Racial Disparity in COVID-19 and the Role of Immunoglobulin Genes

FY21 Topic Area: Emerging Viral Diseases Rationale: Recent reports show tremendous interindividual and interracial variability in the outcome of SARS-CoV-2 infection. Genes encoding the ABO blood groups, ACE2, type I IFN, among others, have been implicated in COVID-19 pathogenesis. Genes implicated thus far, however, are unlikely to account for the total interindividual/interracial variation in the outcome of SARS-CoV-2 infection. There is excellent rationale for the involvement of immunoglobulin GM and KM genes-genetic markers of IgG heavy and kappa-type light chains, respectively-in the pathogenesis of COVID-19. GM and KM alleles influence the magnitude of IgG antibody responses to many infectious pathogens, including viruses. Expression of some GM allotypes is racially restricted. GM genes are functional in that they influence the binding affinity between Fcgamma and FCGR proteins and contribute to the Fc-mediated effector functions, such as ADCC, making them excellent candidates for influencing the immunobiology of SARS-CoV-2. Hypothesis: Immunoglobulin GM, KM, and FCGR genes influence the outcome of SARS-CoV-2 infection, and the underlying mechanisms include their contribution to the magnitude of humoral immunity to the S-RBD and the ADCC of cells expressing this protein. Specific Aims: (1) Determine if the levels of anti-S-RBD IgG antibodies and/or the severity of COVID-19 symptoms are associated with particular GM, KM, and FCGR alleles. (2) Assess whether allelic combinations of Fc (GM) and FCGRIIIa loci influence the level of ADCC against SARS CoV-2 S-transfected cells. Study Design: This investigation will use a cross-sectional study design, using specimens from SARS-CoV-2-infected patients archived in a large biorepository, which has collected blood samples and demographic and clinical data from hundreds of participants. Genotyping will be done by PCR-RFLP, TaqMan®, and direct DNA sequencing methods. Anti-S-RBD IgG antibodies will be measured by ELISA. Quantitative analysis of ADCC will be done by assaying the LDH activity. Expected Results and Future Research: Results from a plethora of investigations conducted so far collectively suggest that COVID-19 is a disease of immune dysregulation. Therefore, a thorough understanding of the immunobiology of this virus is an important prerequisite to inform improvements in the design of immunogens that may generate protective antibody Fc effector responses against the rapidly emerging SARS-CoV-2 variants. Racially associated GM alleles may contribute to the level of antibodies to SARS-CoV-2 as well as to the ADCC mediated by these antibodies, resulting in disparity in the outcome of infection. Results from the ADCC studies will help select appropriate Fc regions for constructing neutralizing antibodies for passive immunotherapy against SARS-CoV-2. This therapy could be personalized by constructing antibodies with a Fc genotype most suited to the patient's FCGR genotype. If the association of GM, KM, and FCGR alleles with antibody responsiveness to SARS-CoV-2 is firmly established, this knowledge would be instrumental in the proper evaluation of ongoing vaccine efficacy trials. Thus, some people could be naturally/genetically high responders to a vaccine, while others could be low responders. This possibility, unless taken into account, could confound the evaluation of vaccine efficacy trials. Innovation: The putative genetic factors that might contribute to racial disparity in COVID-19 are not completely understood due, at least in part, to the paucity of genomic studies involving African-American subjects. Furthermore, none of the studies to date have interrogated the highly polymorphic GM gene complex. IgG gene segments harboring GM genes are highly homologous and apparently not amenable to high-throughput genotyping technology, which could have contributed to their exclusion from major genotyping arrays. Additionally, because these variants were not typed in the HapMap project, they cannot be imputed or tagged through linkage disequilibrium by any determinants that are included in the genotyping platforms. Even in the 1000 Genomes project, the coverage of this region is very low, resulting in poor quality of imputation. This project is novel, as there are no published reports that have examined the contribution of GM allotypes to the magnitude of Fc-mediated effector function (ADCC) in the pathogenesis of COVID-19. Furthermore, this proposal seeks to determine the role of the constant-region determinants of IgG on antibody responses, and thus it challenges the existing paradigm: the variable region of immunoglobulins is the sole determinant of antibody specificity. Less