title: Tumor necrosis factor-alpha promoter variant 2 (TNF2) is associated with pre-term delivery, infant mortality, and malaria morbidity in western Kenya: Asembo Bay Cohort Project IX.
abstract: A polymorphism in the promoter region of the tumor necrosis factor-alpha (TNF-alpha) gene, with a guanine to adenine nucleotide change at position -308, TNF2 is associated with increased TNF-alpha production. TNF2 homozygotes have a higher risk of severe disease and/or death due to cerebral malaria and other infectious diseases. We investigated the impact of this allele on malaria morbidity and mortality in young children who participated in an immuno-epidemiologic cohort study of malaria in an area of intense perennial Plasmodium falciparum transmission in western Kenya. A total of 1,048 children were genotyped. Poisson regression and Cox proportional hazards models were used to determine the relationship between TNF-308 variants and morbidity and mortality. The gene frequencies of the TNF1 and TNF2 alleles were 0.90 and 0.10, respectively. TNF2 homozygosity was associated with pre-term birth when compared with TNF1 homozygotes [relative risk (RR) 7.3, 95% CI, 2.85-18.9, P = 0.002) and heterozygotes (RR 6.7, 95% CI 2.0-23.0, P = 0.008). Among children born prematurely, the TNF2 allele was significantly associated with a higher risk of death in infancy compared with TNF1 (RR 7.47, 95% CI 2.36-23.6). The risk of death was higher among TNF2 homozygotes than among heterozygotes. The TNF2 allele was significantly associated with high density P. falciparum parasitemia (RR 1.11, 95% CI 1.0-1.24). Among low birth weight children, the TNF2 allele was associated with severe anemia (RR 2.16, 95% CI 1.17-4.01) and showed a trend toward a risk for severe malaria anemia (RR 1.99, 95% CI 0.89-4.46). These data suggest that TNF2 is a risk factor for pre-term birth and early childhood mortality and malaria morbidity in children in this region. Further understanding of the pathogenic mechanisms underlying this association is required.
authors.affiliation: Division of Parasitic Diseases, National Center for Infectious Disease, Centers for Disease Control and Prevention, 4770 Buford Highway, Atlanta, GA 30341-3724, USA.
authors.forename: M
authors.initials: M
authors.lastname: Aidoo
authors.forename: P D
authors.initials: PD
authors.lastname: McElroy
authors.forename: M S
authors.initials: MS
authors.lastname: Kolczak
authors.forename: D J
authors.initials: DJ
authors.lastname: Terlouw
authors.forename: F O
authors.initials: FO
authors.lastname: ter Kuile
authors.forename: B
authors.initials: B
authors.lastname: Nahlen
authors.forename: A A
authors.initials: AA
authors.lastname: Lal
authors.forename: V
authors.initials: V
authors.lastname: Udhayakumar
mesh_terms: D000483:Alleles; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007226:Infant Mortality; D007231:Infant, Newborn; D007234:Infant, Premature; D007630:Kenya / Q000453:epidemiology; D016778:Malaria, Falciparum / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D007752:Obstetric Labor, Premature / Q000235:genetics*; D016012:Poisson Distribution; D011110:Polymorphism, Genetic; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D014409:Tumor Necrosis Factor-alpha