2658-6533Research Results in Biomedicine2658-653310.18413/2658-6533-2023-9-2-0-43075Genetics<strong>Genetic markers of knee osteoarthritis in women of the Central Chernozem region of Russia</strong><strong>Genetic markers of knee osteoarthritis in women of the Central Chernozem region of Russia</strong>NovakovVitaly B.NovakovVitaly B.v.novakov@bk.ruNovakovaOlga N.NovakovaOlga N.litovkina@bsu.edu.ruSorokinaInna N.SorokinaInna N.Sorokina@bsu.edu.ruBatlutskayaIrina V.BatlutskayaIrina V.bat@bsu.edu.ruEfremovaOlga A.EfremovaOlga A.efremova@bsu.edu.ruOrlovaValentina S.OrlovaValentina S.orlova@bsu.edu.ru20239200

Background:&nbsp;Knee osteoarthritis (KO) is a multifactorial disease. Among the many risk factors for the disease, the role of the hereditary component is undeniable. The share of genetic factors in the development of OA is about 50%. The aim of the study:&nbsp;To study the role of polymorphic loci of candidate genes in the development of knee osteoarthritis in women from the Central Chernozem region of Russia.&nbsp;Materials and methods:&nbsp;The sample for the study included 590 women, including 292 patients diagnosed with KO and 298 women in the control group. All study participants underwent genotyping of four polymorphic loci of candidate genes (rs2820443 LYPLAL1, rs11177 GNL3, rs56116847 SBNO1 and rs34195470 WWP2), which showed an association with KO in previous genome-wide studies. A logistic regression analysis was carried out (allelic, additive, recessive, dominant genetic models were tested), taking into account covariates (age, BMI, hereditary burden, the presence of diseases of the cardiovascular, endocrine, musculoskeletal systems). Results:&nbsp;The minor allele A rs11177 of the GNL3 gene was found to be associated with the development of KO in women according to allelic (OR=0.74, pperm=0.011), additive (OR=0.65, pperm=0.009), dominant (OR=0.58, рperm=0.025) and recessive (OR=0.56, рperm=0.042) genetic models. The GG genotype rs11177 of the GNL3 gene is a risk factor for the development of KO (OR=1.53, p=0.026). The identified associations of rs11177 of the GNL3 gene with the development of the disease in females may be associated with the pronounced functional effects of this SNP: it determines the missense mutation (Arg39Gln in the GNL3 polypeptide); it is localized in an evolutionarily conservative region, in the area of hypersensitivity to DNase-1, in the area of histones, marking promoters in 10 tissues and enhancers in 14 tissues, in the region of binding to the regulatory protein ZNF263 and in the region of the regulatory DNA motif &ndash; RXRA; it is associated with the level of expression of 24 genes and alternative splicing of 12 genes in various tissues and organs involved in the pathogenesis of KO (adipose tissue, thyroid gland, skeletal muscles, etc.). Conclusion:&nbsp;The A allelic rs11177 variant of the GNL3 gene has a protective role in the development of KO in women of the Central Chernozem Region of Russia (OR=0.56-0.74), the GG genotype rs11177 has a risk role for the disease (OR=1.53).

Background:&nbsp;Knee osteoarthritis (KO) is a multifactorial disease. Among the many risk factors for the disease, the role of the hereditary component is undeniable. The share of genetic factors in the development of OA is about 50%. The aim of the study:&nbsp;To study the role of polymorphic loci of candidate genes in the development of knee osteoarthritis in women from the Central Chernozem region of Russia.&nbsp;Materials and methods:&nbsp;The sample for the study included 590 women, including 292 patients diagnosed with KO and 298 women in the control group. All study participants underwent genotyping of four polymorphic loci of candidate genes (rs2820443 LYPLAL1, rs11177 GNL3, rs56116847 SBNO1 and rs34195470 WWP2), which showed an association with KO in previous genome-wide studies. A logistic regression analysis was carried out (allelic, additive, recessive, dominant genetic models were tested), taking into account covariates (age, BMI, hereditary burden, the presence of diseases of the cardiovascular, endocrine, musculoskeletal systems). Results:&nbsp;The minor allele A rs11177 of the GNL3 gene was found to be associated with the development of KO in women according to allelic (OR=0.74, pperm=0.011), additive (OR=0.65, pperm=0.009), dominant (OR=0.58, рperm=0.025) and recessive (OR=0.56, рperm=0.042) genetic models. The GG genotype rs11177 of the GNL3 gene is a risk factor for the development of KO (OR=1.53, p=0.026). The identified associations of rs11177 of the GNL3 gene with the development of the disease in females may be associated with the pronounced functional effects of this SNP: it determines the missense mutation (Arg39Gln in the GNL3 polypeptide); it is localized in an evolutionarily conservative region, in the area of hypersensitivity to DNase-1, in the area of histones, marking promoters in 10 tissues and enhancers in 14 tissues, in the region of binding to the regulatory protein ZNF263 and in the region of the regulatory DNA motif &ndash; RXRA; it is associated with the level of expression of 24 genes and alternative splicing of 12 genes in various tissues and organs involved in the pathogenesis of KO (adipose tissue, thyroid gland, skeletal muscles, etc.). Conclusion:&nbsp;The A allelic rs11177 variant of the GNL3 gene has a protective role in the development of KO in women of the Central Chernozem Region of Russia (OR=0.56-0.74), the GG genotype rs11177 has a risk role for the disease (OR=1.53).

