Child Health and Development Centre, Makerere University-College of Health Sciences, Kampala, Uganda.
Infectious Diseases Research Collaboration, Kampala, Uganda.
PLoS One. 2018 Sep 17;13(9):e0203229. doi: 10.1371/journal.pone.0203229. eCollection 2018.
Evidence for association between sickle cell and alpha thalassemia trait and severe malaria is compelling. However, for these polymorphisms associations with uncomplicated malaria, and for G6PD deficiency associations with uncomplicated and severe malaria, findings have been inconsistent. We studied samples from a three-arm case-control study with the objective of determining associations between common host erythrocyte polymorphisms and both uncomplicated and severe malaria, including different severe malaria phenotypes.
We assessed hemoglobin abnormalities, α-thalassemia, and G6PD deficiency by molecular methods in 325 children with severe malaria age-matched to 325 children with uncomplicated malaria and 325 healthy community controls. Conditional logistic regression was used to measure associations between specified genotypes and malaria outcomes.
No tested polymorphisms offered significant protection against uncomplicated malaria. α-thalassemia homozygotes (_α/_α) had increased risk of uncomplicated malaria (OR 2.40; 95%CI 1.15, 5.03, p = 0.020). HbAS and α-thalassemia heterozygous (_α/αα) genotypes protected against severe malaria compared to uncomplicated malaria (HbAS OR 0.46; 0.23, 0.95, p = 0.036; _α/αα OR 0.51; 0.24, 0.77; p = 0.001) or community (HbAS OR 0.23; 0.11, 0.50; p<0.001; _α/αα; OR 0.49; 0.32, 0.76; p = 0.002) controls. The α-thalassemia homozygous (_α/_α) genotype protected against severe malaria when compared to uncomplicated malaria controls (OR 0.34; 95%CI 0.156, 0.73, p = 0.005), but not community controls (OR 1.03; 0.46, 2.27, p = 0.935). Stratifying by the severe malaria phenotype, compared to community controls, the protective effect of HbAS was limited to children with severe anemia (OR 0.17; 95%CI 0.04, 0.65; p = 0.009) and that of _α/αα to those with altered consciousness (OR 0.24; 0.09, 0.59; p = 0.002). A negative epistatic effect was seen between HbAS and _α/αα; protection compared to uncomplicated malaria controls was not seen in individuals with both polymorphisms (OR 0.45; 0.11, 1.84; p = 0.269). G6PD deficiency was not protective against severe malaria.
Associations were complex, with HbAS principally protective against severe anemia, _α/αα against altered consciousness, and negative epistasis between the two polymorphisms.
镰状细胞和α地中海贫血性状与严重疟疾之间存在关联的证据令人信服。然而，对于这些多态性与无并发症疟疾的关联，以及 G6PD 缺乏症与无并发症和严重疟疾的关联，研究结果并不一致。我们研究了一项三臂病例对照研究的样本，目的是确定常见宿主红细胞多态性与无并发症和严重疟疾（包括不同的严重疟疾表型）之间的关联。
我们通过分子方法评估了 325 例严重疟疾儿童的血红蛋白异常、α-地中海贫血和 G6PD 缺乏症，这些儿童与 325 例无并发症疟疾儿童和 325 例健康社区对照相匹配。条件逻辑回归用于测量特定基因型与疟疾结局之间的关联。
没有测试的多态性对无并发症疟疾提供显著保护。α-地中海贫血纯合子（_α/_α）发生无并发症疟疾的风险增加（OR 2.40；95%CI 1.15，5.03，p = 0.020）。HbAS 和α-地中海贫血杂合子（_α/αα）基因型与严重疟疾相比，与无并发症疟疾（HbAS OR 0.46；0.23，0.95，p = 0.036；_α/αα OR 0.51；0.24，0.77；p = 0.001）或社区（HbAS OR 0.23；0.11，0.50；p<0.001；_α/αα；OR 0.49；0.32，0.76；p = 0.002）对照相比具有保护作用。与无并发症疟疾对照相比，α-地中海贫血纯合子（_α/_α）基因型与严重疟疾（OR 0.34；95%CI 0.156，0.73，p = 0.005）相比具有保护作用，但与社区对照（OR 1.03；0.46，2.27，p = 0.935）相比则无保护作用。按严重疟疾表型分层，与社区对照相比，HbAS 的保护作用仅限于严重贫血的儿童（OR 0.17；0.04，0.65；p = 0.009），_α/αα 则限于意识改变的儿童（OR 0.24；0.09，0.59；p = 0.002）。HbAS 和_α/αα 之间存在负性上位效应；在同时具有这两种多态性的个体中，与无并发症疟疾对照相比，未见保护作用（OR 0.45；0.11，1.84；p = 0.269）。G6PD 缺乏症对严重疟疾没有保护作用。
关联很复杂，HbAS 主要对严重贫血具有保护作用，_α/αα 对意识改变具有保护作用，两种多态性之间存在负性上位效应。
