Polymorphism of LYPLAL1 and TGFA Genes Associated With Progression of Knee Osteoarthritis in Residents Central Chernozem Region of Russia

Abstract

Background. Кnee osteoarthritis (OA) is a multifactorial disease in which genetic factors play an important role. The share of the hereditary component in the development of OA, according to various literature sources, ranges from 40 to 65%. Кnee OA is a progressive disease that leads to a decrease in the quality of life and disability.

The study aimed to evaluate the role of polymorphic markers of candidate genes rs2820436 and rs2820443 LYPLAL1, rs3771501 TGFA, rs11177 GNL3, rs6976 GLT8D1 in the progression of knee OA in the population of the Central Chernozem Region of Russia.

Methods. The study was performed in a case-control design on a sample of 500 patients with knee OA. Case — patients with III-IV stages of the disease according to Kellgren–Lawrence (n = 325), control (individuals who do not have the analyzed sign — III-IV stages of the disease) — patients with stage II (n = 175). Genotyping of five single nucleotide polymorphisms (SNPs) of candidate genes was performed using the polymerase chain reaction method for DNA synthesis. The study of the associations of the studied polymorphic loci, the calculation of haplotype frequencies and the analysis of their relationship with the progression of knee OA was carried out by the method of logistic regression in the program PLINK v 2.050.

Results. Significant associations with the progression of OA of the knee were established for allelic variant A rs2820436 of LYPLAL1 gene according to allelic (OR = 1.48, p = 0.010, p_perm = 0.012), additive (OR = 1.58, p = 0.009, p_perm = 0.010), dominant (OR = 1.61, p = 0.024, p_perm = 0.030) genetic models and A/A genotype of the same polymorphism (OR = 2.53, p = 0.041). The genotypes C/C rs2820436 LYPLAL1 (OR = 0.67, p = 0.043), A/G rs3771501 TGFA (OR = 0.67, p = 0.042) have a protective role in the progression of the disease. It was found that the frequency of the AC haplotype of haploblock rs2820436-rs2820443 in the group of patients with III-IV stages of the disease was significantly higher than in patients with stage II (OR = 1.83, p = 0.002, p_perm = 0.002). The identified molecular genetic markers rs2820436 and rs2820443 of LYPLAL1 gene, rs3771501 of TGFA gene are associated both with the risk of developing OA according to previous genome-wide studies and, according to our data, are associated with the progression of knee OA.

Conclusions. Genetic risk factors for the development of knee OA of III-IV radiological stages are allelic variant A and genotype A/A rs2820436 of LYPLAL1 gene, haplotype AC of haploblock rs2820436-rs2820443 in the population of the Central Chernozem Region of Russia. Genotypes C/C rs2820436 of LYPLAL1 gene and A/G rs3771501 of TGFA gene have a protective value in the progression of this disease.

Keywords

knee osteoarthritis / LYPLAL1 / TGFA / polymorphic locus / associations / candidate genes

References

[1] Reynard L.N., Barter M.J. Osteoarthritis year in review 2019: genetics, genomics and epigenetics. Osteoarthritis Cartilage. 2020;28(3):275-284. doi: 10.1016/j.joca.2019.11.010.

[2] Katz J.N., Arant K.R., Loeser R.F. Diagnosis and Treatment of Hip and Knee Osteoarthritis: A Review. JAMA. 2021;325(6):568-578. doi: 10.1001/jama.2020.22171.

[3] Alekseeva L.I., Taskina E.A., Kashevarova N.G. [Osteoarthritis: epidemiology, classification, risk factors and progression, clinic, diagnosis, treatment]. Sovremennaya revmatologiya [Modern Rheumatology]. 2019;13(2):9-21. (In Russian). doi: 10.14412/1996-7012-2019-2-9-21.

[4] Алексеева Л.И., Таскина Е.А., Кашеварова Н.Г. Остеоартрит: эпидемиология, классификация, факторы риска и прогрессирования, клиника, диагностика, лечение. Современная ревматология. 2019;13(2): 9-21. doi: 10.14412/1996-7012-2019-2-9-21.

[5] Panikar V.I., Shcherban E.A., Pavlova I.A. [Complex geriatric assessment of osteoarthrosis of knee joints in the senior age]. Nauchnye rezul’taty biomeditsinskikh issledovanii [Research Results in Biomedicine]. 2019;5(1):131-139. (In Russian). doi: 10.18413/2313-8955-2019-5-1-0-10.

[6] Паникар В.И., Щербань Э.А., Павлова И.А. Комплексная гериатрическая оценка остеоартроза коленных суставов в старческом возрасте. Научные результаты биомедицинских исследований. 2019;5(1):131-139. doi: 10.18413/2313-8955-2019-5-1-0-10.

[7] Galushko E.A., Nasonov E.L. [Prevalence of rheumatic diseases in Russia]. Al’manakh klinicheskoi meditsiny [Almanac of Clinical Medicine]. 2018;46(1):32-39. (In Russian). doi: 10.18786/2072-0505-2018-46-1-32-39.

