Skip to main content
PMC home page
Annals of the Rheumatic Diseases logoLink to Annals of the Rheumatic Diseases
. 1998 Jun;57(6):361–365. doi: 10.1136/ard.57.6.361

Linkage of cytokine genes to rheumatoid arthritis. Evidence of genetic heterogeneity

S John 1, A Myerscough 1, A Marlow 1, A Hajeer 1, A Silman 1, W Ollier 1, J Worthington 1
PMCID: PMC1752610  PMID: 9771211

Abstract

OBJECTIVE—To investigate linkage of candidate disease susceptibility genes to rheumatoid arthritis (RA) in affected sibling pair families stratified for specific clinical features. 
METHOD—Two hundred RA affected sibling pair families were genotyped for informative microsatellite markers mapping within or less than 3cM from: INFα, INFγ, INFβ, IL1α, IL1β, IL1R, IL2, IL6, IL5R, IL8R, BCL2, CD40L, NOS3, NRAMP, α1 anti-trypsin, and α1 anti-chymotrypsin, using fluorescence based automated technology. Linkage was examined by defining allele sharing sibling pairs. This was assessed by maximum likelihood—inheritance by descent methods.
RESULTS—An increase in allele sharing was seen for IL5R in female sibling pairs (LOD 0.91, p = 0.03), for INFγ in sibling pairs with an affected male (LOD 0.96, p = 0.03) and most significantly for IL2 in sibling pairs where one or both were persistently seronegative (LOD 1.05, p = 0.02).
CONCLUSION—Weak evidence of linkage of RA to IL5R, IFNγ, and IL2 has been detected in clinical subsets of sibling pairs suggesting that RA is a genetically heterogeneous disease.

