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Opposing effects of the HLA-DRB1*0301-DQB1*0201 haplotype on the risk for multiple sclerosis in diverse Arab populations in Israel

Abstract

Different multiple sclerosis (MS) prevalence rates were reported for Muslim and Christian Arabs in Israel. In this study, we evaluated whether associations of human leukocyte antigen (HLA) genes with MS may contribute to this prevalence difference. DNA samples from Israeli Arab MS patients (n=109) and controls (n=132) were typed for HLA class I (HLA-A, -B and -C) and II (HLA-DRB1 and -DQB1) genes. Global comparisons of HLA allele frequencies revealed significant differences between Christians and Muslims; therefore, case–control analyses were stratified by religious affiliation. Disease characteristics of Muslim and Christian Arab MS patients were similar to those reported for European populations. Opposing association signals with MS were observed for alleles composing the DRB1*0301-DQB1*0201 haplotype: positive association of the HLA-DRB1*0301 allele in Muslims (PBonferroni=0.004, odds ratio (OR)=3.07), and negative association in Christian Arabs (PBonferroni=0.01, OR=0.12), with similar results obtained for HLA-DQB1*0201. HLA-B*52 was negatively associated with MS only in Muslims (PBonferroni=0.01, OR=0.03). The study presents for the first time a high-resolution HLA gene analysis in clinically well-characterized Arab populations with MS, and shows the population-specific contribution of the DRB1*0301-DQB1*0201 haplotype to disease susceptibility.

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References

  1. Oksenberg JR, Baranzini SE, Sawcer S, Hauser SL . The genetics of multiple sclerosis: SNPs to pathways to pathogenesis. Nat Rev Genet 2008; 9: 516–526.

    Article  CAS  Google Scholar 

  2. Ramagopalan SV, Deluca GC, Degenhardt A, Ebers GC . The genetics of clinical outcome in multiple sclerosis. J Neuroimmunol 2008; 201–202: 183–199.

    Article  Google Scholar 

  3. Yeo TW, De Jager PL, Gregory SG, Barcellos LF, Walton A, Goris A et al. A second major histocompatibility complex susceptibility locus for multiple sclerosis. Ann Neurol 2007; 61: 228–236.

    Article  Google Scholar 

  4. Fogdell-Hahn A, Ligers A, Gronning M, Hillert J, Olerup O . Multiple sclerosis: a modifying influence of HLA class I genes in an HLA class II associated autoimmune disease. Tissue Antigens 2000; 55: 140–148.

    Article  CAS  Google Scholar 

  5. Chao MJ, Barnardo MC, Lincoln MR, Ramagopalan SV, Herrera BM, Dyment DA et al. HLA class I alleles tag HLA-DRB1*1501 haplotypes for differential risk in multiple sclerosis susceptibility. Proc Natl Acad Sci USA 2008; 105: 13069–13074.

    Article  CAS  Google Scholar 

  6. Rioux JD, Goyette P, Vyse TJ, Hammarstrom L, Fernando MM, Green T et al. Mapping of multiple susceptibility variants within the MHC region for 7 immune-mediated diseases. Proc Natl Acad Sci USA 2009; 106: 18680–18685.

    Article  CAS  Google Scholar 

  7. Oksenberg JR, Barcellos LF, Cree BA, Baranzini SE, Bugawan TL, Khan O et al. Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans. Am J Hum Genet 2004; 74: 160–167.

    Article  CAS  Google Scholar 

  8. Caillier SJ, Briggs F, Cree BA, Baranzini SE, Fernandez-Vina M, Ramsay PP et al. Uncoupling the roles of HLA-DRB1 and HLA-DRB5 genes in multiple sclerosis. J Immunol 2008; 181: 5473–5480.

    Article  CAS  Google Scholar 

  9. Cree BA, Reich DE, Khan O, De Jager PL, Nakashima I, Takahashi T et al. Modification of multiple sclerosis phenotypes by African ancestry at HLA. Arch Neurol 2009; 66: 226–233.

