J Korean Med Sci.  2007 Dec;22(6):973-980. 10.3346/jkms.2007.22.6.973.

Meta-analysis of the Association between HLA-DRB1 Allele and Rheumatoid Arthritis Susceptibility in Asian Populations

• Jun KR
• Choi SE
• Cha CH
• Oh HB
• Heo YS
• Ahn HY
• Lee KJ

• KMID: 1785756
• DOI: http://doi.org/10.3346/jkms.2007.22.6.973

Abstract

The aims of this study were to summarize results on the association of HLA-DRB1 with rheumatoid arthritis (RA) in Asians and to determine if the shared epitope (SE) hypothesis could explain the meta-analysis results. Among the papers published between January 1987 and July 2006 on RA susceptibility in Asian-Mongoloid populations (Korean, Japanese, Chinese, and Thai), 12 were selected for the metaanalysis. Mongoloid-Asian patients with RA had significantly higher frequencies of HLA-DRB1*0101, *0401, *0410, and *1001 than controls (OR 1.5-2.1, p<0.05 for association). When analyses were restricted to more ethnically homogeneous populations, HLA-DRB1*0405 showed a significant susceptibility to RA in Koreans (OR 5.65, 95% CI 4.32-7.39), whereas the HLA-DRB1*0301, *0403, *0406, *0701, *1301, and *1405 alleles showed protective association with RA (OR 0.32-0.70, p<0.05 for association). In conclusion, it was found that HLA-DRB1 *0101, *0401, *0405, *0410, and *1001 are susceptible, while HLA-DRB1* 0301, *0403, *0406, *0701, *1301, and *1405 are protective in Asian-Mongoloids. All the RA-associated alleles except DRB1*0301 could be explained by the structural model supporting the SE hypothesis that RA susceptibility is determined by the combination of amino acid residues at HLA-DR beta71 and beta74, not by beta71 alone.

Keyword

Arthritis, Rheumatoid; Genetics; Epitopes; HLA-DRB1; Meta-analysis; Asian Continental Ancestry Group

MeSH Terms

*Alleles
Arthritis, Rheumatoid/*genetics
Asian Continental Ancestry Group/*genetics
*Genetic Predisposition to Disease
HLA-DR Antigens/chemistry/*genetics
Humans

Figure

• 

  Fig. 1 Structural analysis of the interactions between the P4 residue of the antigenic peptide and the residues at positions 71 and 74 of DRβ in RA susceptible and protective alleles. (A) Overall structure of the HLA-DR molecule containing a peptide with a negatively charged residue at P4. The positions of DRβ residues 71-74 are indicated by red labels. The region inside the blue rectangle is magnified in panels B-F. (B) Close-up of the interaction of the P4 residue with the HLA DRB1*0401 molecule. Lysine at position 71 makes a salt bridge with the negatively charged P4 residue, leading to the optimal binding of an antigenic peptide for TCR recognition. A small residue, alanine, at amino acid 74 does not inhibit the salt bridge of DRβ 71-P4. The residues at positions 72 and 73 are not involved in peptide binding. (C) Close-up of the interaction of the P4 residue with HLA DRB1*0101, 0404, 0405, 0410, and 1001. The microenvironment is similar to that of DRB1*0401 due to the similar properties of arginine and lysine. (D) Close-up of the interaction of the P4 residue with HLA DRB1* 0403, 0406, and 1405. A negatively charged residue, glutamate, at position 74 would repel the negatively charged P4 residue and inhibit formation of the DRβ 71-P4 salt bridge. (E) Close-up of the interaction of the P4 residue with HLA DRB1*0701. The hydrogen bond between the N atom of the side chain of Q74 and the backbone carbonyl oxygen of the β70 residue causes an electrostatic repulsion between the partial negative charge on the O atom of the side chain of Q74 and an acidic P4 residue. (F) Close-up of the interaction of the P4 residue with HLA DRB1*1301.

Reference

1. Turesson C, Matteson EL. Genetics of rheumatoid arthritis. Mayo Clin Proc. 2006. 81:94–101.

2. 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. 30:1205–1213.

3. 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.