[8] Галушко Е.А., Насонов Е.Л. Распространенность ревматических заболеваний в России. Альманах клинической медицины. 2018;46(1):32-39. doi: 10.18786/2072-0505-2018-46-1-32-39.

[9] Kavalersky G., Smetanin S., Lychagin A., Moisov A. [Risk factors for knee osteoarthritis]. Vrach [Doctor]. 2017;(3):22-24. (In Russian).

[10] Кавалерский Г., Сметанин С., Лычагин А., Мойсов А. Факторы риска развития остеоартроза коленного сустава. Врач. 2017;(3):22-24.

[11] Kashevarova N.G., Alekseeva L.I. [Risk factors of the knee osteoarthritis progression]. Nauchno-prakticheskaya revmatologiya [Rheumatology Science and Practice]. 2014;52(5):553-561. (In Russian). doi: 10.14412/1995-4484-2014-553-561.

[12] Кашеварова Н.Г., Алексеева Л.И. Факторы риска прогрессирования остеоартроза коленных суставов. Научно-практическая ревматология. 2014;52(5):553-561. doi: 10.14412/1995-4484-2014-553-561.

[13] Primorac D., Molnar V., Rod E., Jeleč Ž., Čukelj F., Matišić V. et al. Knee Osteoarthritis: A Review of Pathogenesis and State-Of-The-Art Non-Operative Therapeutic Considerations. Genes (Basel). 2020;11(8):854. doi: 10.3390/genes11080854.

[14] Novakov V.B., Novakova O.N., Churnosov M.I. [Risk factors and molecular entities of the etiopathogenesis of the knee osteoarthritis (literature review)]. Genij Orthopedii [Orthopaedic Genius]. 2021;27(1):112-120. (In Russian). doi: 10.18019/1028-4427-2021-27-1-112-120.

[15] Новаков В.Б., Новакова О.Н., Чурносов М.И. Факторы риска и молекулярные основы этиопатогенеза остеоартроза коленного сустава (обзор литературы). Гений ортопедии. 2021;27(1):112-120. doi: 10.18019/1028-4427-2021-27-1-112-120.

[16] Valdes A.M., Hart D.J., Jones K.A., Surdulescu G., Swarbrick P., Doyle D.V. et al. Association study of candidate genes for the prevalence and progression of knee osteoarthritis. Arthritis Rheum. 2004;50(8):2497-2507. doi: 10.1002/art.20443.

[17] Abd Elazeem M.I., Abdelaleem E.A., Mohamed R.A. Genetic influence of growth and differentiation factor 5 gene polymorphism (+104T/C) on the development of knee osteoarthritis and its association with disease severity. Eur J Rheumatol. 2017;4(2):98-103. doi: 10.5152/eurjrheum.2017.160093.

[18] Gok K., Cemeroglu O., Cakirbay H., Gunduz E., Acar M., Cetin E.N. et al. Relationship between cytosine-adenine repeat polymorphism of ADAMTS9 gene and clinical and radiologic severity of knee osteoarthritis. Int J Rheum Dis. 2018;21(4):821-827. doi: 10.1111/1756-185X.12849.

[19] Wu X., Kondragunta V., Kornman K.S., Wang H.Y., Duff G.W., Renner J.B. et al. IL-1 receptor antagonist gene as a predictive biomarker of progression of knee osteoarthritis in a population cohort. Osteoarthritis Cartilage. 2013;21(7):930-938. doi: 10.1016/j.joca.2013.04.003.

[20] Chen R., Zhang Y., Xu H., Hu H., Chen M., Shuai Z. Val109Asp Polymorphism of the Omentin-1 Gene and Incidence of Knee Osteoarthritis in a Chinese Han Population: A Correlation Analysis. Drug Des Devel Ther. 2021;15:5075-5086. doi: 10.2147/DDDT.S340410.

[21] Alekseeva L.I. [Update of clinical guidelines for the treatment of patients with osteoarthritis 2019]. Russkiy meditsinskiy zhurnal [Russian Medical Journal]. 2019;4: 2-6. (In Russian)

[22] Алексеева Л.И. Обновление клинических рекомендаций по лечению больных остеоартритом 2019 года. Русский медицинский журнал. 2019;4:2-6.

[23] ArcOGEN Consortium; arcOGEN Collaborators, Zeggini E., Panoutsopoulou K., Southam L., Rayner N.W. et al. Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study. Lancet. 2012;380(9844):815-823. doi: 10.1016/S0140-6736(12)60681-3.

[24] Styrkarsdottir U., Lund S.H., Thorleifsson G., Zink F., Stefansson O.A., Sigurdsson J.K. et al. Meta-analysis of Icelandic and UK data sets identifies missense variants in SMO, IL11, COL11A1 and 13 more new loci associated with osteoarthritis. Nat Genet. 2018;50(12):1681-1687. doi: 10.1038/s41588-018-0247-0.

[25] Zengini E., Hatzikotoulas K., Tachmazidou I., Steinberg J., Hartwig F.P., Southam L. et al. Genome-wide analyses using UK Biobank data provide insights into the genetic architecture of osteoarthritis. Nat Genet. 2018;50(4):549-558. doi: 10.1038/s41588-018-0079-y.

