FCGR3A gene duplication, FcγRIIb-232TT and FcγRIIIb-HNA1a associate with an increased risk of vertical acquisition of HIV-1

Abstract

Background Some mother-to-child transmission (MTCT) studies suggest that allelic variations of Fc gamma receptors (FcγR) play a role in infant HIV-1 acquisition, but findings are inconsistent. To address the limitations of previous studies, the present study investigates the association between perinatal HIV-1 transmission and FcγR variability in three cohorts of South African infants born to women living with HIV-1. Methods This nested case-control study combines FCGR genotypic data from three perinatal cohorts at two hospitals in Johannesburg, South Africa. Children with perinatally-acquired HIV-1 (cases, n = 395) were compared to HIV-1-exposed uninfected children (controls, n = 312). All study participants were black South Africans and received nevirapine for prevention of MTCT. Functional variants were genotyped using a multiplex ligation-dependent probe amplification assay, and their representation compared between groups using logistic regression analyses. Results FCGR3A gene duplication associated with HIV-1 acquisition (OR = 10.27; 95% CI 2.00–52.65; P = 0.005) as did the FcγRIIb-232TT genotype even after adjusting for FCGR3A copy number and FCGR3B genotype (AOR = 1.72; 95%CI 1.07–2.76; P = 0.024). The association between FcγRIIb-232TT genotype and HIV-1 acquisition was further strengthened (AOR = 2.28; 95%CI 1.11–4.69; P = 0.024) if adjusted separately for FCGR2C c.134-96C>T. Homozygous FcγRIIIb-HNA1a did not significantly associate with HIV-1 acquisition in a univariate model (OR = 1.42; 95%CI 0.94–2.16; P = 0.098) but attained significance after adjustment for FCGR3A copy number and FCGR2B genotype (AOR = 1.55; 95%CI 1.01–2.38; P = 0.044). Both FcγRIIb-232TT (AOR = 1.83; 95%CI 1.13–2.97; P = 0.014) and homozygous FcγRIIIb-HNA1a (AOR = 1.66; 95%CI 1.07–2.57; P = 0.025) retained significance when birthweight and breastfeeding were added to the model. The common FCGR2A and FCGR3A polymorphisms did not associate with HIV-1 acquisition. Conclusions Collectively, our findings suggest that the FcγRIIb-232TT genotype exerts a controlling influence on infant susceptibility to HIV-1 infection. We also show a role for less studied variants–FCGR3A duplication and homozygous HNA1a. These findings provide additional insight into a role for FcγRs in HIV-1 infection in children.

A Non-Coding Fc Gamma Receptor Cis-Regulatory Variant within the 1q23 Gene Cluster Is Associated with Plasmodium falciparum Infection in Children Residing in Burkina Faso

“…However, this association did not remain significant when considering age as a covariable. Our findings align with the previously described protective effect of the FCGR2B rs1050501-TT genotype against malaria and infant susceptibility to HIV infection [40,41], but we did not find evidence of its protective role in controlling parasitemia in children analyzed in Burkina Faso, mainly belonging to the Bobo ethnic subgroup. These discrepancies may partly depend on agerelated factors, which manifest differently in adults with a more mature immune response controlling the parasite.…”

“…The lack of association between FCGR2A and FCGR2B coding variants with parasitemia could also be attributed to ethnic variations [51], sample size, or the diversity of observed malaria phenotypes, including parameters such as socioeconomic status, access to healthcare, and control measures in previously described cohorts. Studies on the population diversity of FcγR variants have shown differences in ethnic variation, allele distribution, and linkage disequilibrium at the FCGR gene locus, especially for FCGR2B and FCGR2C, among Kenyan, Nigerian, South African, and Caucasian populations [40,41]. The rs1050501 SNP in FCGR2B has notably been shown to be under malaria-driven selective evolutionary pressure [27], and minor allele frequencies of FcγRIIb-232T and FcγRIIIb-HNA1 FCGR variants associated with protection against clinical malaria were reported to be more prevalent in malariaendemic regions than in non-endemic regions.…”

“…These differences in allelic frequencies suggest recent positive selection of this protective mutation in endemic areas, potentially accounting for varying susceptibility to infectious or autoimmune diseases in different geographic regions [31,40]. The FcγRIIB-232TT genotype has notably been associated with an increased risk of vertical acquisition of HIV-1 [41], but it has also shown a strong protective effect against severe malaria in Kenya. However, the underlying mechanisms involving FCGR2A and FCGRB coding mutations remain complex and require further investigation.…”