knee osteoarthritisassociationscandidate genesgene polymorphismGNL3knee osteoarthritisassociationscandidate genesgene polymorphismGNL3Список литературыBalabanova RM, Dubinina TV, Demina AV, et al. The incidence of musculoskeletal diseases in the Russian Federation over 2015&ndash;2016. Rheumatology Science and Practice. 2018;56(1):15-21. Russian. DOI: https://doi.org/10.14412/1995-4484-2018-15-21Jang S, Lee K, Ju JH. Recent Updates of Diagnosis, Pathophysiology, and Treatment on Osteoarthritis of the Knee. International Journal of Molecular Sciences. 2021;22(5):2619. DOI: https://doi.org/10.3390/ijms22052619Madry H, Luyten FP, Facchini A. Biological aspects of early osteoarthritis. Knee Surgery, Sports Traumatology, Arthroscopy. 2012;20(3):407-22. DOI: https://doi.org/10.1007/s00167-011-1705-8Pape D, Tischer T. Kniearthrose des jungen Patienten [Osteoarthritis of the knee in young patients]. Der Orthopade. 2021;50(5):345. DOI: https://doi.org/10.1007/s00132-021-04095-8Galushko EA, Nasonov EL. Prevalence of rheumatic diseases in Russia. Almanac of Clinical Medicine. 2018;46(1):32-39. Russian. DOI: https://doi.org/10.18786/2072-0505-2018-46-1-32-39Deshpande BR, Katz JN, Solomon DH, et al. Number of Persons With Symptomatic Knee Osteoarthritis in the US: Impact of Race and Ethnicity, Age, Sex, and Obesity. Arthritis Care and Research (Hoboken). 2016;68(12):1743-1750. DOI: https://doi.org/10.1002/acr.22897Gaudreault N, Maillette P, Coutu MF, et al. Work disability among workers with osteoarthritis of the knee: risks factors, assessment scales, and interventions. International Journal of Rehabilitation Research. 2014;37(4):290-296. DOI: https://doi.org/10.1097/MRR.0000000000000082Tan JS, Tikoft E, O&#39;Sullivan P, et al. The Relationship Between Changes in Movement and Activity Limitation or Pain in People With Knee Osteoarthritis: A Systematic Review. Journal of Orthopaedic and Sports Physical Therapy. 2021;51(10):492-502. DOI: https://doi.org/10.2519/jospt.2021.10418Weinstein AM, Rome BN, Reichmann WM, et al. Estimating the burden of total knee replacement in the United States. Journal of Bone and Joint Surgery. 2013;95(5):385-92. DOI: https://doi.org/10.2106/JBJS.L.00206Kornilov NN, Kulyaba TA, Fil AS, et al. Data of knee arthroplasty register of Vreden Russian Research Institute of Traumatology and Orthopedics for period 2011-2013. Traumatology and Orthopedics of Russia. 2015;21(1):136-151. Russian. DOI: https://doi.org/10.21823/2311-2905-2015-0-1-136-151Hardenberg M, Spekl&eacute; EM, Coenen P, et al. The economic burden of knee and hip osteoarthritis: absenteeism and costs in the Dutch workforce. BMC Musculoskeletal Disorders. 2022;23(1):364. DOI: https://doi.org/10.1186/s12891-022-05306-9Leung K, Zhang B, Tan J, et al. Prediction of Total Knee Replacement and Diagnosis of Osteoarthritis by Using Deep Learning on Knee Radiographs: Data from the Osteoarthritis Initiative. Radiology. 2020;296(3):584-593. DOI: https://doi.org/10.1148/radiol.2020192091Marsh J, Joshi I, Somerville L, et al. Health care costs after total knee arthroplasty for satisfied and dissatisfied patients. Canadian Journal of Surgery. 2022;65(5):E562-E566. DOI: https://doi.org/10.1503/cjs.006721Hussain SM, Neilly DW, Baliga S, et al. Knee osteoarthritis: a review of management options. Scottish Medical Journal. 2016;61(1):7-16. DOI: https://doi.org/10.1177/0036933015619588Haider MZ, Bhuiyan R, Ahmed S, et al. Risk factors of knee osteoarthritis in Bangladeshi adults: a national survey. BMC Musculoskelet Disord. 2022;23(1):333. DOI: https://doi.org/10.1186/s12891-022-05253-5Novakov VB, Novakova ON, Churnosov MI. Risk factors and molecular entities of the etiopathogenesis of the knee osteoarthritis (literature review). Genij Ortopedii. 