title: Association of HLA Genetic Risk Burden With Disease Phenotypes in Multiple Sclerosis.
abstract: Although multiple HLA alleles associated with multiple sclerosis (MS) risk have been identified, genotype-phenotype studies in the HLA region remain scarce and inconclusive.
  
  
  
  To investigate whether MS risk-associated HLA alleles also affect disease phenotypes.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  We confirm and extend previous observations linking HLA MS susceptibility alleles with disease progression and specific clinical and magnetic resonance imaging phenotypic traits.
authors.affiliation: Department of Neurology, School of Medicine, University of California, San Francisco.
authors.forename: Noriko
authors.initials: N
authors.lastname: Isobe
authors.affiliation: Department of Neurology, School of Medicine, University of California, San Francisco.
authors.forename: Anisha
authors.initials: A
authors.lastname: Keshavan
authors.affiliation: Department of Neurology, School of Medicine, University of California, San Francisco.
authors.forename: Pierre-Antoine
authors.initials: PA
authors.lastname: Gourraud
authors.affiliation: Department of Neurology, School of Medicine, University of California, San Francisco.
authors.forename: Alyssa H
authors.initials: AH
authors.lastname: Zhu
authors.affiliation: Department of Neurology, School of Medicine, University of California, San Francisco.
authors.forename: Esha
authors.initials: E
authors.lastname: Datta
authors.affiliation: Department of Neurology, School of Medicine, University of California, San Francisco2Department of Neurology, University Hospital Basel, University of Basel, Basel, Switzerland.
authors.forename: Regina
authors.initials: R
authors.lastname: Schlaeger
authors.affiliation: Department of Neurology, School of Medicine, University of California, San Francisco.
authors.forename: Stacy J
authors.initials: SJ
authors.lastname: Caillier
authors.affiliation: Department of Neurology, School of Medicine, University of California, San Francisco.
authors.forename: Adam
authors.initials: A
authors.lastname: Santaniello
authors.affiliation: Department of Neurology, School of Medicine, University of California, San Francisco.
authors.forename: Antoine
authors.initials: A
authors.lastname: Lizée
authors.affiliation: Department of Neurology, School of Medicine, University of California, San Francisco3Biological and Medical Informatics, University of California, San Francisco.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Himmelstein
authors.affiliation: Department of Neurology, School of Medicine, University of California, San Francisco3Biological and Medical Informatics, University of California, San Francisco.
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Baranzini
authors.affiliation: Department of Neurology, School of Medicine, University of California, San Francisco.
authors.forename: Jill
authors.initials: J
authors.lastname: Hollenbach
authors.affiliation: Department of Neurology, School of Medicine, University of California, San Francisco.
authors.forename: Bruce A C
authors.initials: BA
authors.lastname: Cree
authors.affiliation: Department of Neurology, School of Medicine, University of California, San Francisco4Institute of Human Genetics, University of California, San Francisco.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hauser
authors.affiliation: Department of Neurology, School of Medicine, University of California, San Francisco4Institute of Human Genetics, University of California, San Francisco.
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Oksenberg
authors.affiliation: Department of Neurology, School of Medicine, University of California, San Francisco5Bioengineering Graduate Group, University of California, San Francisco and Berkeley6Department of Radiology and Biomedical Imaging, University of California, San Francisc.
authors.forename: Roland G
authors.initials: RG
authors.lastname: Henry
mesh_terms: D000328:Adult; D017668:Age of Onset; D000483:Alleles; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D021621:Imaging, Three-Dimensional; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012189:Retrospective Studies; D013116:Spinal Cord / Q000000981:diagnostic imaging / Q000473:pathology; D044465:White People; D055815:Young Adult
chemical_list: D015395:Histocompatibility Antigens Class I