Parasite Genotype Is a Major Predictor of Mortality from Visceral Leishmaniasis.
Parasite Genotype Is a Major Predictor of Mortality from Visceral Leishmaniasis.
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内脏利什曼病（VL）是一种潜在的致命性疾病，主要由南美洲的婴儿利什曼原虫和亚洲和非洲的杜氏利什曼原虫引起。疾病结局与患者基因型、营养、年龄、性别、合并症和合并感染相关。在这项研究中，我们研究了寄生虫遗传变异对巴西VL疾病严重程度的影响。我们收集了109个L.从巴西东北部的患者中分离婴儿病毒，并从病历中检索匹配的患者临床数据，包括死亡率、性别、HIV合并感染和实验室数据（肌酐、血红蛋白、白细胞和血小板计数）。我们确定了寄生虫分离株之间的遗传差异，包括单核苷酸多态性（SNP）、小插入/缺失（indels）以及基因、基因间和染色体拷贝数的变异（拷贝数变异[CNV]）。为了描述寄生虫基因型和临床结果之间的关联，我们应用了遗传力和全基因组关联研究（GWAS）的定量遗传学方法，将临床结果视为可能受寄生虫基因型影响的性状。遗传分析的多个方面表明寄生虫基因型影响临床结果。我们估计寄生虫基因型解释了83%的死亡率（狭义遗传力[h2] = 0.83 ± 0.17），并与患者性别有显著关系（h2 = 0.60 ± 0.27）。寄生虫基因型对其他临床性状的影响较小（h2 ≤ 0.34）。GWAS分析确定了与临床结果显著相关的多个寄生虫遗传位点; 17个CNV与死亡率显著相关，2个与肌酐显著相关，1个与细菌合并感染、黄疸和HIV合并感染显著相关，2个SNP/indel和6个CNV与年龄、黄疸、HIV和细菌合并感染、肌酐和/或出血部位相关。寄生虫基因型是巴西VL疾病严重程度的重要因素。我们的分析表明，寄生虫之间的特定遗传差异作为毒力因子，增加了严重疾病和死亡的风险。对这些毒力因子的更详细的了解可以用于新的治疗。
Visceral leishmaniasis (VL) is a potentially fatal disease caused mainly by Leishmania infantum in South America and Leishmania donovani in Asia and Africa. Disease outcomes have been associated with patient genotype, nutrition, age, sex, comorbidities, and coinfections. In this study, we examine the effects of parasite genetic variation on VL disease severity in Brazil. We collected and sequenced the genomes of 109 L. infantum isolates from patients in northeastern Brazil and retrieved matching patient clinical data from medical records, including mortality, sex, HIV coinfection, and laboratory data (creatinine, hemoglobin, and leukocyte and platelet counts). We identified genetic differences between parasite isolates, including single nucleotide polymorphisms (SNPs), small insertions/deletions (indels), and variations in genic, intergenic, and chromosome copy numbers (copy number variants [CNVs]). To describe associations between the parasite genotypes and clinical outcomes, we applied quantitative genetics methods of heritability and genome-wide association studies (GWAS), treating clinical outcomes as traits that may be influenced by parasite genotype. Multiple aspects of the genetic analysis indicate that parasite genotype affects clinical outcomes. We estimate that parasite genotype explains 83% chance of mortality (narrow-sense heritability [h2] = 0.83 ± 0.17) and has a significant relationship with patient sex (h2 = 0.60 ± 0.27). Impacts of parasite genotype on other clinical traits are lower (h2 ≤ 0.34). GWAS analysis identified multiple parasite genetic loci that were significantly associated with clinical outcomes; 17 CNVs were significantly associated with mortality, two with creatinine, and one with bacterial coinfection, jaundice, and HIV coinfection, and two SNPs/indels and six CNVs were associated with age, jaundice, HIV and bacterial coinfections, creatinine, and/or bleeding sites. Parasite genotype is an important factor in VL disease severity in Brazil. Our analysis indicates that specific genetic differences between parasites act as virulence factors, enhancing risks of severe disease and mortality. More detailed understanding of these virulence factors could be exploited for novel therapies.
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影响因子：
3.3
作者：
Grace CA;Forrester S;Silva VC;Carvalho KSS;Kilford H;Chew YP;James S;Costa DL;Mottram JC;Costa CCHN;Jeffares DC
通讯作者：
Jeffares DC
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
2.3
作者：
Casadevall, Arturo;Pirofski, Liise-anne
通讯作者：
Pirofski, Liise-anne
影响因子：
3.8
作者：
Maia-Elkhoury, Ana Nilce S.;Sierra Romero, Gustavo Adolfo;Sanchez-Vazquez, Manuel J.
通讯作者：
Sanchez-Vazquez, Manuel J.
影响因子：
3.4
作者：
Costa, Dorcas L.;Rocha, Regina L.;Barral, Aldina P.
通讯作者：
Barral, Aldina P.