Clinical Medicine Insights: Arthritis and Musculoskeletal Disorders Tnf-α and Tnf-β Gene Polymorphism in Saudi Rheumatoid Arthritis Patients

Background: Tumor necrosis factor (TNF)-α and-β are cytokines with a wide range of inflammatory, apoptotic and immunomodula-tory activities. TNF-α promoter −308 G , A polymorphism has been reported to be associated with rheumatoid arthritis (RA) with inconsistent results. Objective: The aim of this study is to elucidate a possible association of TNF-α (G−308Α) and TNF-β (A+252G) polymorphisms with the susceptibility of RA in Saudi patients. Patients and methods: This case control study consisted of 232 Saudi subjects including 106 RA patients and 126 matched controls. Genomic DNA was extracted using QIAamp R DNA mini kit (Qiagen CA, USA). TNF-α and TNF-β genes were amplified using Arms primers. Results: The frequencies of TNF-α (−308) allele G and genotype GG were significantly higher in RA patients as compared to controls while allele A and genotype AA were predominant in control group. On the other hand the frequency of TNF-β (+252) GG and AA genotypes were significantly higher in RA patients as compared to controls while GA genotype was predominant in controls. It was inferred that genotype GG positive individuals at position −308 of TNF-α were susceptible to RA while genotype AA might has a protective effect on RA susceptibility in Saudis. Whereas GG and AA genotype of TNF-β at +252 position might exert additive susceptibility to RA and GA might be refractory. However, there was no significant association between duration of morning stiffness, RF positivity and number of joints involved and distribution of alleles/genotypes of TNF-α (−308) or TNF-β (+252) polymorphism. It may be concluded that the TNF-α (−308) and TNF-β (+252) polymorphisms might influence the susceptibility to RA in Saudi population. These results might have prognostic value for future clinical observations.

[1]  R. Misra,et al.  Association of tumor necrosis factor alpha and IL-10 promoter polymorphisms with rheumatoid arthritis in North Indian population , 2010, Rheumatology International.

[2]  M. McCarthy,et al.  Family-based analysis of tumor necrosis factor and lymphotoxin-alpha tag polymorphisms with type 1 diabetes in the population of South Croatia. , 2009, Human immunology.

[3]  G. Hatemi,et al.  Tumor necrosis factor-alpha and Interleukin-10 gene promoter polymorphisms in Turkish rheumatoid arthritis patients , 2008, Clinical Rheumatology.

[4]  S. Duan,et al.  Tumor necrosis factor alpha −308 polymorphism is associated with rheumatoid arthritis in Han population of Eastern China , 2007, Rheumatology International.

[5]  M. Soucek,et al.  Polymorphism in the tumor necrosis factor-α gene promoter is associated with severity of rheumatoid arthritis in the Czech population , 2007, Clinical Rheumatology.

[6]  S. Sobki,et al.  HLA-DRB1 association in Saudi rheumatoid arthritis patients , 2006, Rheumatology International.

[7]  H. Paulus,et al.  Association of tumor necrosis factor α polymorphism, but not the shared epitope, with increased radiographic progression in a seropositive rheumatoid arthritis inception cohort , 2006 .

[8]  M. Tai,et al.  Tumor necrosis factor-beta +252A polymorphism is associated with systemic lupus erythematosus in Taiwan. , 2005, Journal of the Formosan Medical Association = Taiwan yi zhi.

[9]  F. Takeuchi,et al.  The genetic contribution of the TNFa11 microsatellite allele and the TNFb + 252*2 allele in Japanese RA. , 2005, Clinical and experimental rheumatology.

[10]  J. Granados,et al.  Tumor necrosis factor-alpha -308 promoter polymorphism contributes independently to HLA alleles in the severity of rheumatoid arthritis in Mexicans. , 2005, Journal of autoimmunity.

[11]  H. Tiwari,et al.  The influence of genetic variation in the HLA-DRB1 and LTA-TNF regions on the response to treatment of early rheumatoid arthritis with methotrexate or etanercept. , 2004, Arthritis and rheumatism.

[12]  C. Maury,et al.  Tumor necrosis factor alpha, its soluble receptor I, and -308 gene promoter polymorphism in patients with rheumatoid arthritis with or without amyloidosis: implications for the pathogenesis of nephropathy and anemia of chronic disease in reactive amyloidosis. , 2003, Arthritis and rheumatism.

[13]  Nathalie Balandraud,et al.  Polymorphism at position -308 of the tumor necrosis factor alpha gene influences outcome of infliximab therapy in rheumatoid arthritis. , 2003, Arthritis and rheumatism.

[14]  F. Tsai,et al.  Lack of association of tumor necrosis factor alpha gene polymorphism in patients with rheumatoid arthritis in central Taiwan , 2003, Rheumatology International.

[15]  A. Lefvert,et al.  Susceptibility for and clinical manifestations of rheumatoid arthritis are associated with polymorphisms of the TNF-alpha, IL-1beta, and IL-1Ra genes. , 2002, The Journal of rheumatology.

[16]  Chia-Hui Lin,et al.  Tumor necrosis factor promoter polymorphisms in patients with rheumatoid arthritis in Taiwan. , 2001, The Journal of rheumatology.

[17]  C. Bouchard,et al.  G-308A polymorphism of the tumor necrosis factor alpha gene promoter and salivary cortisol secretion. , 2001, The Journal of clinical endocrinology and metabolism.

[18]  T. Saruta,et al.  Tumor necrosis factor alpha gene G-308A polymorphism, insulin resistance, and fasting plasma glucose in young, older, and diabetic Japanese men. , 2000, Metabolism: clinical and experimental.

