Research Article
Volume 11 Issue 3 - 2020
TNFA Genetic Polymorphism is Associated with Risk for Developing Hip but not Knee Osteoarthritis in Croatian Population
Randi Krog Eftedal1, Zdravko Jotanovic2, Sanja Balen3 and Zlatko Dembic1*
1Molecular Genetics Laboratory, Department of Oral Biology, University of Oslo, Norway
2University Hospital for Orthopaedics and Traumatology Lovran, School of Medicine, University of Rijeka, Croatia
3Clinical Institute for Transfusion Medicine, Universal Hospital Center Rijeka, School of Medicine, University of Rijeka, Croatia
*Corresponding Author: Zlatko Dembic, Molecular Genetics Laboratory, Department of Oral Biology, University of Oslo, Norway.
Received: January 20, 2020; Published: February 21, 2020


Aim: We studied genetic epidemiology of primary large-joint (hip and knee) osteoarthritis (OA), in order to find disease risk factors by a candidate-gene approach. We used TNFA gene SNP rs1800629 in a case-control study in the Croatian Caucasian population. 

Method: We analyzed 225 hip and 205 knee OA patients (both with total joint replacements), and 554 healthy individuals, majority being blood donors. We genotyped for TNFA SNP rs1800629 (+308, C>T). Allelic and genotypic frequencies were compared between patients and controls.

Results: The minor allele (T) of rs1800629 significantly conferred susceptibility only to hip OA (p < 5*10-5, OR = 1.81, CI 95% = 1.34 - 2.44). The major (C) allele was significantly associated with the protection to hip (p < 5*10-5, OR = 0.63, CI 95% = 0.41 - 0.74), but not knee OA. Patients with the homozygous genotype C/C had significantly lower risk of developing hip OA (< 3*10-4, OR = 0.53, CI 95% = 0.38 - 0.76), but had no association with knee OA. The homozygosity of the minor allele (T/T) has been significantly associated with susceptibility to only hip OA (< 2*10-2, OR = 2.56, CI 95% = 1.09 - 5.57). 

Conclusion. Our findings demonstrate that major and minor alleles of the rs1800629 are associated with lower or higher risk, respectively, to developing hip, but not knee OA in the Croatian population. The data suggest a difference in the etiology of hip OA from that of the knee, perhaps due to an unknown dissimilarity in vulnerability of these joints to the actions of TNFA. Alternatively, other genetic factors including long non-protein coding LOC100287329 and/or miR6832 in vicinity of rs1800629 might be involved in the observed risk.

