A novel FCGR3A intragenic haplotype is associated with increased FcγRIIIa/CD16a cell surface density and population differences.

FcγRIIIa (CD16a) cell surface density affects immune complex binding and initiation of effector mechanisms. Investigations into the clinical relevance of variable FcγRIIIa surface density require baseline data from healthy individuals. In this study, proportions of FcγRIIIa-positive leukocyte subsets and corresponding FcγRIIIa cell surface densities were determined in whole blood from 53 healthy individuals (22 Black individuals, 31 Caucasians). Compared to Caucasians, Black individuals had significantly lower proportions of FcγRIIIa-positive natural killer (NK) cells (95.2% vs. 96.9%) and CD8(+) T lymphocytes (9.6% vs. 11.7%), whereas the opposite was true for monocytes (24.2% vs. 16.3%). However, Black individuals had significantly lower FcγRIIIa surface densities on monocytes and NK cells compared to Caucasians (P<0.001). We investigated FCGR3A gene copy number and novel polymorphisms, obtained from full gene sequencing, in relation to FcγRIIIa expression levels on NK cells. The broad range of FcγRIIIa surface densities was not attributed to variable FCGR3A gene copy number (all individuals had 2 gene copies except for 2/53 (3.8%) with one extra copy). However, a novel 3-SNP/1-indel FCGR3A intragenic haplotype may account for the significantly increased FcγRIIIa surface densities (P<0.0001) and may explain the population differences. This genetic determinant may serve as predictive marker for a high-expressing FcγRIIIa phenotype.