    Article  Google Scholar 

  10. Pugliatti M, Sotgiu S, Rosati G . The worldwide prevalence of multiple sclerosis. Clin Neurol Neurosurg 2002; 104: 182–191.

    Article  Google Scholar 

  11. Marrosu MG, Murru MR, Costa G, Cucca F, Sotgiu S, Rosati G et al. Multiple sclerosis in Sardinia is associated and in linkage disequilibrium with HLA-DR3 and -DR4 alleles. Am J Hum Genet 1997; 61: 454–457.

    Article  CAS  Google Scholar 

  12. Marrosu MG, Murru MR, Costa G, Murru R, Muntoni F, Cucca F . DRB1-DQA1-DQB1 loci and multiple sclerosis predisposition in the Sardinian population. Hum Mol Genet 1998; 7: 1235–1237.

    Article  CAS  Google Scholar 

  13. Grossman I, Avidan N, Singer C, Paperna T, Lancet D, Beckmann JS et al. Genomic profiling of interpopulation diversity guides prioritization of candidate-genes for autoimmunity. Genes Immun 2004; 5: 493–504.

    Article  CAS  Google Scholar 

  14. Brassat D, Salemi G, Barcellos LF, McNeill G, Proia P, Hauser SL et al. The HLA locus and multiple sclerosis in Sicily. Neurology 2005; 64: 361–363.

    Article  CAS  Google Scholar 

  15. Kallio SP, Jakkula E, Purcell S, Suvela M, Koivisto K, Tienari PJ et al. Use of a genetic isolate to identify rare disease variants: C7 on 5p associated with MS. Hum Mol Genet 2009; 18: 1670–1683.

    Article  CAS  Google Scholar 

  16. Alshubaili AF, Alramzy K, Ayyad YM, Gerish Y . Epidemiology of multiple sclerosis in Kuwait: new trends in incidence and prevalence. Eur Neurol 2005; 53: 125–131.

    Article  CAS  Google Scholar 

  17. Yamout B, Barada W, Tohme RA, Mehio-Sibai A, Khalifeh R, El-Hajj T . Clinical characteristics of multiple sclerosis in Lebanon. J Neurol Sci 2008; 270: 88–93.

    Article  CAS  Google Scholar 

  18. El-Salem K, Al-Shimmery E, Horany K, Al-Refai A, Al-Hayk K, Khader Y . Multiple sclerosis in Jordan: a clinical and epidemiological study. J Neurol 2006; 253: 1210–1216.

    Article  Google Scholar 

  19. Alter M, Kahana E, Zilber N, Miller A . Multiple sclerosis frequency in Israel's diverse populations. Neurology 2006; 66: 1061–1066.

    Article  Google Scholar 

  20. Shifman S, Darvasi A . The value of isolated populations. Nat Genet 2001; 28: 309–310.

    Article  CAS  Google Scholar 

  21. Zalloua PA, Xue Y, Khalife J, Makhoul N, Debiane L, Platt DE et al. Y-chromosomal diversity in Lebanon is structured by recent historical events. Am J Hum Genet 2008; 82: 873–882.

    Article  CAS  Google Scholar 

  22. Confavreux C, Vukusic S, Adeleine P . Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain 2003; 126 (Part 4): 770–782.

    Article  Google Scholar 

  23. Cree BA, Khan O, Bourdette D, Goodin DS, Cohen JA, Marrie RA et al. Clinical characteristics of African Americans vs Caucasian Americans with multiple sclerosis. Neurology 2004; 63: 2039–2045.

    Article  CAS  Google Scholar 

  24. Marrie RA, Cutter G, Tyry T, Vollmer T, Campagnolo D . Does multiple sclerosis-associated disability differ between races? Neurology 2006; 66: 1235–1240.

    Article  CAS  Google Scholar 

  25. Daif AK, Al-Rajeh S, Awada A, Al Bunyan M, Ogunniyi A, AbdulJabar M et al. Pattern of presentation of multiple sclerosis in Saudi Arabia: analysis based on clinical and paraclinical features. Eur Neurol 1998; 39: 182–186.

