巴西亚马逊地区个体中与细胞凋亡相关的变异与疟疾感染和寄生虫密度的关联。

Association of apoptosis-related variants to malaria infection and parasite density in individuals from the Brazilian Amazon.

机构信息

Laboratory of Human and Medical Genetics, Program of Genetics and Molecular Biology, Federal University of Pará (UFPA), Belém, Brazil.

Laboratory of Dermatoimmunology, Federal University of Pará (UFPA), Marituba, Brazil.

出版信息

Malar J. 2023 Oct 4;22(1):295. doi: 10.1186/s12936-023-04729-6.

DOI:10.1186/s12936-023-04729-6

PMID:37794476

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10552311/

Abstract

BACKGROUND

In malaria infection, apoptosis acts as an important immunomodulatory mechanism that leads to the elimination of parasitized cells, thus reducing the parasite density and controlling immune cell populations. Here, it was investigated the association of INDEL variants in apoptotic genes-rs10562972 (FAS), rs4197 (FADD), rs3834129 and rs59308963 (CASP8), rs61079693 (CASP9), rs4647655 (CASP3), rs11269260 (BCL-2), and rs17880560 (TP53)-and the influence of genetic ancestry with susceptibility to malaria and parasite density in an admixed population from the Brazilian Amazon.

METHODS

Total DNA was extracted from 126 malaria patients and 101 uninfected individuals for investigation of genetic ancestries and genotypic distribution of apoptosis-related variants by Multiplex PCR. Association analyses consisted of multivariate logistic regressions, considering the following comparisons: (i) DEL/DEL genotype vs. INS/DEL + INS/INS; and (ii) INS/INS vs. INS/DEL + DEL/DEL.

RESULTS

Individuals infected by Plasmodium falciparum had significantly higher African ancestry proportions in comparison to uninfected controls, Plasmodium vivax, and mixed infections. The INS/INS genotype of rs3834129 (CASP8) seemed to increase the risk for P. falciparum infection (P = 0.038; OR = 1.867; 95% CI 0.736-3.725), while the DEL/DEL genotype presented a significant protective effect against infection by P. falciparum (P = 0.049; OR = 0.446; 95% CI 0.185-0.944) and mixed infection (P = 0.026; OR = 0.545; 95% CI 0.281-0.996), and was associated with lower parasite density in P. falciparum malaria (P = 0.009; OR = 0.383; 95% CI 0.113-1.295). Additionally, the INS/INS genotype of rs10562972 (FAS) was more frequent among individuals infected with P. vivax compared to P. falciparum (P = 0.036; OR = 2.493; 95% CI 1.104-4.551), and the DEL/DEL genotype of rs17880560 (TP53) was significantly more present in patients with mono-infection by P. vivax than in individuals with mixed infection (P = 0.029; OR = 0.667; 95% CI 0.211-1.669).

CONCLUSIONS

In conclusion, variants in apoptosis genes are associated with malaria susceptibility and parasite density, indicating the role of apoptosis-related genetic profiles in immune responses against malaria infection.

摘要

背景

在疟疾感染中，细胞凋亡作为一种重要的免疫调节机制发挥作用，导致寄生细胞被清除，从而降低寄生虫密度并控制免疫细胞群体。在这里，研究了凋亡基因中 INDEL 变体（rs10562972[FAS]、rs4197[FADD]、rs3834129 和 rs59308963[CASP8]、rs61079693[CASP9]、rs4647655[CASP3]、rs11269260[BCL-2]和 rs17880560[TP53]）的关联以及遗传祖先与疟疾易感性和寄生虫密度的关系在巴西亚马逊地区的混合人群中。

方法

从 126 名疟疾患者和 101 名未感染个体中提取总 DNA，通过多重 PCR 检测与细胞凋亡相关的变异的遗传祖先和基因型分布。关联分析包括多元逻辑回归，考虑以下比较：（i）DEL/DEL 基因型与 INS/DEL+INS/INS；和（ii）INS/INS 基因型与 INS/DEL+DEL/DEL。

结果

与未感染对照、间日疟原虫和混合感染相比，感染恶性疟原虫的个体具有更高的非洲祖先比例。rs3834129（CASP8）的 INS/INS 基因型似乎增加了感染恶性疟原虫的风险（P=0.038；OR=1.867；95%CI 0.736-3.725），而 DEL/DEL 基因型对感染恶性疟原虫具有显著的保护作用（P=0.049；OR=0.446；95%CI 0.185-0.944）和混合感染（P=0.026；OR=0.545；95%CI 0.281-0.996），并与恶性疟原虫疟疾中的寄生虫密度降低相关（P=0.009；OR=0.383；95%CI 0.113-1.295）。此外，与感染恶性疟原虫相比，rs10562972（FAS）的 INS/INS 基因型在感染间日疟原虫的个体中更为常见（P=0.036；OR=2.493；95%CI 1.104-4.551），rs17880560（TP53）的 DEL/DEL 基因型在感染间日疟原虫的个体中明显更为常见与混合感染相比（P=0.029；OR=0.667；95%CI 0.211-1.669）。