Impact of age, HIV1, sickle-cell genotypes, and interferon-gamma gene upstream variants on malaria disease outcomes in a longitudinal pediatric cohort

Abstract

This prospective cohort study explored the association between two upstream IFN-γ variants (rs2069709: G>T and rs2069705: A>G) and hazard factors for malaria outcomes in a longitudinal cohort of children (n=941, 3–36 mos.), followed for three years. The impact of age, sex, previous malaria exposure, HIV1 infection, and sickle-cell genotypes (HbAA, HbAS, and HbSS) was also investigated. Reduced malaria episodes were associated with older age at enrollment [HR=0.957 (95% CI=0.953–0.961) per month, P<2.2e-16], HIV1 infection [0.687 (0.545–0.866), P=0.001], being female [0.910 (0.859–0.964), P=0.040], and HbAS [0.823 (0.754–0.898), P=0.005]. The GA/ TA diplotype [0.376 (0.230–0.614), P=0.002] also reduced the hazard of malaria, while TA haplotype increased susceptibility [1.749 (1.159–2.640), P=0.029]. Factors protecting against the development of SMA [Hemoglobin (Hb<6.0 g/dL)] included older age [0.927 (0.913–0.942) per month, P<2.2e-16], previous malaria episodes [0.576 (0.542–0.614, P=9.5e-32)], HbAS [0.553 (0.400-0.766), P=0.015]. The rs2069705AG genotype increased the hazard of SMA [1.697 (1.002–2.875), P=0.042]. Reduced hazard of mortality was observed for older children [0.898 (0.857–0.941), P<2.2e-16], while a higher hazard was present in HIV-infected children [12.475 (6.380-24.392), P<2.2e-16], and in those with HbSS [6.341 (1.944–20.686), P=0.007]. The GG haplotype increased the mortality hazard [1.817 (0.936– 3.527), P=0.078]. The results here highlight critical factors influencing the hazard of malaria, SMA, and mortality