Sarcoidosis is a multiorgan granulomatus inflammatory disorder likely resulting from an exaggerated T-dell response in genetically susceptible individuals. African-Americans are more frequently and severely affected by Sarcoidosis yet few collections of African American patients exist. We however, have amassed a large, well phenotyped cohort of close to 3,000 Sarcoidosis patients, family members and controls on which to perform an extensive search of the genome to identify potential susceptibility loci. Specifically, this """"""""Grand Opportunity"""""""" proposal will, using a unique and easily-accessible cohort, perform the first, and much needed, genome-wide association (GWA) scan in African Americans using the first and only commercially available genotyping product that results in adequate coverage (>85%) of the African genome. Because of the size of our cohort, we are poised to replicate our findings in an independent sample and therefore propose candidate genes and regions for further characterization. We can further characterize the population origin of these effects based on ancestry data already obtained. Finally, we will develop a bioinformatics tool for the repository and investigation of genetic data (e.g. single nucleotide polymorphisms, copy number variants, etc), genomic data (e.g. physical location, genic location, function, degree of conservation, etc), and statistical data from prior linkage, admixture and candidate gene association studies as well as this and other GWA studies. This project aligns with the goals of the GO mechanism in that we can begin immediately upon funding, the discoveries made herein will birth multiple follow-up studies, the database resource will allow our field to take the next step beyond association into pathway-based and bioinformatics-driven analyses and finally, we will stimulate the American research enterprise via the purchase of over $2M in domestically produced goods and services and the creation and retention of several biotech and administrative jobs. In sum, our extensive African American cohort and our genotyping, analysis and bioinformatics resources as well as the extensive experience of our team of experts in AA Sarcoidosis genetics make an experiment of this magnitude and scope very unlikely to be completed by any other group.

Public Health Relevance

This project will fast-forward Sarcoidosis, and likely other granulomatus or inflammatory disorders, genetics research by 1) identifying and replicating association to genetic variants throughout the genome and 2) facilitating characterization of these effects using related statistical, genetics and genomics data. In addition, this project will generate extensive revenue for American biotech products and jobs.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
High Impact Research and Research Infrastructure Programs (RC2)
Project #
1RC2HL101499-01
Application #
7854835
Study Section
Special Emphasis Panel (ZHL1-CSR-R (O5))
Program Officer
Colombini-Hatch, Sandra
Project Start
2009-09-30
Project End
2011-08-31
Budget Start
2009-09-30
Budget End
2010-08-31
Support Year
1
Fiscal Year
2009
Total Cost
$1,700,000
Indirect Cost
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Lareau, C A; DeWeese, C F; Adrianto, I et al. (2017) Polygenic risk assessment reveals pleiotropy between sarcoidosis and inflammatory disorders in the context of genetic ancestry. Genes Immun 18:88-94
Levin, Albert M; Adrianto, Indra; Datta, Indrani et al. (2015) Association of HLA-DRB1 with Sarcoidosis Susceptibility and Progression in African Americans. Am J Respir Cell Mol Biol 53:206-16
Fischer, Annegret; Ellinghaus, David; Nutsua, Marcel et al. (2015) Identification of Immune-Relevant Factors Conferring Sarcoidosis Genetic Risk. Am J Respir Crit Care Med 192:727-36
Li, Jia; Yang, James; Levin, Albert M et al. (2014) Efficient generalized least squares method for mixed population and family-based samples in genome-wide association studies. Genet Epidemiol 38:430-8
Levin, Albert M; Iannuzzi, Michael C; Montgomery, Courtney G et al. (2014) Admixture fine-mapping in African Americans implicates XAF1 as a possible sarcoidosis risk gene. PLoS One 9:e92646
Levin, Albert M; Adrianto, Indra; Datta, Indrani et al. (2014) Performance of HLA allele prediction methods in African Americans for class II genes HLA-DRB1, -DQB1, and -DPB1. BMC Genet 15:72
Levin, A M; Iannuzzi, M C; Montgomery, C G et al. (2013) Association of ANXA11 genetic variation with sarcoidosis in African Americans and European Americans. Genes Immun 14:13-8
McKeigue, Paul M; Colombo, Marco; Agakov, Felix et al. (2013) Extending admixture mapping to nuclear pedigrees: application to sarcoidosis. Genet Epidemiol 37:256-66
Lessard, Christopher J; Ice, John A; Adrianto, Indra et al. (2012) The genomics of autoimmune disease in the era of genome-wide association studies and beyond. Autoimmun Rev 11:267-75
Adrianto, Indra; Lin, Chee Paul; Hale, Jessica J et al. (2012) Genome-wide association study of African and European Americans implicates multiple shared and ethnic specific loci in sarcoidosis susceptibility. PLoS One 7:e43907