Genetic variations in low‐to‐medium‐affinity Fcγ receptors and autoimmune neutropenia in early childhood in a Danish cohort

Abstract

Autoimmune neutropenia (AIN) in early childhood is caused by autoantibodies directed against antigens on the neutrophil membrane and is a frequent cause of neutropenia in children. Association of AIN with Fcγ receptor (FCGR) 3B variants is well described. In this study, we investigate genetic variations in the FCGR locus and copy number variation of FCGR3B. A total of 130 antibody‐positive AIN patients, 64 with specific anti‐HNA‐1a antibodies and 66 with broad‐reacting anti‐FcγRIIIb antibodies, were genotyped with a multiplex ligation probe assay and compared with healthy controls. Positive findings were confirmed with real‐time q‐PCR. We determined copy numbers of the FCGR2 and FCGR3 genes and the following SNPs: FCGR2A Q62W (rs201218628), FCGR2A H166R (rs1801274), FCGR2B I232T (rs1050501), FCGR3A V176F (rs396991), haplotypes for FCGR2B/C promoters (rs3219018/rs780467580), FCGR2C STOP/ORF and HNA‐1 genotypes in FCGR3B (rs447536, rs448740, rs52820103, rs428888 and rs2290834). Generally, associations were antibody specific, with all associations being representative of the anti‐HNA‐1a‐positive group, while the only association found in the anti‐FcγRIIIb group was with the HNA‐1 genotype. An increased risk of AIN was observed for patients with one copy of FCGR3B; the HNA genotypes HNA‐1a, HNA‐1aa or HNA‐1aac; the FCGR2A 166H and FCGR2B 232I variations; and no copies of FCGR2B 2B.4. A decreased risk was observed for HNA genotype HNA‐1bb; FCGR2A 166R; FCGR2B 232T; and one copy of FCGR2B promoter 2B.4. We conclude that in our Danish cohort, there was a strong association between variation in the FCGR locus and AIN. The findings of different genetic associations between autoantibody groups could indicate the presence of two different disease entities and disease heterogeneity.

High‐resolution HLA genotyping identifies risk alleles in both class I and II for primary autoimmune neutropenia in early childhood in a Danish cohort

“…This differentiation between HLA associations and HNA‐1a antibody specificities in AIN patients has been observed previously for both DRB1 and DQB 1 5 but also in regards to genetic variation in low‐to‐medium Fcγ receptors 6 . In this study, we observed differences regarding HLA class I and II alleles.…”

“…33 This differentiation between HLA associations and HNA-1a antibody specificities in AIN patients has been observed previously for both DRB1 and DQB1 5 but also in regards to genetic variation in low-to-medium Fcγ receptors. 6 In this study, we observed differences regarding HLA class I and II alleles. DRB1*01, which is unique to anti-HNA-1a positivity, has been reported to be protective for sarcoidosis [34][35][36][37] and a predisposing factor in diseases such as recurrent lymphocytic meningitis and juvenile idiopathic arthritis in Hungarian patients, 38,39 exhibiting contrary effects depending on the disease.…”

“…Two main types of autoantibodies have been observed in AIN, antibodies directed against a specific HNA variant (HNA‐1a), and broad reactive antibodies against FcγRIIIb. The clinical significance of autoantibody specificities remains unknown, but in several studies, we have reported different genetic backgrounds for the two groups 5,6 …”

“…The clinical significance of autoantibody specificities remains unknown, but in several studies, we have reported different genetic backgrounds for the two groups. 5,6 The cause of AIN is still unknown, and there is not enough data to propose a genetic or environmental cause. Viral infections have been suggested as a possible trigger especially in secondary AIN, 7 initiating the activation of autoreactive B cells and CD4+ T cells, but there are also indications of a general deficiency in peripheral selftolerance mediated by an alteration in either the function or number of CD4+ Treg cells.…”

Primary autoimmune neutropenia in early childhood - Genetic variations and antibody specificity

“…Study II contains two papers. The first paper is "Genetic variations in low-to-mediumaffinity Fcγ receptors and autoimmune neutropenia in early childhood in a Danish cohort" [181]. In this paper, copy numbers and genetic variation in the FCGR2/3 locus were investigated in 130 AIN patients and compared to healthy control groups of different sizes.…”