Keywords: Genetic Risk; TNFA; Osteoarthritis; Hip; SNP


  1. Peach CA., et al. “Recent advances in the genetic investigation of osteoarthritis”. Trends in Molecular Medicine 11.4 (2005): 186-191.
  2. Lories R., et al. “Osteoarthritis: Pathogenesis and Clinical Features”. In EULAR Textbook on Rheumatic Diseases, JWJ Bijlsma and E Hachulla, Editors BMJ Publishing Group Ltd: London. (2015): 811-846.
  3. Vincenti MP and CE Brinckerhoff. “Transcriptional regulation of collagenase (MMP-1, MMP-13) genes in arthritis: integration of complex signaling pathways for the recruitment of gene-specific transcription factors”. Arthritis Research and Therapy 4.3 (2002): 157-164.
  4. Fosang AJ and CB Little. “Drug insight: aggrecanases as therapeutic targets for osteoarthritis”. Nature Clinical Practice Rheumatology 4.8 (2008): 420-427.
  5. Cawston TE and DA Young. “Proteinases involved in matrix turnover during cartilage and bone breakdown”. Cell Tissue Res 339.1 (2010): 221-235.
  6. D'Ambrosia RD. “Epidemiology of osteoarthritis”. Orthopedics 28.2 (2005): s201-205.
  7. Richette P., et al. “Estrogens, cartilage, and osteoarthritis”. Joint Bone Spine 70.4 (2003): 257-262.
  8. Riyazi N., et al. “Evidence for familial aggregation of hand, hip, and spine but not knee osteoarthritis in siblings with multiple joint involvement: the GARP study”. Annals of the Rheumatic Diseases 64.3 (2005): 438-443.
  9. MacGregor AJ and TD Spector. “Twins and the genetic architecture of osteoarthritis”. Rheumatology 38.7 (1999): 583-588.
  10. Chitnavis J., et al. “Genetic influences in end-stage osteoarthritis. Sibling risks of hip and knee replacement for idiopathic osteoarthritis”. The Journal of Bone and Joint Surgery British Volume 79.4 (1997): 660-664.
  11. Loughlin J. “Genetic epidemiology of primary osteoarthritis”. Current Opinion in Rheumatology 13.2 (2001): 111-116.
  12. Spector TD and AJ MacGregor. “Risk factors for osteoarthritis: genetics”. Osteoarthritis Cartilage 12 (2004): S39-S44.
  13. Valdes AM., et al. “Association of the DVWA and GDF5 polymorphisms with osteoarthritis in UK populations”. Annals of the Rheumatic Diseases (2008).
  14. Forster T., et al. “Common variants within the interleukin 4 receptor alpha gene (IL4R) are associated with susceptibility to osteoarthritis”. Human Genetics 114.4 (2004): 391-395.
  15. Roby P., et al. “Autosomal dominant (Beukes) premature degenerative osteoarthropathy of the hip joint maps to an 11-cM region on chromosome 4q35”. The American Journal of Human Genetics 64.3 (1999): 904-908.
  16. Demissie S., et al. “Genome scan for quantity of hand osteoarthritis: the Framingham Study”. Arthritis ad Rheumatology 46.4 (2002): 946-952.
  17. Evangelou, E., et al. “A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip”. Annals of the Rheumatic Diseases 73.12 (2014): 2130-2136.
  18. Meulenbelt, I., et al. “Identification of DIO2 as a new susceptibility locus for symptomatic osteoarthritis”. Human Molecular Genetics 17.12 (2008): 1867-1875.
  19. Frazer KA., et al. “Human genetic variation and its contribution to complex traits”. Nature Reviews Genetics 10.4 (2009): 241-251.
  20. Styrkarsdottir, U., et al. “Whole-genome sequencing identifies rare genotypes in COMP and CHADL associated with high risk of hip osteoarthritis”. Nature Reviews Genetics 49.5 (2017): 801-805.
  21. Tachmazidou I., et al. “Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data”. Nature Reviews Genetics 51.2 (2019): 230-236.
  22. Chapman K., et al. “A meta-analysis of European and Asian cohorts reveals a global role of a functional SNP in the 5' UTR of GDF5 with osteoarthritis susceptibility”. Human Molecular Genetics 17.10 (2008): 1497-1504.
  23. Kizawa H., et al. “An aspartic acid repeat polymorphism in asporin inhibits chondrogenesis and increases susceptibility to osteoarthritis”. Nature Genetics 37.2 (2005): 138-144.
  24. Miyamoto Y., et al. “A functional polymorphism in the 5' UTR of GDF5 is associated with susceptibility to osteoarthritis”. Nature Genetics 39.4 (2007): 529-533.
  25. Syddall CM., et al. “The identification of trans-acting factors that regulate the expression of GDF5 via the osteoarthritis susceptibility SNP rs143383”. PLOS Genetics 9.6 (2013): e1003557.
  26. Valdes AM and TD Spector. “Genetic epidemiology of hip and knee osteoarthritis”. Nature Reviews Rheumatology 7.1 (2011): 23-32.
  27. Valdes AM and TD Spector. “The contribution of genes to osteoarthritis”. Rheumatic Disease Clinics of North America 34.3 (2008): 581-603.
