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To evaluate the effect of polymorphism of the Fcγ receptor IIa, which is associated with differential human IgG subclass binding, on perinatal HIV-1 transmission.FcγRIIa genotype was tested in 448 HIV-seropositive mothers and their infants from a cohort study designed to assess the effect of placental malaria on HIV vertical transmission conducted from 1996 to 2001 in western Kenya. FcγRIIa polymorphism was analyzed for associations with susceptibility to perinatal HIV infection and all-cause child mortality in HIV-positive children.Overall, 20% of infants were perinatally infected with HIV. There was no statistically significant association between maternal genotype and perinatal HIV-1 transmission. However, frequency of the infant FcγRIIa His/His131 genotype was higher in HIV-positive compared with HIV-negative infants (35% and 21%, respectively), whereas the distribution was reversed (15% and 28%, respectively) for infants with the FcγRIIa Arg/Arg131 genotype. Multivariate logistic regression controlling for maternal and infant confounding factors demonstrated that the odds of perinatal HIV infection in infants with the FcγRIIa His/His131 versus FcγRIIa His/Arg131 genotypes were significantly higher (adjusted odds ratio, 2.22; 95% confidence interval, 1.23–4.02; P = 0.009). There was no evidence for an association between HIV-positive child all-cause mortality and FcγRIIa genotype.This study provides the first evidence that the infant FcγRIIa His/His131 genotype is associated with susceptibility to perinatal HIV-1 transmission and further suggests that there is a dose–response relationship for the effect of the FcγRIIa His131 gene on transmission.