PMID- 19022862
OWN - NLM
STAT- MEDLINE
DCOM- 20090310
LR  - 20211020
IS  - 1460-2156 (Electronic)
IS  - 0006-8950 (Print)
IS  - 0006-8950 (Linking)
VI  - 132
IP  - Pt 1
DP  - 2009 Jan
TI  - Genotype-Phenotype correlations in multiple sclerosis: HLA genes influence 
      disease severity inferred by 1HMR spectroscopy and MRI measures.
PG  - 250-9
LID - 10.1093/brain/awn301 [doi]
AB  - 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.
FAU - Okuda, D T
AU  - Okuda DT
AD  - UCSF Multiple Sclerosis Center, University of California, San Francisco, San 
      Francisco, California 94117, USA.
FAU - Srinivasan, R
AU  - Srinivasan R
FAU - Oksenberg, J R
AU  - Oksenberg JR
FAU - Goodin, D S
AU  - Goodin DS
FAU - Baranzini, S E
AU  - Baranzini SE
FAU - Beheshtian, A
AU  - Beheshtian A
FAU - Waubant, E
AU  - Waubant E
FAU - Zamvil, S S
AU  - Zamvil SS
FAU - Leppert, D
AU  - Leppert D
FAU - Qualley, P
AU  - Qualley P
FAU - Lincoln, R
AU  - Lincoln R
FAU - Gomez, R
AU  - Gomez R
FAU - Caillier, S
AU  - Caillier S
FAU - George, M
AU  - George M
FAU - Wang, J
AU  - Wang J
FAU - Nelson, S J
AU  - Nelson SJ
FAU - Cree, B A C
AU  - Cree BA
FAU - Hauser, S L
AU  - Hauser SL
FAU - Pelletier, D
AU  - Pelletier D
LA  - eng
GR  - RG#3517/RG/CSR NIH HHS/United States
GR  - AI067152/AI/NIAID NIH HHS/United States
GR  - NS26799/NS/NINDS NIH HHS/United States
GR  - R01 NS026799/NS/NINDS NIH HHS/United States
GR  - R01 NS049477/NS/NINDS NIH HHS/United States
GR  - U19 AI067152/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20081120
PL  - England
TA  - Brain
JT  - Brain : a journal of neurology
JID - 0372537
RN  - 0 (HLA-DR Antigens)
RN  - 0 (HLA-DRB1 Chains)
RN  - 0 (HLA-DRB1*15:01 antigen)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Brain/pathology
MH  - Cognition Disorders/etiology
MH  - Female
MH  - Genetic Predisposition to Disease
MH  - Genotype
MH  - HLA-DR Antigens/*genetics
MH  - HLA-DRB1 Chains
MH  - Heterozygote
MH  - Histocompatibility Testing/methods
MH  - Humans
MH  - Image Interpretation, Computer-Assisted/methods
MH  - Magnetic Resonance Imaging/methods
MH  - Magnetic Resonance Spectroscopy/methods
MH  - Male
MH  - Middle Aged
MH  - Multiple Sclerosis/*genetics/pathology/psychology
MH  - Neuropsychological Tests
MH  - Phenotype
MH  - Prospective Studies
MH  - Young Adult
PMC - PMC2638695
EDAT- 2008/11/22 09:00
MHDA- 2009/03/11 09:00
PMCR- 2010/01/01
CRDT- 2008/11/22 09:00
PHST- 2008/11/22 09:00 [pubmed]
PHST- 2009/03/11 09:00 [medline]
PHST- 2008/11/22 09:00 [entrez]
PHST- 2010/01/01 00:00 [pmc-release]
AID - awn301 [pii]
AID - 10.1093/brain/awn301 [doi]
PST - ppublish
SO  - Brain. 2009 Jan;132(Pt 1):250-9. doi: 10.1093/brain/awn301. Epub 2008 Nov 20.