Tukwasibwe Stephen, Tumwebaze Patrick, Conrad Melissa, Arinaitwe Emmanuel, Kamya Moses R, Dorsey Grant, Nsobya Samuel L, Greenhouse Bryan, Rosenthal Philip J
Infectious Diseases Research Collaboration, Kampala, Uganda.
Department of Medicine, University of California, Box 0811, San Francisco, CA, 94143, USA.
Malar J. 2017 Mar 21;16(1):125. doi: 10.1186/s12936-017-1777-0.
Plasmodium falciparum genetic polymorphisms that mediate altered drug sensitivity may impact upon virulence. In a cross-sectional study, Ugandan children with infections mutant at pfcrt K76T, pfmdr1 N86Y, or pfmdr1 D1246Y had about one-fourth the odds of symptomatic malaria compared to those with infections with wild type (WT) sequences. However, results may have been confounded by greater likelihood in those with symptomatic disease of higher density mixed infections and/or recent prior treatment that selected for WT alleles.
Polymorphisms in samples from paired episodes of asymptomatic and symptomatic parasitaemia in 114 subjects aged 4-11 years were followed longitudinally in Tororo District, Uganda. Paired episodes occurred within 3-12 months of each other and had no treatment for malaria in the prior 60 days. The prevalence of WT, mixed, and mutant alleles was determined using multiplex ligase detection reaction-fluorescent microsphere assays.
Considering paired episodes in the same subject, the odds of symptomatic malaria were lower for infections with mutant compared to WT or mixed sequence at N86Y (OR 0.26, 95% CI 0.09-0.79, p = 0.018), but not K76T or D1246Y. However, symptomatic episodes (which had higher densities) were more likely than asymptomatic to be mixed (for N86Y OR 2.0, 95% CI 1.04-4.0, p = 0.036). Excluding mixed infections, the odds of symptomatic malaria were lower for infections with mutant compared to WT sequence at N86Y (OR 0.33, 95% CI 0.11-0.98, p = 0.046), but not the other alleles. However, if mixed genotypes were grouped with mutants in this analysis or assuming that mixed infections consisted of 50% WT and 50% mutant genotypes, the odds of symptomatic infection did not differ between infections that were mutant or WT at the studied alleles.
Although infections with only the mutant pfmdr1 86Y genotype were associated with symptomatic infection, this association could primarily be explained by greater parasite densities and therefore greater prevalence of mixed infections in symptomatic children. These results indicate limited association between the tested polymorphisms and risk of symptomatic disease and highlight the value of longitudinal studies for assessing associations between parasite factors and clinical outcomes.
介导药物敏感性改变的恶性疟原虫基因多态性可能影响毒力。在一项横断面研究中，与感染野生型（WT）序列的乌干达儿童相比，感染pfcrt K76T、pfmdr1 N86Y或pfmdr1 D1246Y突变的儿童出现症状性疟疾的几率约为四分之一。然而，结果可能因症状性疾病患者中高密度混合感染和/或近期接受过选择WT等位基因的治疗的可能性更大而受到混淆。
在乌干达托罗罗区，对114名4至11岁受试者无症状和症状性寄生虫血症配对发作样本中的多态性进行纵向跟踪。配对发作在彼此3至12个月内发生，且在之前60天内未接受过疟疾治疗。使用多重连接检测反应 - 荧光微球分析法确定WT、混合和突变等位基因的流行率。
考虑同一受试者的配对发作，与N86Y处的WT或混合序列相比，感染突变体的症状性疟疾几率较低（比值比0.26，95%置信区间0.09 - 0.79，p = 0.018），但K76T或D1246Y处并非如此。然而，症状性发作（密度较高）比无症状发作更可能是混合感染（对于N86Y比值比2.0，95%置信区间1.04 - 4.0，p = 0.036）。排除混合感染后，与N86Y处的WT序列相比，感染突变体的症状性疟疾几率较低（比值比0.33，95%置信区间0.11 - 0.98，p = 0.046），但其他等位基因并非如此。然而，如果在该分析中将混合基因型与突变体归为一组，或者假设混合感染由50% WT和50%突变基因型组成，在研究的等位基因处为突变体或WT的感染之间，症状性感染的几率没有差异。
虽然仅感染突变型pfmdr1 86Y基因型与症状性感染有关，但这种关联主要可以通过更高的寄生虫密度来解释，因此症状性儿童中混合感染的患病率更高。这些结果表明所测试的多态性与症状性疾病风险之间的关联有限，并突出了纵向研究在评估寄生虫因素与临床结果之间关联方面的价值。
