• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of annrheumdAnnals of the Rheumatic DiseasesVisit this articleSubmit a manuscriptReceive email alertsContact usBMJ
Ann Rheum Dis. Aug 2001; 60(8): 791–795.
PMCID: PMC1753809

Tumour necrosis factor microsatellites and HLA-DRB1*, HLA-DQA1*, and HLA-DQB1* alleles in Peruvian patients with rheumatoid arthritis


OBJECTIVE—To study the association between rheumatoid arthritis (RA) and HLA and tumour necrosis factor (TNF) polymorphism in Peruvian mestizo patients in comparison with ethnically similar controls.
METHODS—Seventy nine patients with RA and 65 ethnically matched healthy controls were genotyped for HLA-DRB1, HLA-DQA1, HLA-DQB1, and TNFα and TNFβ alleles using PCR amplification. Clinical severity was assessed as mild, moderate, or severe in 35 of the patients.
RESULTS—TNFα6 showed the strongest association with disease susceptibility. The TNFα6 allele was more common in patients than in controls (p<0.0076) and the proportion of patients with at least one copy of this allele was greater (p<0.015, relative risk 2.35). Among the HLA-DRB1* alleles with the shared epitope sequence, only the DRB1*1402 allele was significantly increased in patients compared with controls (p<0.0311), as was the proportion of patients with at least one copy of this allele (p<0.0232, relative risk 2.74). In contrast, the overall frequency of alleles with the shared epitope was not different in patients and controls. The haplotype HLA-DRB1*1402-DQB1*0301-DQA1*0401 was significantly more common in patients. TNFα6 was more common in patients whether or not they had this haplotype. None of the 11 patients lacking the TNFα6 allele had severe disease.
CONCLUSIONS—This study shows for the first time that TNF gene polymorphism is associated with susceptibility to RA in a non-white population. TNFα6 and HLA-DRB1*1402 independently conferred significantly increased risk in Peruvian mestizo patients.

