Increased occurrence of anti-AQP4 seropositivity and unique HLA Class II associations with neuromyelitis optica (NMO), among Muslim Arabs in Israel Livnat Brill a , Micha Mandel c , Dimitrios Karussis a , Panayiota Petrou a , Keren Miller b , Tamir Ben-Hur a , Arnon Karni d , Ora Paltiel e , Shoshana Israel b,1 , Adi Vaknin-Dembinsky a, ⁎ ,1 a Department of Neurology and Laboratory of Neuroimmunology, and the Agnes-Ginges Center for Neurogenetics, Hadassah Medical Center, Ein–Karem, Jerusalem 91120, Israel b Tissue Typing Laboratory, Hadassah Medical Center, Ein Karem, Jerusalem, 91120, Israel c Department of Statistics, The Hebrew University of Jerusalem, Mount Scopus, Jerusalem 91905, Israel d Neuroimmunology Laboratory, Department of Neurology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel e Department of Hematology, Braun School of Public Health, Hadassah-Hebrew University, Jerusalem, Israel abstract article info Article history: Received 30 September 2015 Received in revised form 24 January 2016 Accepted 8 February 2016 Available online xxxx Background: Previous studies have revealed different human leukocyte antigen (HLA) associations in multiple sclerosis (MS) and neuromyelitis optica (NMO), further discriminating these two demyelinating pathological conditions. In worldwide analyses, NMO and opticospinal MS are represented at higher proportions among de- myelinating conditions in African, East-Asian and Latin American populations. There are currently no data regarding the prevalence of NMO in Middle East Muslims. The population in Israel is diverse in many ways, and includes subpopulations, based on religion and ethnicity; some exhibit genetic homogeneity. In Israel, the incidence of MS is lower in the Muslim population than the Jewish population and Muslims carry different allele frequency distribution of HLA haplotypes. Objective: To evaluate the occurrence of anti-AQP4 seropositivity in the Israeli Muslim population among patients with central nervous system (CNS) demyelinating conditions; and to identify the HLA DR and DQ profiles of Muslim Arab Israeli patients with NMO spectrum of diseases (NMOSD). Methods: The prevalence of anti-AQP4 seropositivity was analyzed in 342 samples, obtained from patients with various CNS demyelinating conditions and in a validation set of 310 samples. HLA class II alleles (HLA-DRB1 and DQB1) were examined in DNA samples from 35 Israeli Muslim Arabs NMO patients and compared to available data from 74 Israeli Muslim controls. Results: Our data reveal a significantly increased prevalence of anti-AQP4 seropositivity, indicative of NMOSD, in Muslim Arab Israeli patients with initial diagnosis of a CNS demyelinating syndrome. In this population, there was a positive association with the HLA-DRB1*04:04 and HLA-DRB1*10:01 alleles (p = 0.03), and a strong negative association with the HLA-DRB1*07 and HLA-DQB1*02:02 alleles (p = 0.003, p = 0.002). Conclusions: Our findings indicate a possibly increased prevalence of NMOSD in Muslim Arabs in Israel with distinct (positive and negative) HLA associations. Further studies in patients with similar genetic backgrounds worldwide could help to confirm our findings and identify more genetic susceptibility factors for NMO, contrib- uting to our general understanding of the pathogenesis of NMOSD. © 2016 Published by Elsevier B.V. Keywords: AQP4 HLA class 2 Multiple sclerosis (MS) Neuromyelitis optica (NMO) Muslims Arabs 1. Introduction Neuromyelitis optica (NMO, Devic's syndrome) is an autoimmune, inflammatory, demyelinating disease of the central nervous system (CNS) that predominantly affects the optic nerves and spinal cord. For many years it was considered a severe variant of multiple sclerosis (MS). Today, NMO can be distinguished from MS by clinical and neuro- imaging criteria (Jarius et al., 2014; Mandler, 2006; Pereira et al., 2015). A breakthrough in defining NMO as a distinct disease entity came from the identification of a highly specific serum antibody, NMO immuno- globulin G (NMO-IgG) directed against the astrocytic water channel protein aquaporin-4 (AQP4) (Lennon et al., 2004; Weinshenker et al., 2006). Although the precise etiology of NMO is still unknown, following the identification of the unique anti-AQP4 antibody in the majority of patients it is thought to be an antibody-mediated autoimmune disease. Moreover, the presence of these antibodies is currently considered one Journal of Neuroimmunology 293 (2016) 65–70 ⁎ Corresponding author at: Neurology Department, Multiple Sclerosis & Immunobiology Research, Hadassah Medical Center, Ein Karem, P.O.B. 12000, Jerusalem 91120, Israel. E-mail address: adembinsky@gmail.com (A. Vaknin-Dembinsky). 1 Equal contribution. http://dx.doi.org/10.1016/j.jneuroim.2016.02.006 0165-5728/© 2016 Published by Elsevier B.V. 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