 Keywords: linkage; rheumatoid arthritis; sibling pairs; cytokine genes

Full Text

The Full Text of this article is available as a PDF (139.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allen R. C., Spriggs M. K., Belmont J. W. Dinucleotide repeat polymorphism in the human CD40 ligand gene. Hum Mol Genet. 1993 Jun;2(6):828–828. doi: 10.1093/hmg/2.6.828-a. [DOI] [PubMed] [Google Scholar]
  2. Byth B. C., Cox D. W. A (CA)n repeat polymorphism at the 5' end of the alpha 1-antitrypsin gene (PI). Hum Mol Genet. 1993 Oct;2(10):1752–1752. [PubMed] [Google Scholar]
  3. Copeman J. B., Cucca F., Hearne C. M., Cornall R. J., Reed P. W., Rønningen K. S., Undlien D. E., Nisticò L., Buzzetti R., Tosi R. Linkage disequilibrium mapping of a type 1 diabetes susceptibility gene (IDDM7) to chromosome 2q31-q33. Nat Genet. 1995 Jan;9(1):80–85. doi: 10.1038/ng0195-80. [DOI] [PubMed] [Google Scholar]
  4. Crisi G. M., Santambrogio L., Hochwald G. M., Smith S. R., Carlino J. A., Thorbecke G. J. Staphylococcal enterotoxin B and tumor-necrosis factor-alpha-induced relapses of experimental allergic encephalomyelitis: protection by transforming growth factor-beta and interleukin-10. Eur J Immunol. 1995 Nov;25(11):3035–3040. doi: 10.1002/eji.1830251108. [DOI] [PubMed] [Google Scholar]
  5. Deighton C. M., Walker D. J. The familial nature of rheumatoid arthritis. Ann Rheum Dis. 1991 Jan;50(1):62–65. doi: 10.1136/ard.50.1.62. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Epplen C., Frank G., Gomolka M., Nagy M., Nürnberg P., Epplen J. T. Dinucleotide repeat polymorphism in the IL2 and IL5RA genes. Hum Mol Genet. 1994 Apr;3(4):679–679. doi: 10.1093/hmg/3.4.679-a. [DOI] [PubMed] [Google Scholar]
  7. Feldmann M., Brennan F. M., Williams R. O., Cope A. P., Gibbons D. L., Katsikis P. D., Maini R. N. Evaluation of the role of cytokines in autoimmune disease: the importance of TNF alpha in rheumatoid arthritis. Prog Growth Factor Res. 1992;4(3):247–255. doi: 10.1016/0955-2235(92)90022-a. [DOI] [PubMed] [Google Scholar]
  8. Gregersen P. K., Silver J., Winchester R. J. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 1987 Nov;30(11):1205–1213. doi: 10.1002/art.1780301102. [DOI] [PubMed] [Google Scholar]
  9. Gyapay G., Morissette J., Vignal A., Dib C., Fizames C., Millasseau P., Marc S., Bernardi G., Lathrop M., Weissenbach J. The 1993-94 Généthon human genetic linkage map. Nat Genet. 1994 Jun;7(2 Spec No):246–339. doi: 10.1038/ng0694supp-246. [DOI] [PubMed] [Google Scholar]
  10. Hajeer A., John S., Ollier W. E., Silman A. J., 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] [Google Scholar]
  11. Holmans P. Asymptotic properties of affected-sib-pair linkage analysis. Am J Hum Genet. 1993 Feb;52(2):362–374. [PMC free article] [PubMed] [Google Scholar]
  12. Holmans P., Clayton D. Efficiency of typing unaffected relatives in an affected-sib-pair linkage study with single-locus and multiple tightly linked markers. Am J Hum Genet. 1995 Nov;57(5):1221–1232. [PMC free article] [PubMed] [Google Scholar]
  13. John S., Marlow A., Hajeer A., Ollier W., Silman A., Worthington J. Linkage and association studies of the natural resistance associated macrophage protein 1 (NRAMP1) locus in rheumatoid arthritis. J Rheumatol. 1997 Mar;24(3):452–457. [PubMed] [Google Scholar]
  14. Kwiatkowski D. J., Diaz M. O. Dinucleotide repeat polymorphism at the IFNA locus (9p22). Hum Mol Genet. 1992 Nov;1(8):658–658. doi: 10.1093/hmg/1.8.658-a. [DOI] [PubMed] [Google Scholar]
  15. Lynn A. H., Kwoh C. K., Venglish C. M., Aston C. E., Chakravarti A. Genetic epidemiology of rheumatoid arthritis. Am J Hum Genet. 1995 Jul;57(1):150–159. [PMC free article] [PubMed] [Google Scholar]
  16. MacGregor A. J., Bamber S., Silman A. J. A comparison of the performance of different methods of disease classification for rheumatoid arthritis. Results of an analysis from a nationwide twin study. J Rheumatol. 1994 Aug;21(8):1420–1426. [PubMed] [Google Scholar]
  17. Marlow A., John S., Hajeer A., Ollier W. E., Silman A. J., Worthington J. The sensitivity of different analytical methods to detect disease susceptibility genes in rheumatoid arthritis sibling pair families. J Rheumatol. 1997 Jan;24(1):208–211. [PubMed] [Google Scholar]
  18. McKenzie C. A., Julier C., Forrester T., McFarlane-Anderson N., Keavney B., Lathrop G. M., Ratcliffe P. J., Farrall M. Segregation and linkage analysis of serum angiotensin I-converting enzyme levels: evidence for two quantitative-trait loci. Am J Hum Genet. 1995 Dec;57(6):1426–1435. [PMC free article] [PubMed] [Google Scholar]
  19. Meyer J. M., Han J., Singh R., Moxley G. Sex influences on the penetrance of HLA shared-epitope genotypes for rheumatoid arthritis. Am J Hum Genet. 1996 Feb;58(2):371–383. [PMC free article] [PubMed] [Google Scholar]
  20. Nadaud S., Bonnardeaux A., Lathrop M., Soubrier F. Gene structure, polymorphism and mapping of the human endothelial nitric oxide synthase gene. Biochem Biophys Res Commun. 1994 Feb 15;198(3):1027–1033. doi: 10.1006/bbrc.1994.1146. [DOI] [PubMed] [Google Scholar]
  21. Peterson A. C., Di Rienzo A., Lehesjoki A. E., de la Chapelle A., Slatkin M., Freimer N. B. The distribution of linkage disequilibrium over anonymous genome regions. Hum Mol Genet. 1995 May;4(5):887–894. doi: 10.1093/hmg/4.5.887. [DOI] [PubMed] [Google Scholar]
  22. Ploski R., Mellbye O. J., Rønningen K. S., Førre O., Thorsby E. Seronegative and weakly seropositive rheumatoid arthritis differ from clearly seropositive rheumatoid arthritis in HLA class II associations. J Rheumatol. 1994 Aug;21(8):1397–1402. [PubMed] [Google Scholar]
  23. Risch N. Linkage strategies for genetically complex traits. II. The power of affected relative pairs. Am J Hum Genet. 1990 Feb;46(2):229–241. [PMC free article] [PubMed] [Google Scholar]
  24. Ruiz-Linares A. Dinucleotide repeat polymorphism in the interferon-gamma (IFNG) gene. Hum Mol Genet. 1993 Sep;2(9):1508–1508. doi: 10.1093/hmg/2.9.1508. [DOI] [PubMed] [Google Scholar]
  25. Silman A. J., MacGregor A. J., Thomson W., Holligan S., Carthy D., Farhan A., Ollier W. E. Twin concordance rates for rheumatoid arthritis: results from a nationwide study. Br J Rheumatol. 1993 Oct;32(10):903–907. doi: 10.1093/rheumatology/32.10.903. [DOI] [PubMed] [Google Scholar]
  26. Spielman R. S., McGinnis R. E., Ewens W. J. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet. 1993 Mar;52(3):506–516. [PMC free article] [PubMed] [Google Scholar]
  27. Worthington J., Ollier W. E., Leach M. K., Smith I., Hay E. M., Thomson W., Pepper L., Carthy D., Farhan A., Martin S. The Arthritis and Rheumatism Council's National Repository of Family Material: pedigrees from the first 100 rheumatoid arthritis families containing affected sibling pairs. Br J Rheumatol. 1994 Oct;33(10):970–976. doi: 10.1093/rheumatology/33.10.970. [DOI] [PubMed] [Google Scholar]

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

RESOURCES