2021;27(1):112-120. Russian. DOI: https://doi.org/10.18019/1028-4427-2021-27-1-112-120Curry ZA, Beling A, Borg-Stein J. Knee osteoarthritis in midlife women: unique considerations and comprehensive management. Menopause. 2022;29(6):748-755. DOI: https://doi.org/10.1097/GME.0000000000001966Werner DM, Golightly YM, Tao M, et al. Environmental Risk Factors for Osteoarthritis: The Impact on Individuals with Knee Joint Injury. Rheumatic Disease Clinics of North America. 2022;48(4):907-930. DOI: https://doi.org/1010.1016/j.rdc.2022.06.010Madyanov IV, Madyanova TS. Menopausal hormone therapy in certain diseases of therapeutic profile. Lechaschi Vrach. 2018;3:50. Russian.Povoroznyuk VV, Grigorieva NV. Osteoarthritis in postmenopausal women: risk factors and association with bone tissue. Reproductive Endocrinology. 2012;6(8):64-71. DOI: https://doi.org/10.18370/2309-4117.2012.8.64-71Kremers HM, Larson DR, Crowson CS, et al. Prevalence of Total Hip and Knee Replacement in the United States. Journal of Bone and Joint Surgery. 2015;97(17):1386-97. DOI: https://doi.org/10.2106/JBJS.N.01141Skousgaard SG, Skytthe A, M&ouml;ller S, et al. Sex differences in risk and heritability estimates on primary knee osteoarthritis leading to total knee arthroplasty: a nationwide population based follow up study in Danish twins. Arthritis Research and Therapy. 2016;18:46. DOI: https://doi.org/10.1186/s13075-016-0939-8Zengini E, Finan C, Wilkinson JM. The Genetic Epidemiological Landscape of Hip and Knee Osteoarthritis: Where Are We Now and Where Are We Going? The Journal of Rheumatology. 2016;43(2):260-266. DOI: https://doi.org/10.3899/jrheum.150710Novakov VB, Novakova ON, Churnosov MI. Genome-wide Studies of Knee Osteoarthritis: Review. Traumatology and Orthopedics of Russia. 2021;27(4):131-144. Russian. DOI: https://doi.org/10.21823/2311-2905-2021-27-1580Novakov V, Novakova O, Churnosova M, et al. Intergenic interactions of SBNO1, NFAT5 and GLT8D1 determine the susceptibility to knee osteoarthritis among Europeans of Russia. Life. 2022;13(2):405. DOI: https://doi.org/10.3390/life13020405MacGregor AJ, Li Q, Spector TD, et al. The genetic influence on radiographic osteoarthritis is site specific at the hand, hip and knee. Rheumatology. 2009;48(3):277-280. DOI: https://doi.org/10.1093/rheumatology/ken475Zhai G, Ding C, Stankovich J, et al. The genetic contribution to longitudinal changes in knee structure and muscle strength: a sibpair study. Arthritis and Rheumatism. 2005;52(9):2830-2834. DOI: https://doi.org/10.1002/art.21267Novakov V, Novakova O, Churnosova M, et al. The pronounced effect of obesity on the association of the rs143384 GDF5 with knee osteoarthritis. Life. 2022;12:x. DOI: https://doi.org/10.3390/xxxxxAlekseeva LI. Update of clinical guidelines for the treatment of patients with osteoarthritis 2019. Russian Medical Journal. 2019;4:2-6. Russian.Altman RD. Criteria for classification of clinical osteoarthritis. The Journal of rheumatology. Supplement. 1991;27:10-12.Abramova MYu. Genetic markers of severe preeclampsia. Research Results in Biomedicine. 2022;8(3):305-316. DOI: https://doi.org/10.18413/2658-6533-2022-8-3-0-4Zeggini E, Panoutsopoulou K, Southam L, et al. Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study. The Lancet. 2012;380(9844):815-823. DOI: https://doi.org/10.1016/S0140-6736(12)60681-3Styrkarsdottir U, Lund SH, Thorleifsson G, 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. Nature Genetics. 2018;50(12):1681-1687. DOI: https://doi.org/10.1038/s41588-018-0247-0Tachmazidou I, Hatzikotoulas K, Southam L, et al. Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data. Nature Genetics. 