Polymorphisms in Fc_γRIIIA Are Genetically Linked to FcγRIIA and May Account for the Primary Predictive Role Ascribed to Polymorphisms in FcγRIIIA-158 in Determining Rituximab Responses.

γWe and others have previously described polymorphisms in codon 158 and 48 for FcγRIIIα as predictors of clinical responses to the anti-CD20 monoclonal antibody rituximab in patients with low-grade non-Hodgkin’s lymphoma, including Waldenström’s Macroglobulinemia. The expression of at least one valine (V) at FcγRIIIα-158 and Leucine/Histidine (L/H) at FcγRIIIα-48 is associated with higher response rates to rituximab, though primacy for FcγRIIIα-158 over 48 polymorphisms for determining rituximab response is attributed to genetic linkage. As part of these studies, we sought to determine if polymorphisms in FCγRIIA were linked to FCγRIIIA since higher response rates have been observed in patients who express Histidine/Histidine (H/H) in FcγRIIA-131. We therefore performed sequence analysis of the whole FcγRIIa gene and exons 3 and 4 of the FcγRIIIa gene in 52 healthy donors. The genetic association between polymorphisms was calculated using the statistical program GOLD and expressed as linkage disequilibrium (D’). Single nucleotide polymorphisms were commonly found in FcγRIIIa at codons 158, 48 and in FcγRIIa at codons 131, 27. The genotype frequencies for polymorphisms are as follows: FcγRIIIa-158: 25% F/F; 63% F/V; 12% V/V; FcγRIIIa-48: 67% L/L; 10% L/R; 17% L/H; FcγRIIa-131: 29% H/H; 46% H/R; 25% R/R; FcγRIIa-27: 71% Q/Q; 27% Q/W; 2% W/W. Strong linkage was found between the FcγRIIIa-158 and −48 (D’=1, p=0.001), as well as between FcγRIIa-131 and -27 (D’=1, p=0.00082). Specifically, the expression of F at FcγRIIIa-158 was found to be associated with expression of L at FcγRIIIa-48, whereas the expression of H at FcγRIIa-131 was associated with the expression of Q at FcγRIIa-27. Importantly, we observed links among polymorphisms at FcγRIIa and FcγRIIIa. Specifically, FcγRIIIa-48 was linked to FcγRIIa-27 (D’=0.765, p<0.00001) and FcγRIIa-131 (D’=1, p=0.0049), since all donors who were FcγRIIIa-48 L/L donors were also FcγRIIa-27Q/Q and -131R/R, respectively. Lastly, we also observed linkage between FcγRIIIa-158 and FcγRIIa-27 (D’=1, p=0.0008). Our results demonstrate significant genetic association between polymorphisms in FcγRIIa and FcγRIIIa genes, and may account for the primary predictive role ascribed to polymorphisms in FcγRIIIa-158 in determining rituximab responses.