    Article  CAS  Google Scholar 

  26. Al-Din AS, Khogali M, Poser CM, al-Nassar KE, Shakir R, Hussain J et al. Epidemiology of multiple sclerosis in Arabs in Kuwait: a comparative study between Kuwaitis and Palestinians. J Neurol Sci 1990; 100: 137–141.

    Article  CAS  Google Scholar 

  27. Almawi WY, Busson M, Tamim H, Al-Harbi EM, Finan RR, Wakim-Ghorayeb SF et al. HLA class II profile and distribution of HLA-DRB1 and HLA-DQB1 alleles and haplotypes among Lebanese and Bahraini Arabs. Clin Diagn Lab Immunol 2004; 11: 770–774.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Amar A, Kwon OJ, Motro U, Witt CS, Bonne-Tamir B, Gabison R et al. Molecular analysis of HLA class II polymorphisms among different ethnic groups in Israel. Hum Immunol 1999; 60: 723–730.

    Article  CAS  Google Scholar 

  29. Sanchez-Velasco P, Karadsheh NS, Garcia-Martin A, Ruiz de Alegria C, Leyva-Cobian F . Molecular analysis of HLA allelic frequencies and haplotypes in Jordanians and comparison with other related populations. Hum Immunol 2001; 62: 901–909.

    Article  CAS  Google Scholar 

  30. Nebel A, Filon D, Weiss DA, Weale M, Faerman M, Oppenheim A et al. High-resolution Y chromosome haplotypes of Israeli and Palestinian Arabs reveal geographic substructure and substantial overlap with haplotypes of Jews. Hum Genet 2000; 107: 630–641.

    Article  CAS  Google Scholar 

  31. Al-Din AS, Al-Saffar M, Siboo R, Behbehani K . Association between HLA-D region epitopes and multiple sclerosis in Arabs. Tissue Antigens 1986; 27: 196–200.

    Article  CAS  Google Scholar 

  32. Al-Din AS, el-Khateeb M, Kurdi A, Mubaidin A, Wriekat A, al-Shehab A et al. Multiple sclerosis in Arabs in Jordan. J Neurol Sci 1995; 131: 144–149.

    Article  CAS  Google Scholar 

  33. Al-Din ASN, Kurdi A, Mubaidin A, El-Khateeb M, Khalil RW, Wriekat AL . Epidemiology of multiple sclerosis in Arabs in Jordan: a comparative study between Jordanians and Palestinians. J Neurol Sci 1996; 135: 162–167.

    Article  Google Scholar 

  34. Al-Shammri S, Nelson RF, Al-Muzairi I, Akanji AO . HLA determinants of susceptibility to multiple sclerosis in an Arabian Gulf population. Mult Scler 2004; 10: 381–386.

    Article  CAS  Google Scholar 

  35. Barcellos LF, Sawcer S, Ramsay PP, Baranzini SE, Thomson G, Briggs F et al. Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis. Hum Mol Genet 2006; 15: 2813–2824.

    Article  CAS  Google Scholar 

  36. Stankovich J, Butzkueven H, Marriott M, Chapman C, Tubridy N, Tait BD et al. HLA–DRB1 associations with disease susceptibility and clinical course in Australians with multiple sclerosis. Tissue Antigens 2009; 74: 17–21.

    Article  CAS  Google Scholar 

  37. Israel S, Kwon OJ, Weintrob N, Sprecher E, Bloch K, Assa S et al. HLA class II immunogenetics of IDDM in Yemenite Jews. Hum Immunol 1998; 59: 728–733.

    Article  CAS  Google Scholar 

  38. Mangalam A, Luckey D, Basal E, Behrens M, Rodriguez M, David C . HLA-DQ6 (DQB1*0601)-restricted T cells protect against experimental autoimmune encephalomyelitis in HLA-DR3.DQ6 double-transgenic mice by generating anti-inflammatory IFN-gamma. J Immunol 2008; 180: 7747–7756.

