Similarity and specificity of the genetic predisposition of the diabetes mellitus type 1 and chronic hepatitis С

Fibrotic processes that occur in different organs and tissues and that lead to the formation of organ failure are characterized by many shared features. However, the pathogenic significance and the genetic component determining the fibrogenesis in various pathological states can have both shared and brightly expressed specific features. The aim of our study was to assess the similarity and specificity of the genetic components of susceptibility to diseases that characterized by fibrotic transformation of various organs: kidneys in diabetes mellitus type 1 (T1D) and liver in chronic hepatitis C (HCV). The group of patients with HCV included 184 persons (71% men and 29% women; mean age 40.2 ± 13.9 years old). The group of patients with T1D included 285 patients (47% men and 53% women; mean age 25.27 ± 12.6 years old). The population-based controls consisted of 285 persons (54% men and 46% women, mean age 56.7 ± 8.4 years old). Genotyping of 48 SNPs was performed using mass spectrometry on the Sequenom MassARRAY® tool (USA). Statistical data analysis was performed in the software environment R using the standard package «stats». We found that the T1D predisposing genotype was «AA» of rs3765124 of ADAMDEC1 gene (OR = 1.52(1.01-2.28), p = 0.004); «TT» of rs1007856 of ITGB5 gene (OR = 1.86(1.20-2.90), p = 0,040); «CC» of rs20579 of LIG1 gene (OR = 1.86(1.20-2.90), p = 0.008); «GG» of rs1143674 of ITGA4 gene (OR = 2.06 (1.29-3.29), p = 0.002); «AA» of rs679620 of MMP3 gene (OR = 2.03 (1.19-3.47), p = 0.008); the allele «C» of rs12980602 of IFNL2 gene (OR = 1.49 (1.04-2.14), p = 0.029) and allele «C» rs4986819 of the PARP4 gene (OR = 1.52 (1.01-2.28), p = 0.044). Comparison of the obtained results with the data on the frequency of studied SNPs in patients with HCV showed that SNPs of ADAMDEC1 (rs3765124), ITGB5 (rs1007856), MMP3 (rs679620) and LIG1 (rs20579) were the shared markers that contribute to predisposition to HCV and T1D. Associations were unidirectional, because the same alleles and genotypes contribute to the risk of as HCV and T1D. Diseases accompanied by fibrotic transformation of various organs characterized by the presence of shared components among the entire genetic landscape that determines the susceptibility to these pathologies. Among the number of shared genes contributing to the development of HCV and T1D, the protein products of genes ADAMDEC1 , ITGB5 and MMP3 are involved in the metabolism of the extracellular matrix and directly in the processes of fibrogenesis.

генетическая предрасположенность, гены фиброгенеза, хронический вирусный гепатит С, сахарный диабет первого типа, genetic predisposition, fibrogenesis genes, chronic hepatitis C, diabetes mellitus type 1

1. Гончарова ИА, Кучер АН, Тарасенко НВ и др. Разработка панели генетических маркёров фиброгенеза и оценка её информативности для русского населения г. Томска. Медицинская генетика. 2015;14(8(158):7-12.

2. Гончарова ИА, Назаренко МС, Тарасенко НВ и др. Генетические маркеры фиброгенеза при хроническом вирусном гепатите С. Медицинская генетика. 2016;15(12):29-36.

3. Li Y, Zhang Q, Liu Y,, et al. Hepatitis C virus activates Bcl-2 and MMP-2 expression through multiple cellular signaling pathways. Journal of Virology. 2012. 86(23): 12531-543.

4. Kadoglou NP, Daskalopoulou SS, Perrea D, Liapis CD, et al. Matrix metalloproteinases and diabetic vascular complications. Angiology. 2005. Feb;56(2):173-189.

5. Гончарова ИА, Тарасенко НВ, Макеева ОА, и др. Полиморфизм гена ADAMDEC1 и его вклад в развитие заболеваний, характеризующихся процессами фиброгенеза. Медицинская генетика. 2015. Т. 14. № 9 (159). С. 24-30.

6. Bohanes P, Yang D, Loupakis F, et al. Integrin genetic variants and stage-specific tumor recurrence in patients with stage II and III colon cancer. Pharmacogenomics J. 2015. Mar; 15(3): 226-234. doi: 10.1038/tpj.2014.66.

7. Azizian-Farsani F, Rafiei G, Saadat M. Impact of Sodium Arsenite on Chromosomal Aberrations With Respect to Polymorphisms of Detoxification and DNA Repair Genes. Int J Toxicol. 2014 Nov-Dec;33(6):518-522. doi: 10.1177/1091581814557953.

