HLA-DRB1*1501 Is Associated with Retinal Deterioration in Multiple Sclerosis (P5.278)

Objective: To assess if HLADRB1*15:01 status, using the marker rs3135388, is associated with longitudinal OCT measurements including ganglion cell-inner plexiform (GCIP) thickness and retinal nerve fiber layer (RNFL) thickness. Background: Variation in loci in the human leucocyte antigen (HLA) region of the major histocompatibility complex is associated with risk of multiple sclerosis (MS). For example, HLA-DRB1*1501 confers the greatest degree genetic susceptibility, while HLA-A*0201 has been associated with reduced risk of MS. There is inconsistent evidence regarding whether DRB1*1501 is also associated with MS severity. Optical Coherence Tomography (OCT) imaging correlates with brain atrophy and visual dysfunction and could serve as a sensitive measure relating genetic factors to MS disease severity and course. Methods: 556 Caucasian MS patients (McDonald criteria) were recruited from the Johns Hopkins University MS Center. Longitudinal follow-up is available for 348 patients, for whom the average follow-up time is 3.62 years. We assessed associations between rs3135388 and longitudinal measures of RNFL and GCIP in a mixed model framework, adjusting for intra-eye correlation. We estimated individual trajectories of RNFL and GCIP, and extracted the residual person-specific intercepts slopes (for longitudinal analyses) following adjustment for age, gender and optic neuritis history for use in SNP-based analyses. Results: In longitudinal analyses, an increase of 1 HLADRB1*15:01 risk allele was associated with significantly faster rates of decline for GCIP (slope=-0.025 95[percnt] CI: -0.047 to -0.004; P=0.022) but not for RNFL. HLA-A*02:01 status (using marker rs2523822) did not have a significant association with GCIP or RNFL trajectories (p= 0.53). Conclusions: Collectively, these results suggest HLADRB1*15:01 status is a contributor to disease severity, as indicated by faster trajectories of decline in GCIP. These data, along with future genotype-phenotype analyses, may eventually prove useful in calculating a genetic prognostic score for people with MS. Disclosure: Dr. Kimbrough has nothing to disclose. Dr. Fitzgerald has nothing to disclose. Dr. Al-Louzi has nothing to disclose. Dr. Button has nothing to disclose. Dr. Dembele has nothing to disclose. Dr. Patsopoulos has nothing to disclose. Dr. Sotirchos has nothing to disclose. Dr. White has nothing to disclose. Dr. Saidha has received personal compensation for activities with Medical Logix for the development of CME programs in neurology, and has received personal compensation for activities with Axon Advisors LLC. Dr. Saidha has received research support from Dr. Mowry has received research support from Teva Pharmaceuticals and Biogen Idec. Dr. De Jager has received research support from Biogen Idec and Genzyme. Dr. Peter A. Calabresi has received personal compensation for activities with Abbott and Vertex as a consultant. Dr. Calabresi has received research support from Novartis, MedImmune and Biogen.