    Article  CAS  Google Scholar 

  39. Mangalam A, Luckey D, Basal E, Jackson M, Smart M, Rodriguez M et al. HLA-DQ8 (DQB1*0302)-restricted Th17 cells exacerbate experimental autoimmune encephalomyelitis in HLA-DR3-transgenic mice. J Immunol 2009; 182: 5131–5139.

    Article  CAS  Google Scholar 

  40. Kivity S, Agmon-Levin N, Blank M, Shoenfeld Y . Infections and autoimmunity—friends or foes? Trends Immunol 2009; 30: 409–414.

    Article  CAS  Google Scholar 

  41. Lorentzen AR, Karlsen TH, Olsson M, Smestad C, Mero IL, Woldseth B et al. Killer immunoglobulin-like receptor ligand HLA-Bw4 protects against multiple sclerosis. Ann Neurol 2009; 65: 658–666.

    Article  CAS  Google Scholar 

  42. Middleton D, Menchaca L, Rood H, Komerofsky R . New allele frequency database: http://www.allelefrequencies.net Tissue Antigens 2003; 61: 403–407.

    Article  CAS  Google Scholar 

  43. Ono T, Zambenedetti MR, Yamasaki K, Kawano Y, Kamikawaji N, Ito H et al. Molecular analysis of HLA class I (HLA-A and -B) and HLA class II (HLA-DRB1) genes in Japanese patients with multiple sclerosis (Western type and Asian type). Tissue Antigens 1998; 52: 539–542.

    Article  CAS  Google Scholar 

  44. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the Diagnosis of Multiple Sclerosis. Ann Neurol 2001; 50: 121–127.

    Article  CAS  Google Scholar 

  45. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13: 227–231.

    Article  CAS  Google Scholar 

  46. Kurtzke JF . Rating neurologic impairment in multiple sclerosis: an Expanded Disability Status Scale (EDSS). Neurology 1983; 33: 1444–1452.

    Article  CAS  Google Scholar 

  47. Parzen M, Lipsitz S, Ibrahim J, Klar N . An estimate of the odds ratio that always exists. J Comput Graph Stat 2002; 11: 420–436.

    Article  Google Scholar 

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Acknowledgements

This study was supported by the National Multiple Sclerosis Society of USA–RG 3520A1/1 (AM); the Wolfson Family Charitable Trust (AM), the Sacta-Rashi Foundation (AM), the Technion's Vice-President for Research funds (AM) and by Grant AI067152 from the National Institutes of Allergy and Infectious Diseases (JRO). We thank the MS patients, their families and the healthy volunteers for participation in this study. We thank Yvonne Nachleh, Anat Volkowich, Matana Galili and Maayan Merhav, Rappaport Faculty of Medicine and Research Institute, Technion–Israel Institute of Technology, Haifa, Israel, for expert technical assistance; Sara Dishon, Carmel Medical Center, Haifa, Israel, for providing patient care and assistance in clinical data management; Dr Ofra Barnett-Griness and Nili Stein Carmel Medical Center, Haifa, Israel, for statistical consultations and Prof Doron Lancet, Weizmann Institute of Science, for critical reviewing of the article.

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Appendix

Appendix

Members of The Israeli MS Genetics Group:

Ester Kahana, MD: Barzilai Medical Center, Ashkelon; Dimitrios Karussis, MD PhD: Hadassah Medical Center, Jerusalem; Rafik Masalha, MD: Soroka Medical Center, Beer-Sheva; Ariel Miller, MD PhD: Carmel Medical Center; Panayiota Petrou, MD: Hadassah Medical Center, Jerusalem; Hana Rawasdeh, MD: Carmel Medical Center, Haifa; Radi Shahein, MD: Sieff Medical Center, Safed.

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Benedek, G., Paperna, T., Avidan, N. et al. Opposing effects of the HLA-DRB1*0301-DQB1*0201 haplotype on the risk for multiple sclerosis in diverse Arab populations in Israel. Genes Immun 11, 423–431 (2010). https://doi.org/10.1038/gene.2010.20

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