[19]  K. Morgan,et al.  A polymorphism in the tumor necrosis factor-alpha gene promoter region may predispose to a poor prognosis in COPD. , 2000, Chest.

[20]  J. Chan,et al.  Tumor necrosis factor alpha gene G-308A polymorphism in the metabolic syndrome. , 2000, Metabolism: clinical and experimental.

[21]  T. Hansen,et al.  The -238 and -308 G-->A polymorphisms of the tumor necrosis factor alpha gene promoter are not associated with features of the insulin resistance syndrome or altered birth weight in Danish Caucasians. , 2000, The Journal of clinical endocrinology and metabolism.

[22]  N. Biteau,et al.  Analysis of the polymorphism of the tumour necrosis factor (TNF) gene and promoter and of circulating TNF-alpha levels in heart-transplant patients suffering or not suffering from severe rejection. , 1999, European journal of immunogenetics : official journal of the British Society for Histocompatibility and Immunogenetics.

[23]  S. Turner,et al.  ARMS-PCR methodologies to determine IL-10, TNF-α, TNF-β and TGF-β1 gene polymorphisms , 1999 .

[24]  P. Tonali,et al.  Tumour necrosis factor beta gene polymorphisms in myasthenia gravis. , 1998, European journal of immunogenetics : official journal of the British Society for Histocompatibility and Immunogenetics.

[25]  P. Burton,et al.  Association of polymorphisms within the tumour necrosis factor (TNF) genes and childhood asthma , 1998, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[26]  B. Weinshenker,et al.  A population-based case-control study of the tumor necrosis factor alpha-308 polymorphism in multiple sclerosis , 1997, Neurology.

[27]  F. Breedveld,et al.  Tumour necrosis factor alpha gene polymorphisms in rheumatoid arthritis: association with susceptibility to, or severity of, disease? , 1997, British journal of rheumatology.

[28]  H. Mcdevitt,et al.  Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[29]  A. E. Campbell,et al.  Scarring trachoma is associated with polymorphism in the tumor necrosis factor alpha (TNF-alpha) gene promoter and with elevated TNF-alpha levels in tear fluid , 1997, Infection and immunity.

[30]  G. Hitman,et al.  Autoimmune renal disease and tumour necrosis factor beta gene polymorphism. , 1993, Clinical nephrology.

[31]  M. French,et al.  Polymorphic MHC ancestral haplotypes affect the activity of tumour necrosis factor‐alpha , 1993, Clinical and experimental immunology.

[32]  M. Feldmann,et al.  TNF alpha--a pivotal role in rheumatoid arthritis? , 1992, British journal of rheumatology.

[33]  U. Spengler,et al.  Polymorphic structure of the tumor necrosis factor (TNF) locus: an NcoI polymorphism in the first intron of the human TNF-beta gene correlates with a variant amino acid in position 26 and a reduced level of TNF- beta production , 1991, The Journal of experimental medicine.

[34]  M. Liang,et al.  The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. , 1988, Arthritis and rheumatism.

[35]  D. Goeddel,et al.  Effect of interleukin 2, interferon-gamma, and mitogens on the production of tumor necrosis factors alpha and beta. , 1985, Journal of immunology.

[36]  A. Svejgaard,et al.  HLA and Disease 1982 ‐ A Survey , 1983, Immunological reviews.

[37]  C. Delclaux,et al.  Association of TNF2 ,aT NF- aPromoter Polymorphism, With Septic Shock Susceptibility and Mortality , 2013 .

[38]  P. Villiger,et al.  The −308 tumour necrosis factor-α gene polymorphism predicts therapeutic response to TNFα-blockers in rheumatoid arthritis and spondyloarthritis patients , 2007 .

[39]  Y. Mándi,et al.  Tumour necrosis factor-alpha and heat-shock protein 70-2 gene polymorphisms in a family with rheumatoid arthritis. , 2004, Acta microbiologica et immunologica Hungarica.

[40]  J. Cuenca,et al.  Genetic polymorphism at position-308 in the promoter region of the tumor necrosis factor (TNF): implications of its allelic distribution on susceptibility or resistance to diseases in the Chilean population. , 2001, Biological research.

[41]  M. Feldmann,et al.  The role of TNF alpha and IL-1 in rheumatoid arthritis. , 2001, Current directions in autoimmunity.

[42]  A. Vasku,et al.  Polymorphisms in inflammation genes (angiotensinogen, TAP1 and TNF-beta) in psoriasis. , 2000, Archives of dermatological research.

[43]  R. Norman,et al.  No association between the –308 polymorphism in the tumour necrosis factor α (TNFα) promoter region and polycystic ovaries , 1999 .

[44]  G. Gerken,et al.  A tumor necrosis factor-alpha (TNF-alpha) promoter polymorphism is associated with chronic hepatitis B infection. , 1998, Clinical and experimental immunology.

[45]  E. Pareja,et al.  Polymorphism at the TNF loci in rheumatoid arthritis. , 1997, Tissue antigens.

[46]  D. Grennan,et al.  Increased frequency of the uncommon allele of a tumour necrosis factor alpha gene polymorphism in rheumatoid arthritis and systemic lupus erythematosus. , 1995, Disease markers.

[47]  P. Kühnl,et al.  Histocompatibility antigens in vitiligo: Hamburg study on 102 patients from northern Germany. , 1993, Dermatology.

[48]  B. Beutler,et al.  The biology of cachectin/TNF--a primary mediator of the host response. , 1989, Annual review of immunology.