Association of HLA genetic risk burden with disease phenotypes in multiple sclerosis

Noriko Isobe, Anisha Keshavan, Pierre Antoine Gourraud, Alyssa H. Zhu, Esha Datta, Regina Schlaeger, Stacy J. Caillier, Adam Santaniello, Antoine Lizée, Daniel S. Himmelstein, Sergio E. Baranzini, Jill Hollenbach, Bruce A.C. Cree, Stephen L. Hauser, Jorge R. Oksenberg, Roland G. Henry

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Abstract

IMPORTANCE Although multiple HLA alleles associated with multiple sclerosis (MS) risk have been identified, genotype-phenotype studies in the HLA region remain scarce and inconclusive. OBJECTIVES To investigate whether MS risk-associated HLA alleles also affect disease phenotypes. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional, case-control study comprising 652 patients with MS who had comprehensive phenotypic information and 455 individuals of European origin serving as controls was conducted at a single academic research site. Patients evaluated at the Multiple Sclerosis Center at University of California, San Francisco between July 2004 and September 2005 were invited to participate. Spinal cord imaging in the data set was acquired between July 2013 and March 2014; analysis was performed between December 2014 and December 2015. MAIN OUTCOMES AND MEASURES Cumulative HLA genetic burden (HLAGB) calculated using the most updated MS-associated HLA alleles vs clinical and magnetic resonance imaging outcomes, including age at onset, disease severity, conversion time from clinically isolated syndrome to clinically definite MS, fractions of cortical and subcortical gray matter and cerebral white matter, brain lesion volume, spinal cord gray and white matter areas, upper cervical cord area, and the ratio of gray matter to the upper cervical cord area. Multivariate modeling was applied separately for each sex data set. RESULTS Of the 652 patients with MS, 586 had no missing genetic data and were included in the HLAGB analysis. In these 586 patients (404 women [68.9%]; mean [SD] age at disease onset, 33.6 [9.4] years), HLAGB was higher than in controls (median [IQR], 0.7 [0-1.4] and 0 [.0.3 to 0.5], respectively; P = 1.8 × 10-27). A total of 619 (95.8%) had relapsing-onsetMS and 27 (4.2%) had progressive-onsetMS. No significant difference was observed between relapsing-onsetMS and primary progressiveMS. A higher HLAGB was associated with younger age at onset and the atrophy of subcortical gray matter fraction in women with relapsing-onsetMS (standard β = -1.20 × 10-1; P = 1.7 × 10-2 and standard β = .1.67 × 10-1; P = 2.3 × 10-4, respectively), which were driven mainly by the HLA-DRB1∗15:01 haplotype. In addition, we observed the distinct role of the HLA-A∗24:02-B∗07:02-DRB1∗15:01 haplotype among the other common DRB1∗15:01 haplotypes and a nominally protective effect of HLA-B∗44:02 to the subcortical gray atrophy (standard β = -1.28 × 10-1; P = 5.1 × 10-3 and standard β = 9.52 × 10-2; P = 3.6 × 10-2, respectively). CONCLUSIONS AND RELEVANCE We confirm and extend previous observations linking HLA MS susceptibility alleles with disease progression and specific clinical and magnetic resonance imaging phenotypic traits.

Original languageEnglish
Pages (from-to)795-802
Number of pages8
JournalJAMA Neurology
Volume73
Issue number7
DOIs
Publication statusPublished - Jul 2016

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All Science Journal Classification (ASJC) codes

  • Clinical Neurology

Cite this

Isobe, N., Keshavan, A., Gourraud, P. A., Zhu, A. H., Datta, E., Schlaeger, R., ... Henry, R. G. (2016). Association of HLA genetic risk burden with disease phenotypes in multiple sclerosis. JAMA Neurology, 73(7), 795-802. https://doi.org/10.1001/jamaneurol.2016.0980