Abstract
To analyse the association between individual HLA-DRB1 locus genotypes and rheumatoid arthritis (RA) susceptibility, taking in account the multiallelic nature of the shared epitope (SE). In total, 538 patients and 536 controls were genotyped for 12 alleles of the HLA-DRB1 locus. A Bayesian partition model and multivariate logistic models were used to assess the role of the SE and of its individual components. The SE was associated with RA susceptibility (odds ratio (OR) 2 versus 0 SE copy=9.99 (95 CI 4.69–15.30) and OR 1 versus 0 SE copy=3.16 (95% CI 2.42–4.12)). The Bayesian partition model supplied a permutation of the HLA-DRBA locus alleles ordered by increasing disease risk. Alleles associated with highest risks are those that code for the SE. The individual OR estimations for the HLA-DRB1 locus genotypes went from OR=1.00 (95% CI 1.00–1.25) for the less associated genotype to OR=21.40 (95% CI 8.02–65.79) for the most associated one. In conclusion, the allele order risk and the OR estimations for individual genotypes of the HLA-DRB1 locus were consistent with the SE theory. Using an exploratory statistical method without a priori hypothesis, our study allowed a detailed analysis of the multiallelic nature of the SE.
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References
Firestein GS . Evolving concepts of rheumatoid arthritis. Nature 2003; 423: 356–361.
Gabriel SE . The epidemiology of rheumatoid arthritis. Rheum Dis Clin North Am 2001; 27: 269–281.
Harney S, Wordsworth BP . Genetic epidemiology of rheumatoid arthritis. Tissue Antigens 2002; 60: 465–473.
Gregersen PK, Silver J, Winchester RJ . The shared epitope hypothesis. An approach to understand the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 1987; 30: 1205–1213.
De Vries N, Tijssen H, van Riel PL, van de Putte LB . Reshaping the shared epitope hypothesis: HLA-associated risk for rheumatoid arthritis is encoded by amino acid substitutions at positions 67–74 of the HLA-DRB1 molecule. Arthritis Rheum 2002; 46: 921–928.
Gonzalez-Gay MA, Garcia-Porrua C, Hajeer AH . Influence of human leukocyte antigen-DRB1 on the susceptibility and severity of rheumatoid arthritis. Semin Arthritis Rheum 2002; 31: 355–360.
Gorman JD, Lum RF, Chen JJ, Suarez-Almazor ME, Thomson G, Criswell LA . Impact of shared epitope genotype and ethnicity on erosive disease. meta-analysis of 3240 rheumatoid arthritis patients. Arthritis Rheum 2004; 50: 400–412, 2004.
Toussirot E, Auge B, Tiberghien P, Chabod J, Cedoz JP, Wendling D . HLA-DRB1 alleles and shared amino acid sequences in disease susceptibility and severity in patients from eastern France with rheumatoid arthritis. J Rheumatol 1999; 26: 1446–1451.
Thomson W, Harrison B, Ollier B, Wiles N, Payton T, Barrett J et al. Quantifying the exact role of HLA-DRB1 alleles in susceptibility to inflammatory polyarthritis: results from a large, population-based study. Arthritis Rheum 1999; 42: 757–762.
Huizinga TWJ, Pisetsky DS, Kimberly RP . Associations, populations, and the truth. Recommendations for genetic associations studies in Arthritis & rheumatism. Arthritis Rheum 2004; 50: 2066–2071.
Seaman SR, Richardson S, Stücker I, Benhamou S . A bayesian partition model for case-control studies on highly polymorphic candidate genes. Genet Epidemiol 2002; 22: 356–368.
Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 315–324.
Mougin B, Garnero P, Borel O, Compagnon C, Barbalat V, Marotte H et al. A routine assay for the direct analysis of HLA-DR-related shared epitope and B27 alleles in chronic inflammatory arthritis. J Immunol Methods 2001; 256: 47–53.
Collins MM, Tang T, Slack R, Sintasath D, Hartzman RJ, Ng J et al. The relative frequencies of HLA-DRB1*01 alleles in the major US populations. Tissue Antigens 2000; 55: 48–52.
McCullagh P, Nelder JA . Generalized Linear Models, 2nd edn. Chapman and Hall: London, 1989.
Breslow NE, Day NE . Statistical Methods in Cancer Research Vol. 1 – The Analysis of Case-Control Studies ed. IARC: Lyon, 1980.
Sham PC, Curtis D . Monte Carlo tests for association between disease and alleles at highly polymorphic loci. Ann Hum Genet 1995; 59: 97–105.
Acknowledgements
We thank Shaun Seaman who kindly gave us the source code (C language) of the Bayesian partition model.
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Appendix A
Appendix A
Details on Seaman's Bayesian partition model
The basic assumptions of the partition model are that all possible genotypes of the HLA-DRB1 locus belong to a number of groups, that all genotypes in the same group convey the same risk of disease for the positive individuals and that genotypes in different groups convey different risks. A genotype partition is built from an allele order risk that corresponds to a classification of the alleles by increasing disease risk. Each genotype partition satisfies a particular assumption: if two genotypes share one allele but differ for the other, then the risk conveyed by a genotype with a higher allele in the order risk cannot be less than the risk conveyed by a genotype with a lower allele in that order risk. Accordingly, if an allele Aj is higher than the allele Ai in the allele order risk, whatever the allele Ak, the risk associated with the Aj/Ak genotype is greater than the risk associated with Ai/Ak. Although the Bayesian partition model clusters the genotypes, it supplies one disease risk estimation per genotype. Indeed, at each iteration of the fitting algorithm, an allele order risk, a partition model and group disease risks are sampled from their posterior distribution. The posterior distribution of each genotype risk is then recovered from the group disease risk the genotype belonged to at each iteration.
Uniform priors were placed on the allele order risk and the partition model. The prior distribution of the log (disease risk) of each group was the normal distribution N(0, σ2), σ2=2.34. This value of σ2 implied the assumption that 95% of groups of genotypes had disease risk in the range (0.05–20).
Results were based on 100 000 iterations. OR estimation and 95% credibility intervals were supplied for each genotype. 95% credibility intervals were constructed from the posterior distributions and could be interpreted as the classical 95% confidence intervals. The posterior probabilities of each allele to be at each rank as well as the mean rank of each allele were also computed. The mean rank of each allele provided the retained allele order risk. Results are presented in Table 5.
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Marotte, H., Tournoud, M., Cazalis, MA. et al. Extensive multiallelic analysis of the relationship between HLA-DRB1 and rheumatoid arthritis using a Bayesian partition model. Genes Immun 7, 487–493 (2006). https://doi.org/10.1038/sj.gene.6364319
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DOI: https://doi.org/10.1038/sj.gene.6364319