Institut Pasteur, Unité de Génétique Fonctionnelle des Maladies Infectieuses, Paris, France.
PLoS One. 2011;6(11):e26364. doi: 10.1371/journal.pone.0026364. Epub 2011 Nov 3.
Despite considerable success of genome wide association (GWA) studies in identifying causal variants for many human diseases, their success in unraveling the genetic basis to complex diseases has been more mitigated. Pathogen population structure may impact upon the infectious phenotype, especially with the intense short-term selective pressure that drug treatment exerts on pathogens. Rigorous analysis that accounts for repeated measures and disentangles the influence of genetic and environmental factors must be performed. Attempts should be made to consider whether pathogen diversity will impact upon host genetic responses to infection.We analyzed the heritability of two Plasmodium falciparum phenotypes, the number of clinical malaria episodes (PFA) and the proportion of these episodes positive for gametocytes (Pfgam), in a family-based cohort followed for 19 years, during which time there were four successive drug treatment regimes, with documented appearance of drug resistance. Repeated measures and variance components analyses were performed with fixed environmental, additive genetic, intra-individual and maternal effects for each drug period. Whilst there was a significant additive genetic effect underlying PFA during the first drug period of study, this was lost in subsequent periods. There was no additive genetic effect for Pfgam. The intra-individual effect increased significantly in the chloroquine period.The loss of an additive genetic effect following novel drug treatment may result in significant loss of power to detect genes in a GWA study. Prior genetic analysis must be a pre-requisite for more detailed GWA studies. The temporal changes in the individual genetic and the intra-individual estimates are consistent with those expected if there were specific host-parasite interactions. The complex basis to the human response to malaria parasite infection likely includes dominance/epistatic genetic effects encompassed within the intra-individual variance component. Evaluating their role in influencing the outcome of infection through host genotype by parasite genotype interactions warrants research effort.
尽管全基因组关联 (GWA) 研究在确定许多人类疾病的因果变异方面取得了相当大的成功，但它们在揭示复杂疾病的遗传基础方面的成功程度有所降低。病原体种群结构可能会影响感染表型，尤其是在药物治疗对病原体施加强烈的短期选择压力时。必须进行严格的分析，考虑到重复测量并厘清遗传和环境因素的影响。应该尝试考虑病原体多样性是否会影响宿主对感染的遗传反应。我们分析了在一个基于家庭的队列中，19 年来经历了四种连续的药物治疗方案且有耐药性记录的情况下，两种恶性疟原虫表型（临床疟疾发作次数（PFA）和这些发作中配子体阳性的比例（Pfgam））的遗传力。对每个药物期进行了固定环境、加性遗传、个体内和母体效应的重复测量和方差分量分析。虽然在研究的第一个药物期，PFA 有显著的加性遗传效应，但在随后的药物期，这种效应消失了。Pfgam 没有加性遗传效应。在氯喹期间，个体内效应显著增加。在新型药物治疗后，加性遗传效应的丧失可能导致在 GWA 研究中检测基因的能力显著下降。在进行更详细的 GWA 研究之前，必须进行先前的遗传分析。个体内和个体内估计的个体遗传变化与如果存在特定的宿主-寄生虫相互作用时预期的变化一致。人类对疟原虫感染的复杂反应可能包括个体内方差分量中包含的显性/上位遗传效应。通过宿主基因型与寄生虫基因型相互作用评估它们在影响感染结果方面的作用值得研究。
