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. 1995 Jul;57(1):150–159.

Genetic epidemiology of rheumatoid arthritis.

A H Lynn 1, C K Kwoh 1, C M Venglish 1, C E Aston 1, A Chakravarti 1
PMCID: PMC1801237  PMID: 7611283

Abstract

We conducted family studies and segregation analyses of rheumatoid arthritis (RA) that were based on consecutive patients with RA ascertained without regard to family history or known risk factors. First-degree relatives from 135 simplex and 30 multiplex families were included in the analyses. A highly penetrant recessive major gene, with a mutant allele frequency of .005, was identified as the most parsimonious genetic risk factor. Significant evidence for heterogeneity in risk for RA was observed for proband gender but not for proband age at onset. Kaplan-Meier risk analysis demonstrated significant evidence for differences in the distribution of risk among first-degree relatives. These analyses demonstrated that both proband gender and age at onset are important risk factors but that proband gender appears to be the more important determinant of risk, with relatives of male probands having the greatest cumulative risk for RA. In addition, log-linear modeling identified proband gender, familiality (multiplex or simplex), and an interaction term between these two variables as being adequate to define the distribution of risk in families. The pattern of risk for RA among susceptible individuals and its inheritance is thus heterogeneous. For future genetic analyses, families with an excess of affected males having a young age at onset may be the most informative in identifying the putative recessive gene and its modifiers.