8. Gaymes TJ, Mohamedali AM, Patterson M, et al. Microsatellite instability induced mutations in DNA repair genes CtIP and MRE11 confer hypersensitivity to poly (ADP-ribose) polymerase inhibitors in myeloid malignancies. Haematologica. 2013 Sep;98(9):1397-406. doi: 10.3324/haematol.2012.079251.

9. Sobczuk A, Poplawski T, Blasiak J. Polymorphisms of DNA repair genes in endometrial cancer. Pathol Oncol Res. 2012 Oct;18(4):1015-1020.

10. Лукманова ЛИ, Давлетшин РА, Юлдашев ВЛ и др. Поиск ассоциаций полиморфных вариантов генов XRCC1, XPD и XRCC3 с повышенным риском развития алкогольного гепатита. Медицинская генетика. 2011;9:31-35.

11. Jung SW, Park NH, Shin JW et al. Polymorphisms of DNA repair genes in Korean hepatocellular carcinoma patients with chronic hepatitis B: Possible implications on survival. J Hepatol. 2012 Sep;57(3):621-7. doi: 10.1016/j.jhep.2012.04.039.

12. Гончарова ИА, Макеева О.А, Голубенко М.В и др. Гены фиброгенеза в детерминации предрасположенности к инфаркту миокарда. Молекулярная биология. 2016;50(1):94-105.

13. Daugherty MD, Young JM, Kerns JA, Malik HS. Rapid evolution of PARP genes suggests a broad role for ADP-ribosylation in host-virus conflicts. PLoS Genet. 2014 May 29;10(5):e1004403. doi: 10.1371/journal.pgen.1004403.

14. Chen Y, Wang L, Xu H, et al. Exome capture sequencing reveals new insights into hepatitis B virus-induced hepatocellular carcinoma at the early stage of tumorigenesis. Oncol Rep. 2013 Oct;30(4):1906-12. doi: 10.3892/or.2013.2652.

15. Liu Y, Snow BE, Kickhoefer VA et al. Vault poly(ADP-ribose) polymerase is associated with mammalian telomerase and is dispensable for telomerase function and vault structure in vivo. Mol Cell Biol. 2004 Jun;24(12):5314-23.

16. Database GTExPortal [Electronic resource]: URL: http://www.gtexportal.org/home/gene/IFNL2 (accessed: 2016).

17. Torkamani A, Topol EJ, Schork NJ. Pathway analysis of seven common diseases assessed by genome-wide association. Genomics. 2008 Nov;92(5):265-272. doi: 10.1016/j.ygeno.2008.07.011.

18. Bluestone JA, Herold K, Eisenbarth G. Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature. 2010 Apr 29;464(7293):1293-1300.

19. Zhang AM, Ma K, Song Y. et al. Genetic polymorphisms of the IFNλ genes are associated with biochemical features in Han Chinese with HCV infection from Yunnan Province, China. Infect Genet Evol. 2014 Jan;21:161-165. doi: 10.1016/j.meegid.2013.11.013.

20. Aspord C, Rome S, Thivolet CJ. Early events in islets and pancreatic lymph nodes in autoimmune diabetes. Autoimmun. 2004. Jan; 23(1): 27-35. DOI:10.1016/j.jaut.2004.03.007.

21. Karamizadeh Z, Kamali Sarvestani E, Saki F, et al. Investigation of osteopontin levels and genomic variation of osteopontin and its receptors in Type 1 diabetes mellitus. J Endocrinol Invest. 2013. Nov; 36(11);1090-93. doi: 10.3275/9098.

22. Bailey SD, Xie C, Do R, et al. Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study. Diabetes Care. 2010 Oct;33(10):2250-3. doi: 10.2337/dc10-0452.

23. Щёкотова АП, Котельникова ЛП, Мугатаров ИН, Федачук НН. Эндотелиальная дисфункция, воспаление и фиброз при гепатобилиарной патологии. Фундаментальные исследования. 2013. № 5-2. С. 451-455.

24. Boyd J, Luo B, Peri S, et al. Whole exome sequence analysis of serous borderline tumors of the ovary. Gynecol Oncol. 2013.Sep;130(3):560-4. doi: 10.1016/j.ygyno.2013.06.007.

25. Erdmann J, Willenborg C, Nahrstaedt J, et al. Genome-wide association study identifies a new locus for coronary artery disease on chromosome 10p11.23. Eur. Heart J. 2011. 32: 158-168. doi: 10.1093/eurheartj/ehq405.