Genetic Linkage of FcgγRIIa and FcγRIIIa and Implications for Their Use in Predicting Clinical Responses to CD20-Directed Monoclonal Antibody Therapy

Background:Polymorphisms in FcγRIIa and FcγRIIIa receptors are associated with responses to the CD20-directed immunoglobulin G1 (IgG1) monoclonal antibody rituximab among patients with indolent lymphoma. At odds with the aforementioned clinical observations has been the finding that IgG1 binding is impacted by polymorphisms in FcγRIIIa but not FcγRIIa. One possibility for this discrepancy might involve linkage of polymorphisms between FcγRIIa and FcγRIIIa.Materials and Methods:As such, we performed allelespecific polymerase chain reaction and directed sequencing of the genomic DNA coding region of FcγRIIA and FcγRIIIA for 52 healthy individuals.Results:Two common polymorphisms were observed for FcγRIIA (at positions 27 and 131) and FcγRIIIA (at positions 48 and 158). Importantly, we observed linkage among polymorphisms within and between FcγRIIa and FcγRIIIa, including the expression of histidine at FcγRIIa-131 and valine at FcγRIIIa, both of which are associated with enhanced responses to rituximab. The results of these studies demonstrate that there is wide linkage within and between polymorphisms in FcγRIIa and FcγRIIIa and might provide an explanation for why polymorphisms at FcγRIIa are associated with rituximab responses despite a lack of impact on IgG1 binding.Conclusion:Knowledge of such linkages could facilitate the development of diagnostic tests aimed at identifying patients who might be more suitable for treatment with rituximab and possibly other therapeutic antibodies.