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Selected References

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  1. Arnett F. C., Edworthy S. M., Bloch D. A., McShane D. J., Fries J. F., Cooper N. S., Healey L. A., Kaplan S. R., Liang M. H., Luthra H. S. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315–324. doi: 10.1002/art.1780310302. [DOI] [PubMed] [Google Scholar]
  2. Chakraborty R., Weiss K. M., Majumder P. P., Strong L. C., Herson J. A method to detect excess risk of disease in structured data: cancer in relatives of retinoblastoma patients. Genet Epidemiol. 1984;1(3):229–244. doi: 10.1002/gepi.1370010303. [DOI] [PubMed] [Google Scholar]
  3. Clerget-Darpoux F., Babron M. C., Prum B., Lathrop G. M., Deschamps I., Hors J. A new method to test genetic models in HLA associated diseases: the MASC method. Ann Hum Genet. 1988 Jul;52(Pt 3):247–258. doi: 10.1111/j.1469-1809.1988.tb01102.x. [DOI] [PubMed] [Google Scholar]
  4. Deighton C. M., Cavanagh G., Rigby A. S., Lloyd H. L., Walker D. J. Both inherited HLA-haplotypes are important in the predisposition to rheumatoid arthritis. Br J Rheumatol. 1993 Oct;32(10):893–898. doi: 10.1093/rheumatology/32.10.893. [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. Deighton C. M. What is the future for the genetics of rheumatoid arthritis? Br J Rheumatol. 1993 Oct;32(10):857–858. doi: 10.1093/rheumatology/32.10.857. [DOI] [PubMed] [Google Scholar]
  7. Dizier M. H., Eliaou J. F., Babron M. C., Combe B., Sany J., Clot J., Clerget-Darpoux F. Investigation of the HLA component involved in rheumatoid arthritis (RA) by using the marker association-segregation chi-square (MASC) method: rejection of the unifying-shared-epitope hypothesis. Am J Hum Genet. 1993 Sep;53(3):715–721. [PMC free article] [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. Hasstedt S. J., Clegg D. O., Ingles L., Ward R. H. HLA-linked rheumatoid arthritis. Am J Hum Genet. 1994 Oct;55(4):738–746. [PMC free article] [PubMed] [Google Scholar]
  10. Hochberg M. C. Adult and juvenile rheumatoid arthritis: current epidemiologic concepts. Epidemiol Rev. 1981;3:27–44. doi: 10.1093/oxfordjournals.epirev.a036238. [DOI] [PubMed] [Google Scholar]
  11. Khan M. A., Khan M. K. HLA studies in familial and sporadic rheumatoid arthritis. Dis Markers. 1986 Jun;4(1-2):67–76. [PubMed] [Google Scholar]
  12. Lalouel J. M., Morton N. E. Complex segregation analysis with pointers. Hum Hered. 1981;31(5):312–321. doi: 10.1159/000153231. [DOI] [PubMed] [Google Scholar]
  13. Lalouel J. M., Rao D. C., Morton N. E., Elston R. C. A unified model for complex segregation analysis. Am J Hum Genet. 1983 Sep;35(5):816–826. [PMC free article] [PubMed] [Google Scholar]
  14. Lawrence J. S. Heberden Oration, 1969. Rheumatoid arthritis--nature or nurture? Ann Rheum Dis. 1970 Jul;29(4):357–379. doi: 10.1136/ard.29.4.357. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lawrence R. C., Hochberg M. C., Kelsey J. L., McDuffie F. C., Medsger T. A., Jr, Felts W. R., Shulman L. E. Estimates of the prevalence of selected arthritic and musculoskeletal diseases in the United States. J Rheumatol. 1989 Apr;16(4):427–441. [PubMed] [Google Scholar]
  16. Linos A., Worthington J. W., O'Fallon W. M., Kurland L. T. The epidemiology of rheumatoid arthritis in Rochester, Minnesota: a study of incidence, prevalence, and mortality. Am J Epidemiol. 1980 Jan;111(1):87–98. doi: 10.1093/oxfordjournals.aje.a112878. [DOI] [PubMed] [Google Scholar]
  17. Morton N. E., MacLean C. J. Analysis of family resemblance. 3. Complex segregation of quantitative traits. Am J Hum Genet. 1974 Jul;26(4):489–503. [PMC free article] [PubMed] [Google Scholar]
  18. Nepom G. T., Hansen J. A., Nepom B. S. The molecular basis for HLA class II associations with rheumatoid arthritis. J Clin Immunol. 1987 Jan;7(1):1–7. doi: 10.1007/BF00915418. [DOI] [PubMed] [Google Scholar]
  19. Rigby A. S., Silman A. J., Voelm L., Gregory J. C., Ollier W. E., Khan M. A., Nepom G. T., Thomson G. Investigating the HLA component in rheumatoid arthritis: an additive (dominant) mode of inheritance is rejected, a recessive mode is preferred. Genet Epidemiol. 1991;8(3):153–175. doi: 10.1002/gepi.1370080303. [DOI] [PubMed] [Google Scholar]
  20. Rigby A. S., Voelm L., Silman A. J. Epistatic modeling in rheumatoid arthritis: an application of the Risch theory. Genet Epidemiol. 1993;10(5):311–320. doi: 10.1002/gepi.1370100504. [DOI] [PubMed] [Google Scholar]
  21. Risch N. Linkage strategies for genetically complex traits. I. Multilocus models. Am J Hum Genet. 1990 Feb;46(2):222–228. [PMC free article] [PubMed] [Google Scholar]
  22. Sanders P. A., Grennan D. M., Dyer P. A., Thomson W., deLange G. G. A comparison of clinical and immunogenetic features in familial and sporadic rheumatoid arthritis. J Rheumatol. 1987 Aug;14(4):718–722. [PubMed] [Google Scholar]
  23. Stastny P. Association of the B-cell alloantigen DRw4 with rheumatoid arthritis. N Engl J Med. 1978 Apr 20;298(16):869–871. doi: 10.1056/NEJM197804202981602. [DOI] [PubMed] [Google Scholar]
  24. Wallin J., Hillert J., Olerup O., Carlsson B., Ström H. Association of rheumatoid arthritis with a dominant DR1/Dw4/Dw14 sequence motif, but not with T cell receptor beta chain gene alleles or haplotypes. Arthritis Rheum. 1991 Nov;34(11):1416–1424. doi: 10.1002/art.1780341112. [DOI] [PubMed] [Google Scholar]
  25. Weyand C. M., Hicok K. C., Conn D. L., Goronzy J. J. The influence of HLA-DRB1 genes on disease severity in rheumatoid arthritis. Ann Intern Med. 1992 Nov 15;117(10):801–806. doi: 10.7326/0003-4819-117-10-801. [DOI] [PubMed] [Google Scholar]
  26. Wordsworth P., Bell J. Polygenic susceptibility in rheumatoid arthritis. Ann Rheum Dis. 1991 Jun;50(6):343–346. doi: 10.1136/ard.50.6.343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Yamashita T. S., Khan M. A., Kushner I. Genetic analysis of families with multiple cases of rheumatoid arthritis. Dis Markers. 1986 Jun;4(1-2):113–119. [PubMed] [Google Scholar]
  28. del Junco D., Luthra H. S., Annegers J. F., Worthington J. W., Kurland L. T. The familial aggregation of rheumatoid arthritis and its relationship to the HLA-DR4 association. Am J Epidemiol. 1984 May;119(5):813–829. doi: 10.1093/oxfordjournals.aje.a113802. [DOI] [PubMed] [Google Scholar]

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