Full Text

The Full Text of this article is available as a PDF (150K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Eberhardt K, Fex E. Clinical course and remission rate in patients with early rheumatoid arthritis: relationship to outcome after 5 years. Br J Rheumatol. 1998 Dec;37(12):1324–1329. [PubMed]
  • Abdel-Nasser AM, Rasker JJ, Valkenburg HA. Epidemiological and clinical aspects relating to the variability of rheumatoid arthritis. Semin Arthritis Rheum. 1997 Oct;27(2):123–140. [PubMed]
  • Silman AJ, MacGregor AJ, Thomson W, Holligan S, Carthy D, Farhan A, Ollier WE. Twin concordance rates for rheumatoid arthritis: results from a nationwide study. Br J Rheumatol. 1993 Oct;32(10):903–907. [PubMed]
  • Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 1987 Nov;30(11):1205–1213. [PubMed]
  • Eberhardt K, Fex E, Johnson U, Wollheim FA. Associations of HLA-DRB and -DQB genes with two and five year outcome in rheumatoid arthritis. Ann Rheum Dis. 1996 Jan;55(1):34–39. [PMC free article] [PubMed]
  • Jongeneel CV, Briant L, Udalova IA, Sevin A, Nedospasov SA, Cambon-Thomsen A. Extensive genetic polymorphism in the human tumor necrosis factor region and relation to extended HLA haplotypes. Proc Natl Acad Sci U S A. 1991 Nov 1;88(21):9717–9721. [PMC free article] [PubMed]
  • Campbell DA, Nelson S, Madhok R, Field M, Gallagher G. TNF Nco-I RFLP is not an independent risk factor in rheumatoid arthritis. Eur J Immunogenet. 1994 Dec;21(6):461–467. [PubMed]
  • Udalova IA, Nedospasov SA, Webb GC, Chaplin DD, Turetskaya RL. Highly informative typing of the human TNF locus using six adjacent polymorphic markers. Genomics. 1993 Apr;16(1):180–186. [PubMed]
  • Jacob CO, Fronek Z, Lewis GD, Koo M, Hansen JA, McDevitt HO. Heritable major histocompatibility complex class II-associated differences in production of tumor necrosis factor alpha: relevance to genetic predisposition to systemic lupus erythematosus. Proc Natl Acad Sci U S A. 1990 Feb;87(3):1233–1237. [PMC free article] [PubMed]
  • Pociot F, Briant L, Jongeneel CV, Mölvig J, Worsaae H, Abbal M, Thomsen M, Nerup J, Cambon-Thomsen A. Association of tumor necrosis factor (TNF) and class II major histocompatibility complex alleles with the secretion of TNF-alpha and TNF-beta by human mononuclear cells: a possible link to insulin-dependent diabetes mellitus. Eur J Immunol. 1993 Jan;23(1):224–231. [PubMed]
  • Ciusani E, Allen M, Sandberg-Wollheim M, Eoli M, Salmaggi A, Milanese C, Nespolo A, Gyllensten U. Analysis of HLA-class II DQA1, DQB1, DRB1 and DPB1 in Italian multiple sclerosis patients. Eur J Immunogenet. 1995 Apr;22(2):171–178. [PubMed]
  • Ciusani E, Salmaggi A, Pocio F, Nespolo A, Sandberg-Wollheim M. Tumour necrosis factor microsatellite alleles in an Italian population. Eur J Immunogenet. 1997 Feb;24(1):9–13. [PubMed]
  • Reveille JD. The genetic contribution to the pathogenesis of rheumatoid arthritis. Curr Opin Rheumatol. 1998 May;10(3):187–200. [PubMed]
  • Willkens RF, Nepom GT, Marks CR, Nettles JW, Nepom BS. Association of HLA-Dw16 with rheumatoid arthritis in Yakima Indians. Further evidence for the "shared epitope" hypothesis. Arthritis Rheum. 1991 Jan;34(1):43–47. [PubMed]
  • Nelson JL, Boyer G, Templin D, Lanier A, Barrington R, Nisperos B, Smith A, Mickelson E, Hansen JA. HLA antigens in Tlingit Indians with rheumatoid arthritis. Tissue Antigens. 1992 Aug;40(2):57–63. [PubMed]
  • Williams RC, Jacobsson LT, Knowler WC, del Puente A, Kostyu D, McAuley JE, Bennett PH, Pettitt DJ. Meta-analysis reveals association between most common class II haplotype in full-heritage Native Americans and rheumatoid arthritis. Hum Immunol. 1995 Jan;42(1):90–94. [PubMed]
  • Thomson W, Harrison B, Ollier B, Wiles N, Payton T, Barrett J, Symmons D, Silman A. Quantifying the exact role of HLA-DRB1 alleles in susceptibility to inflammatory polyarthritis: results from a large, population-based study. Arthritis Rheum. 1999 Apr;42(4):757–762. [PubMed]
  • Hajeer AH, Worthington J, Silman AJ, Ollier WE. Association of tumor necrosis factor microsatellite polymorphisms with HLA-DRB1*04-bearing haplotypes in rheumatoid arthritis patients. Arthritis Rheum. 1996 Jul;39(7):1109–1114. [PubMed]
