The pathoetiology of multiple sclerosis (MS) involves underlying genetic susceptibility acting in concert with undefined environmental factors. African Americans (AAs) with MS are a unique population that may allow a better understanding of the biology of MS. AA patients have an older age of onset, are at high risk for optic nerve and spinal cord manifestations and suffer from a more severe disease course. Because these characteristics are more prevalent in AAs than in White Americans (WAs), identification of the underlying genes associated with these traits will be more readily accomplished in AAs. Furthermore compared to WA chromosomes, AA chromosomes have smaller blocks of linkage disequilibrium allowing higher resolution genetic mapping in this population. The goals of this proposal are two fold. The first goal is to develop robust and well-characterized cohorts of AA and WA MS patients. To date, 534 AAs and 672 WAs have been recruited and we will recruit a total of 1,000 affected subjects in each group within the first 2 years of this project. The second goal is to use this dataset to identify specific disease alleles that modify disease expression. This dataset has already attained sufficient statistical power to detect phenotypic differences between these populations and, when complete, should have adequate power to make phenotype-genotype correlations. There are currently three loci that have the most consistent association with MS: 6p21, 19q13, and 17q22. Although the HLA-DRB, APOE, and iNOS genes are assumed to account for the effect of these respective loci, the confounding consequences of linkage disequilibrium in WAs prevent definitive mapping of the MS genes. In parallel with this proposal, fine mapping studies will be performed using the AA cohort to determine the genes at these loci associated with MS susceptibility and disease expression. Specific alleles will then be tested for association with MS phenotypes. These studies are expected to substantially improve the understanding of the genetic basis of MS pathogenesis and have practical applications for prognosis and perhaps for therapeutic selection based on an individual's genetic background. ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZNS1-SRB-S (09))
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Utz, Ursula
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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University of California, San Francisco MS-EPIC Team:; Cree, Bruce A C; Gourraud, Pierre-Antoine et al. (2016) Long-term evolution of multiple sclerosis disability in the treatment era. Ann Neurol 80:499-510
Gelfand, J M; Cree, B A C; McElroy, J et al. (2011) Vitamin D in African Americans with multiple sclerosis. Neurology 76:1824-30
Cree, Bruce A C; Rioux, John D; McCauley, Jacob L et al. (2010) A major histocompatibility Class I locus contributes to multiple sclerosis susceptibility independently from HLA-DRB1*15:01. PLoS One 5:e11296
McElroy, Joseph P; Cree, Bruce A C; Caillier, Stacy J et al. (2010) Refining the association of MHC with multiple sclerosis in African Americans. Hum Mol Genet 19:3080-8
Green, A J; Cree, B A C (2009) Distinctive retinal nerve fibre layer and vascular changes in neuromyelitis optica following optic neuritis. J Neurol Neurosurg Psychiatry 80:1002-5
Mowry, E M; Beheshtian, A; Waubant, E et al. (2009) Quality of life in multiple sclerosis is associated with lesion burden and brain volume measures. Neurology 72:1760-5
Cree, Bruce A C; Reich, David E; Khan, Omar et al. (2009) Modification of Multiple Sclerosis Phenotypes by African Ancestry at HLA. Arch Neurol 66:226-33
Caillier, Stacy J; Briggs, Farren; Cree, Bruce A C et al. (2008) Uncoupling the roles of HLA-DRB1 and HLA-DRB5 genes in multiple sclerosis. J Immunol 181:5473-80
Jacob, Anu; Weinshenker, Brian G; Violich, Ivo et al. (2008) Treatment of neuromyelitis optica with rituximab: retrospective analysis of 25 patients. Arch Neurol 65:1443-8