Immunogenetic risk factors for exacerbations in African American people with COPD

Project summary/abstract Individuals with frequent exacerbations of COPD (ECOPD) experience increased risk for mortality and accelerated lung function decline. We have shown that reduced total IgG, IgG subclasses, and pneumococcal antibody levels and function are associated with increased ECOPD risk. However, the roles of underlying genetic variants in IgG and its receptor are not well-known. Our preliminary studies have shown that a distinct set of IgG are associated with exacerbations among African American participants in a large COPD cohort study. Our study will investigate the hypothesis that variants in the IgG heavy chain (IGHG) and Fc receptor for IgG (FCGR) interact to enhance susceptibility to functional antibody deficiencies and ECOPD in African American patients. Specific Aim 1 will investigate interaction between G3m6 variant of IgG3 and low- functioning FcγRIIIb alleles as a risk factor for severe ECOPD in African American participants in the SPIROMICS and COPDGene cohorts. To investigate the hypothesis that G3m6 allotype, in the presence of the ‘NA2’ FCGR3B variant predict increased risk for severe ECOPD, we will first use novel genomic analyses to determine haplotypes (combinations of alleles inherited from a single parent) for these variants. We will then confirm these variants using conventional qPCR-based methods. Associations with ECOPD will be analyzed using longitudinal follow-up data available in both cohorts. Specific Aim 2 will evaluate IgG3 hinge length as a mechanism for discordance between antibody levels and function, investigating the hypothesis that short hinge length will be associated with impaired antibody function with preserved antibody levels. We will first measure antibody levels and function in African American participants in SPIROMICS. We will then compare IgG3 hinge region length between participants with impaired vs intact antibody function in the presence of normal antibody levels. This investigation will be used to facilitate further studies of immunogenetic variation as a risk factor for antibody deficiencies and exacerbations in COPD, and will represent the most detailed study of these variants in African American cohorts to date. This study will also serve to address a knowledge gap regarding characterization of IGHG and FCGR variants in people of non-European ancestry. Ultimately these studies will contribute to our overall goal of developing personalized diagnostic and therapeutic approaches to mitigate the detrimental effects of frequent ECOPD.