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

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...

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Published in:	Malaria journal 2023-10, Vol.22 (1), p.1-295, Article 295
Main Authors:	Sena-dos-Santos, Camille, Cavalcante, Giovanna C, Marques, Diego, Silva, Caio S, de Moraes, Milene Raiol, Pinto, Pablo, Santana-da-Silva, Mayara Natália, Ferraz, Rafaella S, Costa, Sheyla Patrícia T, Ventura, Ana Maria R, Póvoa, Marinete M, Cunha, Maristela G, Ribeiro-dos-Santos, Ãndrea
Format:	Article
Language:	eng
Subjects:	Analysis Antigens Apoptosis Bcl-2 protein Capillary electrophoresis Cell death Control Disease control Disease susceptibility DNA Ethylenediaminetetraacetic acid FADD protein Genes Genetic ancestry Genetic aspects Genetic markers Genetic testing Genotypes Health aspects Health risks Human diseases Identification and classification Immune response Immunomodulation Infection Infections Lymphocytes Malaria Mitochondrial DNA Mixed infection Native North Americans Nucleotide sequence p53 Protein Parasites Parasitic diseases PCR Plasmodium Plasmodium falciparum Population Population density Prevention Risk factors Scientific equipment and supplies industry Tumor necrosis factor-TNF Tumor proteins Vector-borne diseases
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Summary:	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.
ISSN:	1475-2875 1475-2875