 % vs. 9 %; χ² = 6.3; p = 0.01; OR = 3.98; CI 95 % = 1.28 -12.4) were found. In the group of male patients with gout, there is a higher frequency of the mutant G allele compared to the control group (53.6 % vs. 4 %; χ² = 5.66; p = 0.01; OR = 2.24; CI95 % = 1, 14-4.40) and a statistically significant decrease in the frequency of the T allele (46.4 % vs. 96 %; χ² = 5.66, p = 0.01, OR = 0.45, CI95 % = 0.23-0, 87).

   Conclusion. Differences were found in the distribution of allele and genotype frequencies of the APEX1 T444G rs1130409 polymorphic locus in patients with gout and healthy respondents. The presence of the G/G genotype G increases the risk of gout by 3.9 times respectively. In male respondents, the carriage of the wild-type (T) allele has a protective effect, while the carriage of the minor allele was associated with an increased likelihood of developing the disease. The data obtained indicate the possible role of the APEX1 T444G rs1130409 gene polymorphism in the pathogenesis of gout.

1. Suhih Zh.L., Shtonda M.V., Petrov S.A., Vorob'eva E.P. Gout: modern aspects of diagnosis and treatment. Mezhdunarodnye obzory: klinicheskaja praktika i zdorov'e. 2014. 5(11). 79-89. in Russian.

2. Denisov I.S., Eliseev M.S., Barskova V.G. Gout outcomes. A review of literature. Part 1. Gout: Epidemiology, risk factors, course of the disease with the development of chronic tophus form. Rheumatology Science and Practice. 2013. 51(5). 569-573. URL: https://rsp.mediar-press.net/rsp/article/view/1677?locale=ru_RU.. in Russian.

3. Tsurko V.V., Gromova M.A., Chervyakova Yu.B., Kopelev A.A. Hyperuricemia and Cardiovascular Diseases: Modern Aspects of Therapy. Lechebnoe delo. 2019. 1. 14-19. URL: 10.24411/2071-5315-2019-12085. in Russian.

4. Denisov I.S., Eliseev M.S.., Barskova VG. Gout outcomes. Literature review. Part II. Comorbid diseases, risk of developing cardiovascular catastrophes and death in gout patients. Rheumatology Science and Practice. 2013. 51(6). 703-710. URL: https://rsp.mediar-press.net/rsp/article/view/1683.. in Russian.

5. Ledyakhova M.V., Nasonova S.N., Tereshchenko S.N. Hyperuricemia as a predictor of chronic heart failure. Ration Pharmacother Cardiol. 2015. 11(4). 355-358. DOI: 10.20996/1819-6446-2015-11-4-355-358. in Russian.

6. Singh J.A., Gaffo A. Gout epidemiology and comorbidities/ Semin Arthritis Rheum. 2020. 50 (3S). S11-S16. DOI: 10.1016/j.semarthrit.2020.04.008.

7. Eliseev M.S., Novikova A.M. Comorbidity in gout and hyperuricemia: prevalence, causes, prospects of urate lowering therapy. Therapeutic Archive. 2019. 91(5). 120-128. DOI: 10.26442/00403660.2019.05.000232. in Russian.

8. Merriman T.R. An update on the genetic architecture of hyperuricemia and gout. Arthritis Res Ther. 2015. 17 (1). 98. URL: https://www.researchgate.net/publication/274838354_An_update_on_the_genetic_architecture_of_hyperuricemia_and_gout.

9. Zheng M., Ma J.W. Research progress in the genetics of hyperuricaemia and gout. Yi Chuan. 2016 Apr. 38(4). 300-13. DOI: 10.16288/j.yczz.15-385.

10. Chen C.J., Tseng C.C., Yen J.H., et al. ABCG2 contributes to the development of gout and hyperuricemia in a genome-wide association study. Sci Rep. 2018. 8(1). 3137. DOI: 10.1038/s41598-018-21425-7.

11. Nakatochi M., Kanai M., Nakayama A., et al. Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals. Commun Biol. 2019. 2. 115. DOI: 10.1038/s42003-019-0339-0.

12. Kushnarenko N.N., Mishko M.Yu., Medvedeva T.A., Vitkovsky Yu.A. ABCG2 gene polymorphism in patients with gout in Zabaikalsky krai. Complex Issues of Cardiovascular Diseases. 2019. 8(2). 77-86. DOI: 10.17802/2306-1278-2019-8-2-77-86. in Russian.

13. Mishko M. Yu., Kushnarenko N. N., Medvedeva T. A. Analysis of intergenic interactions predisposing to gout among the russian population of the Trans-Baikal territory. Zabajkal'skij medicinskij vestnik : jelektronnoe nauchnoe izdanie. 2020. 4. 96-109. URL: https://elibrary.ru/item.asp?id=44600202 (date of the application: 14. 11. 2022). DOI: 10.52485/19986173_2020_4_96. in Russian.

14. Eliseev M.S., Chikina M.N., Guseva I.A., Zhelyabina O.V., Samarkina E.Yu., Konovalova N.V., Varlamov D.A. Association of the Q141K polymorphism of the ABCG2 gene with the effectiveness of urate-lowering therapy in patients with gout (a pilot study). Modern Rheumatology Journal. 2021. 15(6). 55-60. DOI: 10.14412/1996-7012-2021-6-55-60. in Russian.

