Study on antimalarial efficacy and genetic diversities of human, parasites and mosquitoes

人类和疟疾寄生虫在不同地理区域以不同的频率表现出的遗传多样性是制定疟疾控制战略的主要障碍，包括疟疾化疗和疟疾疫苗。我们调查了瓦努阿图群岛的一些遗传多样性，这些岛屿具有不同的疟疾地方性。瓦努阿图疟疾不稳定，以亚-中流行和季节性为主，偶有流行，细胞色素P450(CYP)2C19突变等位基因频率在瓦努阿图一致较高。然而，来自不同岛屿的种群之间存在差异。遗传、语言和地理模式的比较表明，短距离基因流动在很大程度上导致了目前在瓦努阿图的CYP2C19等位基因的分布。我们在疟疾患者中的数据显示，CYP2C19突变与普鲁瓜尼对环瓜尼代谢不良有关，环瓜尼是一种强二氢叶酸还原酶(Dhfr)抑制剂，明显的基因…更多的剂量效应关系。在瓦努阿图孤立岛屿上总共140例恶性疟原虫病例中，dhfr基因显示出限制性多样性。所有菌株都有相同的ASN-108突变，除Gaua外，所有菌株也都有Arg-59突变，通常与对DHFR抑制药物的中度耐药有关。Gaua剩下的3个分离物具有His-51，这一变化在以前的文献中没有报道。尽管有这些部分耐药的变种，乙胺嘧啶和磺胺多辛治疗仍然非常有效。在瓦努阿图群岛不稳定的疟疾流行中，DHFR基因的有限多样性至少部分可以解释为来自周期性中断传播和岛间基因流动有限的隔离的寄生虫种群的杂合性丧失。人类CYP2C19和寄生虫DHFR基因的突变分别与普罗瓜尼的代谢不良和对环瓜尼的抗药性有关，都被认为与普瓜尼的抗疟疾效果差有关。然而，我们观察到普罗瓜尼在与CYP2C19相关的代谢不良基因和常见的DHFR基因(Arg-59和ASN-108)的患者中也有很高的抗疟疾效果。这表明母体化合物普罗瓜尼具有独立于代谢物环鸟酚和DHFR突变的内在疗效。细胞色素P450(CYP)2C19突变等位基因在瓦努阿图的频率一致较高。然而，来自不同岛屿的种群之间存在差异。遗传、语言和地理模式的比较表明，短距离基因流动在很大程度上导致了目前在瓦努阿图的CYP2C19等位基因的分布。我们在疟疾患者中的数据表明，CYP2C19突变与普鲁瓜尼对环瓜尼的代谢不良有关，环瓜尼是一种强二氢叶酸还原酶(DHFR)抑制剂，并且存在明显的基因剂量效应关系。较少

The genetic diversities displayed by human and malaria parasites at different frequencies in different geographical areas represent a major obstacle for the development of malaria control strategies including malaria chemotherapy and malaria vaccine. We investigated some genetic diversities on Vanuatu islands with various malaria endemicities. Malaria in Vanuatu is unstable, mainly hypo-to mesoendemic and seasonal with occasional epidemics.The frequencies of the cytochrome P450 (CYP) 2C19 mutant alleles were uniformly greater in Vanuatu. However there were differences between populations from different islands. Comparisons of genetic, linguistic and geographic patterns suggested that short range gene flow is largely responsible for the current distribution of CYP2C19alleles in Vanuatu. Our data in malaria patients demonstrated an association between CYP2C19 mutations and poor metabolism of proguanil to cycloguanil, a strong dihydrofolate reductase (DHFR) inhibitor, and an apparent gene … More dose effect relationship.Restricted diversity in the dhfr gene was shown in a total of 140 P.falciparunm cases on isolated islands of Vanuatu. All isolates had the same Asn- 108 mutation, and all, except in Gaua, also had Arg-59 mutation, normally associated with moderate resistance to DHFR-inhibiting drugs. The 3 remaining isolates in Gaua had His-51, a change not previously reported in the literature. Despite these partly resistant variants, pyrimethamine and sulfadoxine treatment was still highly effective. The restricted diversity of the dhfr gene in unstable malaria endemicity on Vanuatu islands may be at least partly explained by a loss in heterozygosity of the parasite populations derived from periodically interrupted transmission and isolation with limited gene flows between islands.Mutations in human CYP2C19 and parasite dhfr genes, related to poor metabolism of proguanil and resistance to cycloguanil respectively, have both been assumed to be associated with poor antimalarial effect by proguanil. We however observed high antimalarial efficacy of proguanil also in patients with CYP2C19 related poor metabolize genotype and the common dhfr genotype (Arg-59 and Asn-108). This suggested that the parent compound proguanil has an intrinsic efficacy independent of the metabolite cycloguanil and the dhfr mutation.The frequencies of the cytochrome P450 (CYP) 2C19 mutant alleles were uniformly greater in Vanuatu. However there were differences between populations from different islands. Comparisons of genetic, linguistic and geographic patterns suggested that short range gene flow is largely responsible for the current distribution of CYP2C19alleles in Vanuatu. Our data in malaria patients demonstrated an association between CYP2C19 mutations and poor metabolism of proguanil to cycloguanil, a strong dihydrofolate reductase (DHFR) inhibitor, and an apparent gene dose effect relationship. Less