Mackinnon M J, Gunawardena D M, Rajakaruna J, Weerasingha S, Mendis K N, Carter R
Institute of Cell, Animal, and Population Biology, University of Edinburgh, Edinburgh, EH9 3JT, United Kingdom.
Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12661-6. doi: 10.1073/pnas.220267997.
Explaining the causes of variation in the severity of malarial disease remains a major challenge in the treatment and control of malaria. Many factors are known to contribute to this variation, including parasite genetics, host genetics, acquired immunity, and exposure levels. However, the relative importance of each of these to the overall burden of malarial disease in human populations has not been assessed. Here, we have partitioned variation in the incidence of malarial infection and the clinical intensity of malarial disease in a rural population in Sri Lanka into its component causes by pedigree analysis of longitudinal data. We found that human genetics, housing, and predisposing systematic effects (e. g., sex, age, occupation, history of infections, village) each explained approximately 15% of the variation in the frequency of malarial infection. For clinical intensity of illness, 20% of the variation was explained by repeatable differences between patients, about half of which was attributable to host genetics. The other half was attributable to semipermanent differences among patients, most of which could be explained by known predisposing factors. Three percent of variation in clinical intensity was explained by housing, and an additional 7% was explained by current influences relating to infection status (e.g., parasitemia, parasite species). Genetic control of Plasmodium falciparum infections appeared to modulate the frequency and intensity of infections, whereas genetic control of Plasmodium vivax infections appeared to confer absolute susceptibility or refractoriness but not intensity of disease. Overall, the data show consistent, repeatable differences among hosts in their susceptibility to clinical disease, about half of which are attributable to host genes.
解释疟疾疾病严重程度的差异原因仍然是疟疾治疗和控制中的一项重大挑战。已知许多因素会导致这种差异，包括寄生虫遗传学、宿主遗传学、获得性免疫和接触水平。然而，这些因素对人类群体中疟疾疾病总体负担的相对重要性尚未得到评估。在此，我们通过对纵向数据进行系谱分析，将斯里兰卡农村人口中疟疾感染发病率和疟疾疾病临床严重程度的差异分解为其组成原因。我们发现，人类遗传学、住房条件以及易感性系统效应（如性别、年龄、职业、感染史、村庄）各自解释了疟疾感染频率差异的约15%。对于疾病的临床严重程度，20%的差异可由患者之间的可重复性差异解释，其中约一半归因于宿主遗传学。另一半归因于患者之间的半永久性差异，其中大部分可由已知的易感性因素解释。住房条件解释了临床严重程度3%的差异，另外7%的差异可由与感染状态相关的当前影响因素（如疟原虫血症、疟原虫种类）解释。恶性疟原虫感染的遗传控制似乎调节了感染的频率和严重程度，而间日疟原虫感染的遗传控制似乎赋予了绝对易感性或难治性，但与疾病严重程度无关。总体而言，数据显示宿主在对临床疾病的易感性方面存在一致的、可重复的差异，其中约一半归因于宿主基因。