  28. Zhang R., et al. “A comprehensive meta-analysis of association between genetic variants of GDF5 and osteoarthritis of the knee, hip and hand”. Inflammation Research 64.6 (2015): 405-414.
  29. Wojdasiewicz P., et al. “The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis”. Mediators of Inflammation 2014 (2014): 561459.
  30. Kapoor M., et al. “Role of proinflammatory cytokines in the pathophysiology of osteoarthritis”. Nature Reviews Rheumatology 7.1 (2011): 33-42.
  31. Jotanovic Z., et al. “Hip osteoarthritis susceptibility is associated with IL1B -511(G>A) and IL1 RN (VNTR) genotypic polymorphisms in Croatian Caucasian population”. Journal of Orthopaedic Research 29.8 (2011): 1137-1144.
  32. Jotanovic Z., et al. “IL1B -511(G>A) and IL1RN (VNTR) allelic polymorphisms and susceptibility to knee osteoarthritis in Croatian population”. Rheumatology International (2011).
  33. Kaarvatn MH., et al. “Associations of the interleukin-1 gene locus polymorphisms with risk to hip and knee osteoarthritis: gender and subpopulation differences”. Scandinavian Journal of Immunology 77.2 (2013): 151-161.
  34. Vrgoc G., et al. “Interleukin-17 and Toll-like Receptor 10 genetic polymorphisms and susceptibility to large joint osteoarthritis”. Journal of Orthopaedic Research 36.6 (2017): 1684-1693.
  35. Eftedal R., et al. “Alternative Interleukin 17A/F Locus Haplotypes are Associated with Increased Risk to Hip and Knee Osteoarthritis”. Journal of Orthopaedic Research (2019).
  36. Goldring MB. “The role of cytokines as inflammatory mediators in osteoarthritis: lessons from animal models”. Connective Tissue Research 40.1 (1999): 1-11.
  37. Klooster AR and SM Bernier. “Tumor necrosis factor alpha and epidermal growth factor act additively to inhibit matrix gene expression by chondrocyte”. Arthritis Research and Therapy 7.1 (2005): R127-138.
  38. Chen, J., et al. “Association between tumor necrosis factor alpha rs1800629 polymorphism and risk of osteoarthritis in a Chinese population”. Brazilian Journal of Medical and Biological Research 51.8 (2018): e7311.
  39. Abdel Galil SM., et al. “The single-nucleotide polymorphism (SNP) of tumor necrosis factor alpha -308G/A gene is associated with early-onset primary knee osteoarthritis in an Egyptian female population”. Clinical Rheumatology 36.11 (2017): 2525-2530.
  40. Munoz-Valle JF., et al. “High expression of TNF alpha is associated with -308 and -238 TNF alpha polymorphisms in knee osteoarthritis”. Clinical and Experimental Medicine 14.1 (2014): 61-67.
  41. Kou S and Y Wu. “Meta-analysis of tumor necrosis factor alpha -308 polymorphism and knee osteoarthritis risk”. BMC Musculoskeletal Disorders 15 (2014): 373.
  42. Altman R., et al. “The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the hip”. Arthritis and Rheumatology 34.5 (1991): 505-514.
  43. Bellamy N. “WOMAC: a 20-year experiential review of a patient-centered self-reported health status questionnaire”. The Journal of Rheumatology 29.12 (2002): 2473-2476.
  44. Kellgren JH and JS Lawrence. “Radiological assessment of osteo-arthrosis”. Annals of the Rheumatic Diseases 16.4 (1957): 494-502.
  45. Faul F., et al. “Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses”. Behavior Research Methods 41.4 (2009): 1149-1160.
  46. Excoffier L., et al. “Arlequin (version 3.0): An integrated software package for population genetics data analysis”. Evolutionary Bioinformatics 1 (2005): 47-50.
  47. Namer LS., et al. “An Ancient Pseudoknot in TNF-alpha Pre-mRNA Activates PKR, Inducing eIF2alpha Phosphorylation that Potently Enhances Splicing”. Cell Reports 20.1 (2017): 188-200.
  48. Kaempfer, R., et al. “Control of mRNA splicing by noncoding intragenic RNA elements that evoke a cellular stress response”. The International Journal of Biochemistry and Cell Biology 105 (2018): 20-23.
  49. Warner SC and AM Valdes. “Genetic association studies in osteoarthritis: is it fairytale?”. Current Opinion in Rheumatology 29.1 (2017): 103-109.
  50. Rodriguez-Fontenla C., et al. “Assessment of osteoarthritis candidate genes in a meta-analysis of nine genome-wide association studies”. Arthritis and Rheumatology 66.4 (2014): 940-949.
Citation: Randi Krog Eftedal., et al. “TNFA Genetic Polymorphism is Associated with Risk for Developing Hip but not Knee Osteoarthritis in Croatian Population”. EC Orthopaedics 11.3 (2020): 01-11.

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