15. Peng Q., Lu Y., Lao X., et al. Association between OGG1 Ser326Cys and APEX1 Asp148Glu polymorphisms and breast cancer risk: a meta-analysis. Diagnostic Pathology. 2014. 9. 108. DOI: 10.1186/1746-1596-9-108.

16. Das S., Nath S., Bhowmik A., Ghosh S.K., Choudhry Y. Association between OGG1 Ser326Cys polymorphism and risk of upper aero-digestive tract and gastrointestinal cancers: a metaanalysis. SpringerPlus. 2016. 5. 227. DOI: 10.1186/s40064-016-1858-5.

17. Naganuma T., Nakayama T., Sato N., et al. Haplotype-Based Case–Control Study on Human Apurinic/Apyrimidinic Endonuclease 1/Redox Effector Factor-1 Gene and Essential Hypertension. American Journal of Hypertension. 2010. 23(2). 186-191. DOI: 10.1038/ajh.2009.221.

18. Das S., Purkayastha S., Roy H., Sinha A., Choudhry Y. Polymorphisms in DNA repair genes increase the risk for type 2 diabetes mellitus and hypertension. BioMol Concepts. 2018. 9. 80-93. DOI: 10.1515/bmc-2018-0008.

19. Kushnarenko N.N. Cardiovascular disorders in men with gout: clinical features, mechanisms of development, prognosis [dissertation]. Chita. Chita State Medical Academy. 2012. in Russian.

20. Kushnarenko N.N., Medvedeva T.A., Govorin A.V., Mishko M.Yu. The role of fatty acid contents of erythrocytes membranes in cardiohemodynamics disorder in gout patients with insulin resistance syndrome. Russian Journal of Cardiology. 2018. 23(5). 49-55. DOI: 10.15829/1560-4071-2018-5-49-55. in Russian.

21. Ndrepepa G. Uric acid and cardiovascular disease. Clin Chim Acta. 2018. 484. 150-163. DOI: 10.1016/j.cca.2018.05.046.

22. Maiuolo J., Oppedisano F., Gratteri S., Muscoli C., Mollace V. Regulation of uric acid metabolism and excretion. Int J Cardiol. 2016. 213. 8-14. DOI: 10.1016/j.ijcard.2015.08.109.

23. Dyrkheeva N.S., Lebedeva N.A., Lavrik O.I. AP endonuclease 1 is a key enzyme in repair of apurine/apyrimidine sites. Review. Biochemistry. 2016. 81(9). 1198-1216. in Russian.

24. Chatterjee N., Walker G.C. Mechanisms of DNA damage, repair, and mutagenesis. Environ Mol Mutagen. 2017. 58(5). 235-263. DOI: 10.1002/em.22087.

25. Bokhari В., Sharma S. Stress Marks on the Genome: Use or Lose? Int J Mol Sci. 2019. 20(2). 364. DOI: 10.3390/ijms20020364.

26. Weber D., Stuetz W., Toussaint O., et al. Associations between Specific Redox Biomarkers and Age in a Large European Cohort: The MARK-AGE Project/ Oxid Med Cell Longev. 2017. 2017. 1401452. DOI: 10.1155/2017/1401452.

27. Luo C., Lian X., Hong L., et al. High Uric Acid Activates the ROS-AMPK Pathway, Impairs CD68 Expression and Inhibits OxLDL-Induced Foam-Cell Formation in a Human Monocytic Cell Line, THP-1. Cell Physiol Biochem. 2016. 40 (3-4). 538-548. DOI: 10.1159/000452567.

28. Yan Z., Yuan Z., Ni J., Gu L., Shen Y. Crystal structure of the crenarchaeal ExoIII AP endonuclease SisExoIII reveals a conserved disulfide bond endowing the protein with thermostability. Biochem Biophys Res Commun. 2017. 490(3). 774-779. DOI: 10.1016/j.bbrc.2017.06.116.

29. Esadze A., Rodriguez G., Cravens S.L., Stivers J.T. AP-Endonuclease 1 Accelerates Turnover of Human 8-Oxoguanine DNA Glycosylase by Preventing Retrograde Binding to the Abasic-Site Product. Biochemistry. 2017. 56(14). 1974-1986. DOI: 10.1021/acs.biochem.7b00017.

30. Lai Y., Jiang Z., Zhou J., Osemota E., Liu Y. AP endonuclease 1 prevents the extension of a T/G mismatch by DNA polymerase β to prevent mutations in CpGs during base excision repair. DNA Repair (Amst). 2016. 43. 89-97. DOI: 10.1016/j.dnarep.2016.03.006.

31. Ito H., Matsuo K., Hamajima N., et al. Gene-environment interactions between the smoking habit and polymorphisms in the DNA repair genes, APE1 Asp148Glu and XRCC1 Arg399Gln, in Japanese lung cancer risk. Carcinogenesis. 2004. 25(8). 1395-1401. DOI: 10.1093/carcin/bgh153.