  • Wordsworth BP, Pile KD, Gibson K, Burney RO, Mockridge I, Powis SH. Analysis of the MHC-encoded transporters TAP1 and TAP2 in rheumatoid arthritis: linkage with DR4 accounts for the association with a minor TAP2 allele. Tissue Antigens. 1993 Sep;42(3):153–155. [PubMed]
  • Vandevyver C, Geusens P, Cassiman JJ, Raus J. Peptide transporter genes (TAP) polymorphisms and genetic susceptibility to rheumatoid arthritis. Br J Rheumatol. 1995 Mar;34(3):207–214. [PubMed]
  • Eberhardt K, Grubb R, Johnson U, Pettersson H. HLA-DR antigens, Gm allotypes and antiallotypes in early rheumatoid arthritis--their relation to disease progression. J Rheumatol. 1993 Nov;20(11):1825–1829. [PubMed]
  • Reviron D, Tezenas du Montcel S, Foutrier C, Guis S, Benazet JF, Auquier P, Busson M, Roux H, Mercier P, Roudier J. HLA DRB1, DMA, and DMB gene polymorphisms in rheumatoid arthritis. Hum Immunol. 1999 Mar;60(3):245–249. [PubMed]
  • Perdriger A, Guggenbuhl P, Chalès G, Yaouanq J, Quelvennec E, Bonnard MN, Pawlotsky Y, Semana G. Positive association of the HLA DMB1*0101-0101 genotype with rheumatoid arthritis. Rheumatology (Oxford) 1999 May;38(5):448–452. [PubMed]
  • Park MH, Oh MD, Song YW, Pai HJ, Takeuchi F, Tokunaga K, Hong GH, Park KS. Association of complement alleles C4AQ0 and C4B5 with rheumatoid arthritis in Koreans. Ann Rheum Dis. 1996 Oct;55(10):776–778. [PMC free article] [PubMed]
  • Paimela L, Leirisalo-Repo M, Lokki ML, Koskimies S. Prognostic significance of complement alleles Bf and C4 in early rheumatoid arthritis. Clin Rheumatol. 1996 Nov;15(6):594–598. [PubMed]
  • Vandevyver C, Raus P, Stinissen P, Philippaerts L, Cassiman JJ, Raus J. Polymorphism of the tumour necrosis factor beta gene in multiple sclerosis and rheumatoid arthritis. Eur J Immunogenet. 1994 Oct;21(5):377–382. [PubMed]
  • Wilson AG, de Vries N, van de Putte LB, Duff GW. A tumour necrosis factor alpha polymorphism is not associated with rheumatoid arthritis. Ann Rheum Dis. 1995 Jul;54(7):601–603. [PMC free article] [PubMed]
  • Mulcahy B, Waldron-Lynch F, McDermott MF, Adams C, Amos CI, Zhu DK, Ward RH, Clegg DO, Shanahan F, Molloy MG, et al. Genetic variability in the tumor necrosis factor-lymphotoxin region influences susceptibility to rheumatoid arthritis. Am J Hum Genet. 1996 Sep;59(3):676–683. [PMC free article] [PubMed]
  • Hajeer A, John S, Ollier WE, Silman AJ, Dawes P, Hassell A, Mattey D, Fryer A, Strange R, Worthington J. Tumor necrosis factor microsatellite haplotypes are different in male and female patients with RA. J Rheumatol. 1997 Jan;24(1):217–219. [PubMed]
  • Mattey DL, Hassell AB, Dawes PT, Ollier WE, Hajeer A. Interaction between tumor necrosis factor microsatellite polymorphisms and the HLA-DRB1 shared epitope in rheumatoid arthritis: influence on disease outcome. Arthritis Rheum. 1999 Dec;42(12):2698–2704. [PubMed]
  • Martínez A, Fernández-Arquero M, Pascual-Salcedo D, Conejero L, Alves H, Balsa A, de la Concha EG. Primary association of tumor necrosis factor-region genetic markers with susceptibility to rheumatoid arthritis. Arthritis Rheum. 2000 Jun;43(6):1366–1370. [PubMed]
  • Brinkman BM, Huizinga TW, Kurban SS, van der Velde EA, Schreuder GM, Hazes JM, Breedveld FC, Verweij CL. Tumour necrosis factor alpha gene polymorphisms in rheumatoid arthritis: association with susceptibility to, or severity of, disease? Br J Rheumatol. 1997 May;36(5):516–521. [PubMed]
  • Verweij CL. Tumour necrosis factor gene polymorphisms as severity markers in rheumatoid arthritis. Ann Rheum Dis. 1999 Nov;58 (Suppl 1):I20–I26. [PMC free article] [PubMed]
  • Mu H, Chen JJ, Jiang Y, King MC, Thomson G, Criswell LA. Tumor necrosis factor a microsatellite polymorphism is associated with rheumatoid arthritis severity through an interaction with the HLA-DRB1 shared epitope. Arthritis Rheum. 1999 Mar;42(3):438–442. [PubMed]

Figures and Tables

Figure 1
Proportion of patients and controls carrying none, one, or two alleles with the shared epitope sequences. The distribution is not significantly increased (χ2=1.03; p>0.5).
Figure 2
Proportion of patients and controls carrying none, one, or two TNFα6 alleles. The distribution differs significantly (χ2=7.54; p<0.023).

Articles from Annals of the Rheumatic Diseases are provided here courtesy of BMJ Group


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...