0201 Haplotype on the Risk for Multiple Sclerosis in Diverse Arab Populations in Israel

Genes and Immunity (2010) 11, 423–431 & 2010 Macmillan Publishers Limited All rights reserved 1466-4879/10 www.nature.com/gene ORIGINAL ARTICLE Opposing effects of the HLA-DRB1*0301-DQB1*0201 haplotype on the risk for multiple sclerosis in diverse Arab populations in Israel G Benedek1,6, T Paperna2,6, N Avidan2, I Lejbkowicz2, JR Oksenberg3, J Wang3, C Brautbar1,4, S Israel4 and A Miller2,5, for the Israeli MS Genetics group7 1The Lautenberg Center for Immunology, Hebrew University Hadassah Medical School, Jerusalem, Israel; 2Faculty of Medicine, Rappaport Research Institute, Technion–Israel Institute of Technology, Haifa, Israel; 3Department of Neurology, University of California, San Francisco, CA, USA; 4Tissue Typing and Immunogenetics Unit, Hadassah Medical Center, Jerusalem, Israel and 5Division of Neuroimmunology and Multiple Sclerosis Center, Carmel Medical Center, Haifa, Israel 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 ¼ 109) and controls (n ¼ 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 ¼ 0.004, odds ratio (OR) ¼ 3.07), and negative association in Christian Arabs (PBonferroni ¼ 0.01, OR ¼ 0.12), with similar results obtained for HLA-DQB1*0201. HLA-B*52 was negatively associated with MS only in Muslims (PBonferroni ¼ 0.01, OR ¼ 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. Genes and Immunity (2010) 11, 423–431; doi:10.1038/gene.2010.20; published online 13 May 2010 Keywords: association studies; autoimmune disease; human leukocyte antigen; major histocompatibility complex; multiple sclerosis; population genetics Introduction Most genetic studies in MS focused, not surprisingly, on populations of Northern European descent, where Multiple sclerosis (MS) is a neurological disease with a prevalence of MS is relatively high. These studies have strong inflammatory component. The precise etiology repeatedly affirmed the contribution of the HLA DR2 of MS remains unknown; however, both genetic and haplotype DQB1*0602-DQA1*0102-DRB1*1501-DRB5*0101 environmental factors presumably underlie disease to disease risk; however, further dissection of the specific pathogenesis. The major genetic effect has been attrib- role of the genes within this haplotype has been limited uted to the 6p major histocompatibility complex region, by the high linkage disequilibrium structure prevalent in comprising the human leukocyte antigen (HLA) genes.1,2 this chromosomal region. Recognition of this limitation Within this region, HLA class II genes such as HLA- has provoked studies in non-European populations, DRB1 and HLA-DQB1 appear to be important in taking advantage of their different fine genomic archi- susceptibility and progression of disease, but a growing tecture. For example, studies in African-American body of evidence is consistent with contributions beyond cohorts confirmed the contribution of DRB1*0301 and the HLA class II region, including effects from the nearby DRB1*1503 to MS risk, and the influence of HLA-DRB5 HLA class I genes HLA-A, -B and -C.3–6 on disease progression.7–9 In addition, studies on populations with unique MS prevalence patterns, or lower rates of the major susceptibility DR2 haplotype Correspondence: Dr A Miller, Division of Neuroimmunology and have revealed the full range of allelic heterogeneity at the Multiple Sclerosis Center, Carmel Medical Center, 7 Michal Street, DRB1 locus. Haifa 34362, Israel. Epidemiology studies suggest a relation between MS E-mails: [email protected] or [email protected] 6 prevalence and latitude, with risk increasing with distance These authors contributed equally to this work. 10 7See Appendix. from the equator. However, specific enclaves of high or Received 29 October 2009; revised 29 January 2010; accepted low risk have been reported in some populations, like 11 February 2010; published online 13 May 2010 Sardinia.11 The presence of population-specific factors, Genetics of multiple sclerosis in Israeli Arabs G Benedek et al 424 including founder effects, particularly in immune-related Table 1 Demographic data of participants and clinical character- genes, may modulate MS risk in different populations istics of MS patients residing in the same geographical region.12–15 Middle East Arab populations have a range of MS prevalence in the Muslims Christians low to medium rates.16–19 A recent epidemiological survey in Israel revealed that prevalence rates for Christian Arabs N (Cases/Controls) 66/90 43/42 are thrice as high as for Muslim Arabs, suggesting that Female/male (% females) Cases 46/20 (70) 29/14 (67) different risk factors operate in these two subethnic Controls 37/53 (41) 17/25 (40) groups.19 The Christian Arab population is a minority group among the Arab populations (B1.7% of the total Age at recruitment, years population in Israel versus 16.6% for Muslim Arabs, Mean±s.d. (range) according to the 2008 census, http://www1.cbs.gov.il/ Cases 37.6±10.7 (19–58) 38.3±11.6 (18–62) ± ± shnaton59/st02_19.pdf). It has therefore been the subject of Controls 37.7 11.0 (19–71) 40.0 14.3 (19–76) few genetic studies and little is known on its population Age of onset, years structure. It is not clear whether these MS prevalence Mean±s.d. (range) 30.7±9.2 (15–54) 29.7±9.6 (13–53) differences between Christians and other Israeli Arabs are the result of genetic differences, environmental effects or Disease duration from onset to recruitment, years both. Because religion in the Middle East Arab population Median (range) 5.5 (0–34) 6.0 (1–23) ± ± ± has shaped marriage practice over generations, it is likely Mean s.d. 6.8 5.8 8.6 5.9 that relatively high genetic homogeneity is present, which Years from onset to diagnosis may be advantageous for genetic studies as it is expected Median (range) 1.0 (0–10) 1.0 (0–20) to increase the statistical power.20 Mean±s.d. 2.1±2.7 3.4±5.0 Accordingly, two motives served as the driving force for this study: first, the advantage of genetic studies in EDSS at recruitment, N (%) non-European, inbred populations, where different p3 25 (37.9) 23 (53.5) 3o and o6 32 (48.5) 17 (39.5) linkage disequilibrium structure may lead to unmasking 6p 9 (13.6) 3 (7.0) of new genetics factors for MS; and second, to provide clinical and epidemiological data on specific Arab Disease type, N (%) populations for which there is relatively scarce informa- Relapsing-remitting 43 (65.2) 34 (79.1) tion. Identification of distinct genetic profiles associated Secondary-progressive 11 (16.7) 5 (11.6) with MS may explain the different prevalence rates for Primary-progressive 3 (4.5) 0 Relapsing-progressive 9 (13.6) 4 (9.3) MS in Muslims and Christian Arabs residing in Israel. Patients with relapsing 61 (96.8) 38 (88.4) onset ever treated with Results immunomodulatory treatment, N (%)a Demographic data of the study participants and clinical characteristics are presented in Table 1. The female/male Abbreviation: EDSS, expanded disability status scale. ratio and the age of onset in the two patient populations aInterferon-b-1a, interferon-b-1b or glatiramer acetate, as recorded (Muslim and Christian Arabs) were similar, as were the at the day of recruitment. other clinical characteristics, including disease duration, and access to disease-modifying treatments. Many of the individuals serving as controls were the spouses of the Table 2 P-values for allelic exact tests comparing Muslim and patients. This enrollment strategy was chosen to increase Christian cohorts for HLA genesa similarity between cases and controls regarding domi- ciles and lifestyle factors; therefore gender ratio was HLA-DQB1 HLA-DRB1 HLA-B HLA-C HLA-A significantly different between the case and control groups (Pp0.01). Case and control groups were well Cases 0.002 0.001 0.02 0.008 0.42 matched for age in both ethnic groups. Controls 0.31 0.53 0.30 0.79 0.03 HLA allele frequencies in the Israeli Muslim and Christian aGlobal w2 exact tests compared between religion groups in either Arab populations case groups or controls. Global P-values are shown; significant P Global comparisons of allele frequency distributions values (o0.05) shown in gray. revealed significant differences between Christians and Muslims among the cases for HLA-DQB1,-DRB1,-B and (Table 3; P ¼ 0.005 and 0.047, respectively). Further -C (P ¼ 0.002, 0.001, 0.02 and 0.008), and for HLA-A in the analysis indicated that in the Muslim population, control group (P ¼ 0.03) (Table 2); therefore, case–control DRB1*0301 is a major susceptibility allele, positively analyses were stratified by religious affiliation. Tables 3, associated to MS (PB ¼ 0.004, odds ratio (OR) ¼ 3.07). 5–7 present the allele frequencies for the five HLA loci Although the previously established risk allele studied. Deviation from Hardy–Weinberg equilibrium DRB1*1501 was more frequent in the patient group, this was not observed for any of the HLA gene alleles tested.

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