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HLA DRB1*1501 tagging rs3135388 polymorphism associated with multiple sclerosis is inversely associated with NMO

Background: Association of the haplotype including DRB1*1501 with multiple sclerosis (MS) is well established. Recent studies have suggested lack of association of this haplotype with neuromyelitis optica (NMO) (Z?phir et al. Mult Scler. 2009; Matsushita et al. Tissue Antigens. 2009). Rs3135388 single nucleotide polymorphism tags HLA-DRB1*1501 (r2= 0.97) (de Bakker et al. Nat Genet. 2006). Objectives: To investigate the sensitivity of rs3135388 in tagging HLA DRB1*1501 in association with susceptibility to MS and determine the association of HLA DRB1*1501 with susceptibility to NMO. Methods: Genomic DNA from a population based cohort of MS patients (n=221), a multi-center clinic based cohort of seropositive NMO patients (n=162) and ethnically matched controls (n=1142) were genotyped for rs3135388 by Taqman based assay. In 109 of the MS patients, rs3135388 based HLA-DRB1*1501genotypes were compared to earlier genotyping performed by sequence-specific PCR (Weinshenker et al. Neurology 1998). Susceptibility analysis was performed by logistic regression and chi-square statistics as appropriate. Results: Rs3135388 was concordant with DRB1*1501 carrier status in 101/109 (92,7%) individuals within the MS group. Rs3135388*T allele was associated with susceptibility to MS (OR=3.93; 95%CI= 2.58-5.97, p less than 0.0001) but inversely associated with susceptibility to NMO (OR=0.57; 95%CI=0.36-0.91, p=0.01). Discussion: Rs3135388 was highly concordant with HLA-DRB1*1501. The significant but opposite association of MS and NMO with DRB1*1501 suggests different HLA genetic susceptibility loci for NMO. NMO Genetics Study Group contributors include: Walton Centre, Liverpool, UK (Anu Jacob, Mike Boggild); SMZ-Ost-Donauspital, Vienna, Austria (Wolfgang Kristoferitsch); Washington Unversity, St. Louis, MO (Anne Cross; Laura Piccio); Accelerated Cure Project, Waltham, MA; Charite-University Medicine, Berlin, Germany (Paul Friedemann and Sven Jarius); Legacy Emanuel Hospital, Portland OR (Daniel Kingsbury);Medical School of Riberao Preto-USP-Brazil (Doralina Brum and Amilton Barreira); MS Center of Oklahoma, OK (Gabriel Pardo); University of Minnesota (Gareth Parry) and Allegheny Neurological -Pittsburgh, PA (Thomas Scott)

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