Multiple sclerosis (MS) is a common inflammatory disorder of the central nervous system characterized by a complex etiology that includes a strong genetic component. Our goal is to integrate modern statistical and molecular genomic methods to identify susceptibility and modifier genomic determinants in this disease. Based on the hypothesis that MS encompasses more than one basic phenotype, and the understanding that patterns of genomic dysequilibrium are shaped by the population history, we propose the study of contrasting ethnic groups to identify early recombination events and minimal genomic regions harboring disease genes. We will use rigorous clinical criteria to ascertain 1000 MS patients of African-American descent.
Specific Aim 1 describes a whole genome association screen of medium resolution (approximately 6,000 microsatellite markers) using a highly effective DNA pooling approach.
Specific Aim 2 is primarily concerned with the detailed analysis of the candidate chromosomal regions 6p21 and 19q13.
In Specific Aim 3, promising candidate genes will be directly tested for mutations and informative polymorphisms associated with disease susceptibility. Clinical and paraclinical variables will be stratified by genotypes to address the question of heterogeneity in MS and the correlation between different phenotypes and genotypes. Key to the success of these studies will be the acquisition of a large and informative dataset, together with the standardization of rigorous and consistent methods to collect relevant clinical data, and availability of efficient genotyping methods, adequate bioinformatic tools, and innovative analytical strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS046297-04
Application #
7052789
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Utz, Ursula
Project Start
2003-07-16
Project End
2009-01-14
Budget Start
2006-05-01
Budget End
2009-01-14
Support Year
4
Fiscal Year
2006
Total Cost
$339,413
Indirect Cost
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Pappas, D J; Lizee, A; Paunic, V et al. (2018) Significant variation between SNP-based HLA imputations in diverse populations: the last mile is the hardest. Pharmacogenomics J 18:367-376
Hollenbach, J A; Pando, M J; Caillier, S J et al. (2016) The killer immunoglobulin-like receptor KIR3DL1 in combination with HLA-Bw4 is protective against multiple sclerosis in African Americans. Genes Immun 17:199-202
Didonna, Alessandro; Oksenberg, Jorge R (2015) Genetic determinants of risk and progression in multiple sclerosis. Clin Chim Acta 449:16-22
Isobe, Noriko; Madireddy, Lohith; Khankhanian, Pouya et al. (2015) An ImmunoChip study of multiple sclerosis risk in African Americans. Brain 138:1518-30
Baranzini, Sergio E (2014) The role of antiproliferative gene Tob1 in the immune system. Clin Exp Neuroimmunol 5:132-136
Gourraud, Pierre-Antoine; Khankhanian, Pouya; Cereb, Nezih et al. (2014) HLA diversity in the 1000 genomes dataset. PLoS One 9:e97282
Isobe, Noriko; Gourraud, Pierre-Antoine; Harbo, Hanne F et al. (2013) Genetic risk variants in African Americans with multiple sclerosis. Neurology 81:219-27
Gelfand, J M; Cree, B A C; McElroy, J et al. (2011) Vitamin D in African Americans with multiple sclerosis. Neurology 76:1824-30
McElroy, J P; Isobe, N; Gourraud, P A et al. (2011) SNP-based analysis of the HLA locus in Japanese multiple sclerosis patients. Genes Immun 12:523-30
Gourraud, Pierre-Antoine; International Multiple Sclerosis Genetics Consortium (IMSGC) (2011) When is the absence of evidence, evidence of absence? Use of equivalence-based analyses in genetic epidemiology and a conclusion for the KIF1B rs10492972*C allelic association in multiple sclerosis. Genet Epidemiol 35:568-71

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