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Original Investigation |

Association of HLA Genetic Risk Burden With Disease Phenotypes in Multiple Sclerosis

Noriko Isobe, MD, PhD1; Anisha Keshavan, BSc1; Pierre-Antoine Gourraud, PhD, MPH1; Alyssa H. Zhu, MSc1; Esha Datta, MSc1; Regina Schlaeger, MD1,2; Stacy J. Caillier, BSc1; Adam Santaniello, BSc1; Antoine Lizée, MSc1; Daniel S. Himmelstein, BSc1,3; Sergio E. Baranzini, PhD1,3; Jill Hollenbach, PhD, MPH1; Bruce A. C. Cree, MD, PhD, MAS1; Stephen L. Hauser, MD1,4; Jorge R. Oksenberg, PhD1,4; Roland G. Henry, PhD1,5,6
[+] Author Affiliations
1Department of Neurology, School of Medicine, University of California, San Francisco
2Department of Neurology, University Hospital Basel, University of Basel, Basel, Switzerland
3Biological and Medical Informatics, University of California, San Francisco
4Institute of Human Genetics, University of California, San Francisco
5Bioengineering Graduate Group, University of California, San Francisco and Berkeley
6Department of Radiology and Biomedical Imaging, University of California, San Francisco
JAMA Neurol. 2016;73(7):795-802. doi:10.1001/jamaneurol.2016.0980.
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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-onset MS and 27 (4.2%) had progressive-onset MS. No significant difference was observed between relapsing-onset MS and primary progressive MS. A higher HLAGB was associated with younger age at onset and the atrophy of subcortical gray matter fraction in women with relapsing-onset MS (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.

Figures in this Article

Figures

Place holder to copy figure label and caption
Figure 1.
Distribution of HLA Genetic Burden (HLAGB) Scores

The HLAGB scores were plotted for the whole cohort of patients with multiple sclerosis (MS) (ie, relapsing-onset and progressive-onset MS) and the controls using box plots. Heavy horizontal lines in the boxes represent median values and the heights of the boxes show the interquartile range (IQR). The horizontal bars at the top and bottom edges of the whiskers represent the highest values within the 75th percentile values +1.5 × IQR and the lowest values within the 25th percentile values −1.5 × IQR. A Wilcoxon rank sum test P value was determined for each comparison. The patients with MS had a higher HLAGB than the controls, even when data sets were stratified by sex (P = 2.3 × 10−23 for women; P = 5.1 × 10−6 for men). No significant difference was observed for HLAGB scores by sexes in the control group (P = 1.4 × 10−1). Both disease courses had comparable HLAGB scores.

aP = 1.8 × 10−27 whole MS compared with controls.

bP = 7.5 × 10−27 relapsing-onset MS compared with controls.

cP = 6.1 × 10−4 progressive-onset MS compared with controls.

dP = 8.6 × 10−1 progressive-onset MS compared with relapsing-onset MS.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Effect Size Comparison Between HLA-DRB1 Haplotypes on Subcortical Gray Matter Fraction

Effect sizes of multiple sclerosis–associated HLA-DRB1 haplotypes on subcortical gray matter fraction. The error bars indicate 95% CI of the estimated effect sizes.

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