4. Gorman JD, Criswell LA. The shared epitope and severity of rheumatoid arthritis. Rheum Dis Clin North Am. 2002. 28:59–78.

5. Gorman JD, David-Vaudey E, Pai M, Lum RF, Criswell LA. Lack of association of the HLA-DRB1 shared epitope with rheumatoid nodules: an individual patient data meta-analysis of 3,272 Caucasian patients with rheumatoid arthritis. Arthritis Rheum. 2004. 50:753–762.

6. Lee HS, Lee KW, Song GG, Kim HA, Kim SY, Bae SC. Increased susceptibility to rheumatoid arthritis in Koreans heterozygous for HLA-DRB1*0405 and *0901. Arthritis Rheum. 2004. 50:3468–3475.

7. Chan SH, Lin YN, Wee GB, Koh WH, Boey ML. HLA class 2 genes in Singaporean Chinese rheumatoid arthritis. Br J Rheumatol. 1994. 33:713–717.

8. Tokunaga NK, Noda R, Kaneoka H, Ogahara S, Murata T, Hiratsuka T, Michinaga I, Naito S. Association between HLA-DRB1*15 and Japanese patients with rheumatoid arthritis complicated by renal involvement. Nephron. 1999. 81:165–171.

9. Yukioka M, Wakitani S, Murata N, Toda Y, Ogawa R, Kaneshige T, Ochi T. Elderly-onset rheumatoid arthritis and its association with HLA-DRB1 alleles in Japanese. Br J Rheumatol. 1998. 37:98–101.

10. Apple RJ, Erlich H. Browning MJ, McMichael AJ, editors. HLA class II genes: structure and diversity. HLA and MHC: genes, molecules and function. 1996. Oxford (UK): BIOS Scientific Publishers, Ltd;100.

11. Conn VS, Rantz MJ. Research methods: managing primary study quality in meta-analyses. Res Nurs Health. 2003. 26:322–333.

12. Huwiler-Muntener K, Juni P, Junker C, Egger M. Quality of reporting of randomized trials as a measure of methodologic quality. JAMA. 2002. 287:2801–2804.

13. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959. 22:719–748.

14. Attia J, Thakkinstian A, D'Este C. Meta-analyses of molecular association studies: methodologic lessons for genetic epidemiology. J Clin Epidemiol. 2003. 56:297–303.

15. Sterne JA, Egger M. Funnel plots for detecting bias in meta-analysis: guidelines on choice of axis. J Clin Epidemiol. 2001. 54:1046–1055.

16. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997. 315:629–634.

17. Sterne JA, Gavaghan D, Egger M. Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol. 2000. 53:1119–1129.

18. Duval S, Tweedie R. Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000. 56:455–463.

19. Laskowski RA, MacArthur MW, Moss DS, Thornton JM. PROCHECK: a program to check the stereochemical quality for assessing the accuracy of protein structures. J Appl Cryst. 1993. 26:283–291.

20. Kim TG, Choi HB, Park SH, Kim HY, Han H. DQCAR 113 and DQCAR 115 in combination with HLA-DRB1 alleles are significant markers of susceptibility to rheumatoid arthritis in the Korean population. Tissue Antigens. 1999. 54:552–559.

21. Hong GH, Park MH, Takeuchi F, Oh MD, Song YW, Nabeta H, Nakano K, Ito K, Park KS. Association of specific amino acid sequence of HLA-DR with rheumatoid arthritis in Koreans and its diagnostic value. J Rheumatol. 1996. 23:1699–1703.

22. Kim HY, Kim TG, Park SH, Lee SH, Cho CS, Han H. Predominance of HLA-DRB1*0405 in Korean patients with rheumatoid arthritis. Ann Rheum Dis. 1995. 54:988–990.

23. Molkentin J, Gregersen PK, Lin X, Zhu N, Wang Y, Wang Y, Chen S, Chen S, Baxter-Lowe LA, Silver J. Molecular analysis of HLA-DR beta and DQ beta polymorphism in Chinese with rheumatoid arthritis. Ann Rheum Dis. 1993. 52:610–612.

24. Seglias J, Li EK, Cohen MG, Wong RW, Potter PK, So AK. Linkage between rheumatoid arthritis susceptibility and the presence of HLA-DR4 and DR beta allelic third hypervariable region sequences in southern Chinese persons. Arthritis Rheum. 1992. 35:163–167.

