Abstract

The goal of this project is to perform a detailed characterization of HLA variants in patients afflicted by multiple sclerosis (MS), neuromyelitis optica (NMO), myasthenia gravis (MG), Parkinson's disease (PD), and schizophrenia (SCZD), all neurological diseases with documented 6p21 genetic association signals. We will use a cost-effective and highly reproducible next-generation sequencing methodology, customized genotyping algorithms, and a multi-layered analytical approach to assess allelic and haplotypic associations with disease risk.
Specific Aim 1 will develop and implement the methodologies for unambiguously genotyping the HLA-A, B, C, DRB1, DRB3/4/5, DQA1, DQB1, DPA1 and DPB1 loci in patients and controls.
Specific Aim 2 will characterize HLA noncoding polymorphisms and their association with neurological diseases, and enhance the study design through trans-ancestry analyses and the collaboration with Project 2 to identify relevant HLA-KIR interactions. This project is submitted as a key component of the larger INDIGO consortium effort. Central to immunity and critically important for human health, HLA molecules are encoded by complex genetic systems with extraordinarily high levels of sequence and structural variation and complex expression patterns. Characterization of HLA variation at high resolution will permit us to fully appreciate the impact of this diversity across a wide range of neurological diseases.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19NS095774-01
Application #
9114277
Study Section
Special Emphasis Panel (ZAI1-ALW-I (M1))
Program Officer
Utz, Ursula
Project Start
Project End
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
1
Fiscal Year
2015
Total Cost
$362,773
Indirect Cost

  Institution

Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143

  Publications

Misra, Maneesh K; Damotte, Vincent; Hollenbach, Jill A (2018) The immunogenetics of neurological disease. Immunology 153:399-414
Amorim, Leonardo M; Santos, Tiago H S; Hollenbach, Jill A et al. (2018) Cost-effective and fast KIR gene-content genotyping by multiplex melting curve analysis. HLA 92:384-391
Misra, Maneesh K; Damotte, Vincent; Hollenbach, Jill A (2018) Structure-based selection of human metabolite binding P4 pocket of DRB1*15:01 and DRB1*15:03, with implications for multiple sclerosis. Genes Immun :
Wagner, Ines; Schefzyk, Daniel; Pruschke, Jens et al. (2018) Allele-Level KIR Genotyping of More Than a Million Samples: Workflow, Algorithm, and Observations. Front Immunol 9:2843
Nemat-Gorgani, Neda; Hilton, Hugo G; Henn, Brenna M et al. (2018) Different Selected Mechanisms Attenuated the Inhibitory Interaction of KIR2DL1 with C2+ HLA-C in Two Indigenous Human Populations in Southern Africa. J Immunol 200:2640-2655
Creary, Lisa E; Mallempati, Kalyan C; Gangavarapu, Sridevi et al. (2018) Deconstruction of HLA-DRB1*04:01:01 and HLA-DRB1*15:01:01 class II haplotypes using next-generation sequencing in European-Americans with multiple sclerosis. Mult Scler :1352458518770019
Misra, Maneesh K; Augusto, Danillo G; Martin, Gonzalo Montero et al. (2018) Report from the Killer-cell Immunoglobulin-like Receptors (KIR) component of the 17th International HLA and Immunogenetics Workshop. Hum Immunol 79:825-833
Isobe, Noriko; Keshavan, Anisha; Gourraud, Pierre-Antoine et al. (2016) Association of HLA Genetic Risk Burden With Disease Phenotypes in Multiple Sclerosis. JAMA Neurol 73:795-802
Norman, Paul J; Hollenbach, Jill A; Nemat-Gorgani, Neda et al. (2016) Defining KIR and HLA Class I Genotypes at Highest Resolution via High-Throughput Sequencing. Am J Hum Genet 99:375-91
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

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