title: Genotype-Phenotype correlations in multiple sclerosis: HLA genes influence disease severity inferred by 1HMR spectroscopy and MRI measures.
abstract: Genetic susceptibility to multiple sclerosis (MS) is associated with the human leukocyte antigen (HLA) DRB1*1501 allele. Here we show a clear association between DRB1*1501 carrier status and four domains of disease severity in an investigation of genotype-phenotype associations in 505 robust, clinically well characterized MS patients evaluated cross-sectionally: (i) a reduction in the N-acetyl-aspartate (NAA) concentration within normal appearing white matter (NAWM) via (1)HMR spectroscopy (P = 0.025), (ii) an increase in the volume of white matter (WM) lesions utilizing conventional anatomical MRI techniques (1,127 mm(3); P = 0.031), (iii) a reduction in normalized brain parenchymal volume (nBPV) (P = 0.023), and (iv) impairments in cognitive function as measured by the Paced Auditory Serial Addition Test (PASAT-3) performance (Mean Z Score: DRB1*1501+: 0.110 versus DRB1*1501-: 0.048; P = 0.004). In addition, DRB1*1501+ patients had significantly more women (74% versus 63%; P = 0.009) and a younger mean age at disease onset (32.4 years versus 34.3 years; P = 0.025). Our findings suggest that DRB1*1501 increases disease severity in MS by facilitating the development of more T2-foci, thereby increasing the potential for irreversible axonal compromise and subsequent neuronal degeneration, as suggested by the reduction of NAA concentrations in NAWM, ultimately leading to a decline in brain volume. These structural aberrations may explain the significant differences in cognitive performance observed between DRB1*1501 groups. The overall goal of a deep phenotypic approach to MS is to develop an array of meaningful biomarkers to monitor the course of the disease, predict future disease behaviour, determine when treatment is necessary, and perhaps to more effectively recommend an available therapeutic intervention.
authors.affiliation: UCSF Multiple Sclerosis Center, University of California, San Francisco, San Francisco, California 94117, USA.
authors.forename: D T
authors.initials: DT
authors.lastname: Okuda
authors.forename: R
authors.initials: R
authors.lastname: Srinivasan
authors.forename: J R
authors.initials: JR
authors.lastname: Oksenberg
authors.forename: D S
authors.initials: DS
authors.lastname: Goodin
authors.forename: S E
authors.initials: SE
authors.lastname: Baranzini
authors.forename: A
authors.initials: A
authors.lastname: Beheshtian
authors.forename: E
authors.initials: E
authors.lastname: Waubant
authors.forename: S S
authors.initials: SS
authors.lastname: Zamvil
authors.forename: D
authors.initials: D
authors.lastname: Leppert
authors.forename: P
authors.initials: P
authors.lastname: Qualley
authors.forename: R
authors.initials: R
authors.lastname: Lincoln
authors.forename: R
authors.initials: R
authors.lastname: Gomez
authors.forename: S
authors.initials: S
authors.lastname: Caillier
authors.forename: M
authors.initials: M
authors.lastname: George
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: S J
authors.initials: SJ
authors.lastname: Nelson
authors.forename: B A C
authors.initials: BA
authors.lastname: Cree
authors.forename: S L
authors.initials: SL
authors.lastname: Hauser
authors.forename: D
authors.initials: D
authors.lastname: Pelletier
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001921:Brain / Q000473:pathology; D003072:Cognition Disorders / Q000209:etiology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006579:Heterozygote; D006650:Histocompatibility Testing / Q000379:methods; D006801:Humans; D007090:Image Interpretation, Computer-Assisted / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics* / Q000473:pathology / Q000523:psychology; D009483:Neuropsychological Tests; D010641:Phenotype; D011446:Prospective Studies; D055815:Young Adult
chemical_list: D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C489631:HLA-DRB1*15:01 antigen