Brain Advance Access published online on November 20, 2008
Brain, doi:10.1093/brain/awn301
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Genotype–Phenotype correlations in multiple sclerosis: HLA genes influence disease severity inferred by 1HMR spectroscopy and MRI measures
1Departments of Neurology, Multiple Sclerosis Center at UCSF, 2Department of Radiology, University of California, San Francisco, California, USA and 3Neurologische Klinik, Universitätsspital Basel, Switzerland
Correspondence to:
Daniel Pelletier, MD, University of California, San Francisco, UCSF Multiple Sclerosis Center, 350 Parnassus Avenue, Suite 908, San Francisco, California 94117, USA E-mail: daniel.pelletier{at}ucsf.edu
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 1HMR spectroscopy (P = 0.025), (ii) an increase in the volume of white matter (WM) lesions utilizing conventional anatomical MRI techniques (1,127 mm3; 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.
Key Words: multiple sclerosis; HLA; spectroscopy; brain atrophy; cognition
Abbreviations: HLA, human leukocyte antigen; MS, multiple sclerosis; NAA, N-acetyl-aspartate; NAWM, normal appearing white matter; nBPV, normalized brain parenchymal volume; PASAT, paced auditory serial addition test; WM, white matter
Received June 30, 2008. Revised September 25, 2008. Accepted October 20, 2008.