Genetic linkage of FcγRIIa and FcγRIIIa and implications for their use in predicting clinical responses to CD20-directed monoclonal antibody therapy

Background: Polymorphisms in Fc gamma RIIa and Fc gamma RIIIa 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 Fc gamma RIIIa but not Fc gamma RIIa. One possibility for this discrepancy might involve linkage of polymorphisms between Fc gamma RIIa and Fc gamma RIIIa. Materials and Methods: As such, we performed allele-specific polymerase chain reaction and directed sequencing of the genomic DNA coding region of Fc gamma RIIA and Fc gamma RIIIA for 52 healthy individuals. Results: Two common polymorphisms were observed for Fc gamma RIIA (at positions 27 and 131) and Fc gamma RIIIA (at positions 48 and 158). Importantly, we observed linkage among polymorphisms within and between Fc gamma RIIa and Fc gamma RIIIa, including the expression of histidine at Fc gamma RIIa-131 and valine at Fc gamma RIIIa, 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 Fc gamma RIIa and Fc gamma RIIIa and might provide an explanation for why polymorphisms at Fc gamma RIIa 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.