Aidoo M, McElroy P D, Kolczak M S, Terlouw D J, ter Kuile F O, Nahlen B, Lal A A, Udhayakumar V
Division of Parasitic Diseases, National Center for Infectious Disease, Centers for Disease Control and Prevention, 4770 Buford Highway, Atlanta, GA 30341-3724, USA.
Genet Epidemiol. 2001 Nov;21(3):201-11. doi: 10.1002/gepi.1029.
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.
肿瘤坏死因子-α（TNF-α）基因启动子区域存在一种多态性，在-308位核苷酸处发生鸟嘌呤到腺嘌呤的变化，即TNF2，它与TNF-α产生增加有关。TNF2纯合子因脑型疟疾和其他传染病导致严重疾病和/或死亡的风险更高。我们调查了该等位基因对参与肯尼亚西部恶性疟原虫常年高强度传播地区疟疾免疫流行病学队列研究的幼儿疟疾发病率和死亡率的影响。共对1048名儿童进行了基因分型。采用泊松回归和Cox比例风险模型来确定TNF-308变体与发病率和死亡率之间的关系。TNF1和TNF2等位基因的基因频率分别为0.90和0.10。与TNF1纯合子[相对风险（RR）7.3，95%可信区间（CI），2.85 - 18.9，P = 0.002]和杂合子（RR 6.7，95% CI 2.0 - 23.0，P = 0.008）相比，TNF2纯合性与早产有关。在早产儿童中，与TNF1相比，TNF2等位基因与婴儿期更高的死亡风险显著相关（RR 7.47，95% CI 2.36 - 23.6）。TNF2纯合子的死亡风险高于杂合子。TNF2等位基因与恶性疟原虫高密度血症显著相关（RR 1.11，95% CI 1.0 - 1.24）。在低出生体重儿童中，TNF2等位基因与严重贫血有关（RR 2.16，95% CI 1.17 - 4.01），并且显示出患严重疟疾贫血风险的趋势（RR 1.99，95% CI 0.89 - 4.46）。这些数据表明，TNF2是该地区儿童早产、幼儿期死亡和疟疾发病的一个风险因素。需要进一步了解这种关联背后的致病机制。