25. Takeuchi F, Nakano K, Matsuta K, Nabeta H, Bannai M, Tanimoto K, Ito K. Positive and negative association of HLA-DR genotypes with Japanese rheumatoid arthritis. Clin Exp Rheumatol. 1996. 14:17–22.

26. Higami K, Hakoda M, Matsuda Y, Ueda H, Kashiwazaki S. Lack of association of HLA-DRB1 genotype with radiologic progression in Japanese patients with early rheumatoid arthritis. Arthritis Rheum. 1997. 40:2241–2247.

27. Pimtanothai N, Kimkong I, Inwattana R, Deesomchok U, Charoenwongse P. DRB1*04 subtype in Thai patients with rheumatoid arthritis. J Med Assoc Thai. 2002. 85:Suppl 1. S366–S370.

28. Penzotti JE, Doherty D, Lybrand TP, Nepom GT. A structural model for TCR recognition of the HLA class II shared epitope sequence implicated in susceptibility to rheumatoid arthritis. J Autoimmun. 1996. 9:287–293.

29. Garboczi DN, Ghosh P, Utz U, Fan QR, Biddison WE, Wiley DC. Structure of the complex between human T-cell receptor, viral peptide and HLA-A2. Nature. 1996. 384:134–141.

30. Garcia KC, Degano M, Stanfield RL, Brunmark A, Jackson MR, Peterson PA, Teyton L, Wilson IA. An alphabeta T cell receptor structure at 2.5 A and its orientation in the TCR-MHC complex. Science. 1996. 274:209–219.

31. Rigby AS, Silman AJ, Voelm L, Gregory JC, Ollier WE, Khan MA, Nepom GT, 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. 8:153–175.

32. Fries JF, Wolfe F, Apple R, Erlich H, Bugawan T, Holmes T, Bruce B. HLA-DRB1 genotype associations in 793 white patients from a rheumatoid arthritis inception cohort: frequency, severity, and treatment bias. Arthritis Rheum. 2002. 46:2320–2329.

33. Gjertson DW, Terasaki PI. HLA 1998. 1998. Kansas: American Society for Histocampatibility and Immunogenetics;202–221.

34. Reveille JD. The genetic basis of autoantibody production. Autoimmun Rev. 2006. 5:389–398.

35. Czaja AJ. Current concepts in autoimmune hepatitis. Ann Hepatol. 2005. 4:6–24.

36. Brintnell W, Zeggini E, Barton A, Thomson W, Eyre S, Hinks A, Silman AJ, Worthington J. Evidence for a novel rheumatoid arthritis susceptibility locus on chromosome 6p. Arthritis Rheum. 2004. 50:3823–3830.

37. Jawaheer D, Li W, Graham RR, Chen W, Damle A, Xiao X, Monteiro J, Khalili H, Lee A, Lundsten R, Begovich A, Bugawan T, Erlich H, Elder JT, Criswell LA, Seldin MF, Amos CI, Behrens TW, Gregersen PK. Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis. Am J Hum Genet. 2002. 71:585–594.

38. Mok JW, Lee YJ, Kim JY, Lee EB, Song YW, Park MH, Park KS. Association of MICA polymorphism with rheumatoid arthritis patients in Koreans. Hum Immunol. 2003. 64:1190–1194.

39. Song EY, Park MH, Kang SJ, Park HJ, Kim BC, Tokunaga K, Akaza T, Juji T. HLA class II allele and haplotype frequencies in Koreans based on 107 families. Tissue Antigens. 2002. 59:475–486.

40. Saito S, Ota S, Yamada E, Inoko H, Ota M. Allele frequencies and haplotypic associations defined by allelic DNA typing at HLA class I and class II loci in the Japanese population. Tissue Antigens. 2000. 56:522–529.

41. Ncbi.nlm.nih.gov [homepage on the Internet]. updated 2006 Oct 30; cited 2006 Nov 29. Bethesda: National Center for Biotechnology Information;Available from: http://www.ncbi.nlm.nih.gov/projects/mhc/ihwg.cgi .