Immunoglobulin receptor polymorphisms in stroke and sickle cell disease

Stroke is a major cause of morbidity and mortality in sickle cell disease (SS), occuring with an estimated frequency of 10%. Based upon a number of clinical studies, a risk factor for hemorrhagic stroke in adults is an elevated peripheral leukocyte count. It has been demonstrated that sickle cells coated with immunoglobulin have increased adherence to endothelial cells, possibly via binding to the low affinity Fcyreceptors (FcyRs). Therefore, we investigated the mechanistic hypothesis that a similar phenomenon could be expected for interaction between sickle erythrocytes and FcyRs of white blood cells, namely phagocytes. It is possible that common allelic variants, previously shown to possess differences in biological activity in vitro could alter critical immune effector functions that would influence the risk for hemorrhagic stroke, such as phagocytosis of opsonized antigens, antibody mediated cellular cytotoxicity (ADCC), and release of inflammatory mediators. To test for an association with stroke in sickle cell disease, we conducted a case control study using common variants of the low affinity Fcyreceptors as candidate genes in a Jamaican population of 50 adult stroke cases with SS disease and 51 SS disease matched controls. We chose the candidate genes on the basis of three criteria: each variant is common (> 10% allelic frequency), prior in vitro data demonstrating biological differences between common alleles, prior clinical association studies. Comparison of allelic distributions between cases and controls at each of 3 loci, FCGR2A (H/H 10% versus 20%, H/R 54% versus 47%, R/R 36% versus 33%, P = 0.39), FCGR3A (V/V 8% versus 10%, V/F 44% versus 35%, F/F 48% versus 55%, P =0.67), FCGR3B (NA1/NA1 26% versus 39%, NA1/NA2 40% versus 35%, NA2/NA2 34% versus 25%, P=0.35) failed to demonstrate a significant association. Two loci are in Hardy-Weinberg equilibrium; however, there is a suggestion of a nonrandom distribution of FCGR3B alleles (single locus test, x: 5.71, P=0.058) in this selected population, suggesting a possible role in sickle cell disease unrelated to stroke. We conclude that common polymorphisms of the low affinity FcyRs are not associated with stroke in sickle cell disease in this population.