[26] Tachmazidou I., Hatzikotoulas K., Southam L., Esparza-Gordillo J., Haberland V., Zheng J. et al. Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data. Nat Genet. 2019;51(2):230-236. doi: 10.1038/s41588-018-0327-1.

[27] Boer C.G., Hatzikotoulas K., Southam L., Stefánsdóttir L., Zhang Y., Coutinho de Almeida R. et al. Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations. Cell. 2021;184(18):4784-4818.e17. doi: 10.1016/j.cell.2021.07.038.

[28] Polonikov A.V., Klyosova E.Yu., Azarova I.E. [Bioinformatic tools and internet resources for functional annotation of polymorphic loci detected by genome wide association studies of multifactorial diseases (review)]. Nauchnye rezul’taty biomeditsinskikh issledovanii [Research Results in Biomedicine]. 2021;7(1):15-31. (In Russian). doi: 10.18413/2658-6533-2020-7-1-0-2.

[29] Полоников А.В., Клёсова Е.Ю., Азарова Ю.Э. Биоинформатические инструменты и интернет-ресурсы для оценки регуляторного потенциала полиморфных локусов, установленных полногеномными ассоциативными исследованиями мультифакториальных заболеваний (обзор). Научные результаты биомедицинских исследований. 2021;7(1): 15-31. doi: 10.18413/2658-6533-2020-7-1-0-2.

[30] Gabriel S.B., Schaffner S.F., Nguyen H., Moore J.M., Roy J., Blumenstiel B. et al. The structure of haplotype blocks in the human genome. Science. 2002;296(5576): 2225-2229. doi: 10.1126/science.1069424.

[31] Che R., Jack J.R., Motsinger-Reif A.A., Brown C.C. An adaptive permutation approach for genome-wide association study: evaluation and recommendations for use. BioData Min. 2014;7:9. doi: 10.1186/1756-0381-7-9.

[32] Gong J., Nishimura K.K., Fernandez-Rhodes L., Haessler J., Bien S., Graff M. et al. Trans-ethnic analysis of metabochip data identifies two new loci associated with BMI. Int J Obes (Lond). 2018;42(3):384-390. doi: 10.1038/ijo.2017.304.

[33] Kulkarni K., Karssiens T., Kumar V., Pandit H. Obesity and osteoarthritis. Maturitas. 2016;89:22-28. doi: 10.1016/j.maturitas.2016.04.006.

[34] Belluzzi E., El Hadi H., Granzotto M., Rossato M., Ramonda R., Macchi V. et al. Systemic and Local Adipose Tissue in Knee Osteoarthritis. J Cell Physiol. 2017;232(8):1971-1978. doi: 10.1002/jcp.25716.

[35] Fernández-Rhodes L., Gong J., Haessler J., Franceschini N., Graff M., Nishimura K.K. et al. Trans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci. Hum Genet. 2017;136(6):771-800. doi: 10.1007/s00439-017-1787-6.

[36] Lundbäck V., Kulyte A., Strawbridge R.J., Ryden M., Arner P., Marcus C. et al. FAM13A and POM121C are candidate genes for fasting insulin: functional follow-up analysis of a genome-wide association study. Diabetologia. 2018;61(5):1112-1123. doi: 10.1007/s00125-018-4572-8.

[37] Rask-Andersen M., Karlsson T., Ek W.E., Johansson Å. Genome-wide association study of body fat distribution identifies adiposity loci and sex-specific genetic effects. Nat Commun. 2019;10(1):339. doi: 10.1038/s41467-018-08000-4.

[38] Christakoudi S., Evangelou E., Riboli E., Tsilidis K.K. GWAS of allometric body-shape indices in UK Biobank identifies loci suggesting associations with morphogenesis, organogenesis, adrenal cell renewal and cancer. Sci Rep. 2021;11(1):10688. doi: 10.1038/s41598-021-89176-6.

[39] Boer C.G., Yau M.S., Rice S.J., Coutinho de Almeida R., Cheung K., Styrkarsdottir U. et al. Genome-wide association of phenotypes based on clustering patterns of hand osteoarthritis identify WNT9A as novel osteoarthritis gene. Ann Rheum Dis. 2021;80(3):367-375. doi: 10.1136/annrheumdis-2020-217834.

[40] Stelzer G., Rosen N., Plaschkes I., Zimmerman S., Twik M., Fishilevich S. et al. The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses. Curr Protoc Bioinformatics. 2016;54:1.30.1-1.30.33. doi: 10.1002/cpbi.5.

[41] Appleton C.T., Usmani S.E., Mort J.S., Beier F. Rho/ROCK and MEK/ERK activation by transforming growth factor-alpha induces articular cartilage degradation. Lab Invest. 2010;90(1):20-30. doi: 10.1038/labinvest.2009.111.

[42] Appleton C.T., Usmani S.E., Pest M.A., Pitelka V., Mort J.S., Beier F. Reduction in disease progression by inhibition of transforming growth factor α-CCL2 signaling in experimental posttraumatic osteoarthritis. Arthritis Rheumatol. 2015;67(10):2691-2701. doi: 10.1002/art.39255.

RIGHTS & PERMISSIONS

Eco-Vector