2019;51(2):230-236. DOI: https://doi.org/10.1038/s41588-018-0327-1Boer CG, Hatzikotoulas K, Southam L, et al.&nbsp; Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations. Cell. 2021;184(18):4784-4818.e17. DOI: https://doi.org/10.1016/j.cell.2021.07.038Ward LD, Kellis M. HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease. Nucleic Acids Research. 2016;44(D1):D877-D881. DOI: https://doi.org/10.1093/nar/gkv1340Yarosh SL, Kokhtenko EV, Starodubova NI, et al. Smoking status modifies the relation between CYP1A1*2C gene polymorphism and idiopathic male infertility: the importance of gene-environment interaction analysis for genetic studies of the disease. Reproductive Sciences. 2013;20(11):1302-1307. DOI: https://doi.org/10.1177/1933719113483013Yarosh SL, Kokhtenko EV, Churnosov MI, et al. Joint effect of glutathione S-transferase genotypes and cigarette smoking on idiopathic male infertility. Andrologia. 2015;47(9):980-986. DOI: https://doi.org/10.1111/and.12367Polonikov A, Bykanova M, Ponomarenko I, et al. The contribution of CYP2C gene subfamily involved in epoxygenase pathway of arachidonic acids metabolism to hypertension susceptibility in Russian population. Clinical and Experimental Hypertension. 2017;39(4):306-311. DOI: https://doi.org/10.1080/10641963.2016.1246562Ponomarenko IV, Polonikov AV, Churnosov MI. Association of polymorphism rs4986938 of the ESR2 gene with the development of endometrial hyperplasia. Obstetrics and Gynecology. 2019;4:66-72. Russian. DOI: https://dx.doi.org/10.18565/aig.2019.4.66-72Purcell S, Neale B, Todd-Brown K, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. American Journal of Human Genetics. 2007;81(3):559-75. DOI: https://doi.org/10.1086/519795Reshetnikov EA. Study of associations of candidate genes differentially expressing in the placenta with the development of placental insufficiency with fetal growth restriction. Research Results in Biomedicine. 2020;6(3):338-349. DOI: https://doi.org/10.18413/2658- 6533-2020-6-3-0-5GTEx Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science. 2020;369(6509):1318-1330. DOI: https://doi.org/10.1126/science.aaz1776Yau MS, Yerges-Armstrong LM, Liu Y, et al. Genome-Wide Association Study of Radiographic Knee Osteoarthritis in North American Caucasians. Arthritis and Rheumatology. 2017;69(2):343-351. DOI: https://doi.org/10.1002/art.39932Liu B, Cheng H, Ma W, et al. Common variants in the GNL3 contribute to the increasing risk of knee osteoarthritis in Han Chinese population. Scientific Reports. 2018;8(1):9610. DOI: https://doi.org/10.1038/s41598-018-27971-4Shapovalova D A. The study of the molecular genetic basis of osteoarthritis in women with undifferentiated connective dysplasia [dissertation]. Ufa; 2020. Russian.Panoutsopoulou K, Thiagarajah S, Zengini E, et al. Radiographic endophenotyping in hip osteoarthritis improves the precision of genetic association analysis. Annals of The Rheumatic Diseases. 2017;76(7):1199-1206. DOI: https://doi.org/10.1136/annrheumdis-2016-210373Romanova L, Kellner S, Katoku-Kikyo N, et al. Novel role of nucleostemin in the maintenance of nucleolar architecture and integrity of small nucleolar ribonucleoproteins and the telomerase complex. Journal of Biological Chemistry. 2009;284(39):26685-94. DOI: https://doi.org/10.1074/jbc.M109.013342Gee F, Clubbs CF, Raine EV, et al. Allelic expression analysis of the osteoarthritis susceptibility locus that maps to chromosome 3p21 reveals cis-acting eQTLs at GNL3 and SPCS1. BMC Medical Genetics. 2014;15:53. DOI: https://doi.org/10.1074/10.1186/1471-2350-15-53Louka ML, Zakaria ZM, Nagaty MM, et al. Expression of nucleostemin gene in primary osteoarthritis. Gene. 2016;587(1):27-32. DOI: https://doi.org/10.1016/j.gene.2016.04.019