Quantitative trait locus analysis of parasite density reveals that HbS gene carriage protects severe malaria patients against Plasmodium falciparum hyperparasitaemia

This deposit is composed by the main article, and it hasn't any supplementary materials associated.Haemoglobin S (HbS) is the gene known to confer the strongest advantage against malaria morbidity and mortality. Multiple HbS effects have been described resulting in protection against parasitaemia and reduction of severe malaria risk. This study aimed to explore HbS protection against severe malaria and Plasmodium falciparum parasitaemia in Angolan children exhibiting different severe malaria syndromes.Instituto Gulbenkian de Ciência

Modeling malaria infection and immunity against variant surface antigens in Príncipe Island, West Africa

After remarkable success of vector control campaigns worldwide, concerns about loss of immunity against Plasmodium falciparum due to lack of exposure to the parasite are relevant since an increase of severe cases in less immune individuals is expected. We present a mathematical model to investigate the impact of reducing exposure to the parasite on the immune repertoire against P. falciparum erythrocyte membrane protein 1 (PfEMP1) variants. The model was parameterized with data from Príncipe Island, West Africa, and applied to simulate two alternative transmission scenarios: one where control measures are continued to eventually drive the system to elimination; and another where the effort is interrupted after 6 years of its initiation and the system returns to the initial transmission potential. Population dynamics of parasite prevalence predict that in a few years infection levels return to the pre-control values, while the re-acquisition of the immune repertoire against PfEMP1 is slower, creating a window for increased severity. The model illustrates the consequences of loss of immune repertoire against PfEMP1 in a given setting and can be applied to other regions where similar data may be available

Transforming Growth Factor Beta 2 and Heme Oxygenase 1 Genes Are Risk Factors for the Cerebral Malaria Syndrome in Angolan Children

BACKGROUND: Cerebral malaria (CM) represents a severe outcome of the Plasmodium falciparum infection. Recent genetic studies have correlated human genes with severe malaria susceptibility, but there is little data on genetic variants that increase the risk of developing specific malaria clinical complications. Nevertheless, susceptibility to experimental CM in the mouse has been linked to host genes including Transforming Growth Factor Beta 2 (TGFB2) and Heme oxygenase-1 (HMOX1). Here, we tested whether those genes were governing the risk of progressing to CM in patients with severe malaria syndromes. METHODOLOGY/PRINCIPAL FINDINGS: We report that the clinical outcome of P. falciparum infection in a cohort of Angolan children (n = 430) correlated with nine TGFB2 SNPs that modify the risk of progression to CM as compared to other severe forms of malaria. This genetic effect was explained by two haplotypes harboring the CM-associated SNPs (Pcorrec. = 0.035 and 0.036). In addition, one HMOX1 haplotype composed of five CM-associated SNPs increased the risk of developing the CM syndrome (Pcorrec. = 0.002) and was under-transmitted to children with uncomplicated malaria (P = 0.036). Notably, the HMOX1-associated haplotype conferred increased HMOX1 mRNA expression in peripheral blood cells of CM patients (P = 0.012). CONCLUSIONS/SIGNIFICANCE: These results represent the first report on CM genetic risk factors in Angolan children and suggest the novel hypothesis that genetic variants of the TGFB2 and HMOX1 genes may contribute to confer a specific risk of developing the CM syndrome in patients with severe P. falciparum malaria. This work may provide motivation for future studies aiming to replicate our findings in larger populations and to confirm a role for these genes in determining the clinical course of malaria

Transforming Growth Factor Beta 2 and Heme Oxygenase 1 Genes Are Risk Factors for the Cerebral Malaria Syndrome in Angolan Children

BACKGROUND: Cerebral malaria (CM) represents a severe outcome of the Plasmodium falciparum infection. Recent genetic studies have correlated human genes with severe malaria susceptibility, but there is little data on genetic variants that increase the risk of developing specific malaria clinical complications. Nevertheless, susceptibility to experimental CM in the mouse has been linked to host genes including Transforming Growth Factor Beta 2 (TGFB2) and Heme oxygenase-1 (HMOX1). Here, we tested whether those genes were governing the risk of progressing to CM in patients with severe malaria syndromes. METHODOLOGY/PRINCIPAL FINDINGS: We report that the clinical outcome of P. falciparum infection in a cohort of Angolan children (n = 430) correlated with nine TGFB2 SNPs that modify the risk of progression to CM as compared to other severe forms of malaria. This genetic effect was explained by two haplotypes harboring the CM-associated SNPs (Pcorrec. = 0.035 and 0.036). In addition, one HMOX1 haplotype composed of five CM-associated SNPs increased the risk of developing the CM syndrome (Pcorrec. = 0.002) and was under-transmitted to children with uncomplicated malaria (P = 0.036). Notably, the HMOX1-associated haplotype conferred increased HMOX1 mRNA expression in peripheral blood cells of CM patients (P = 0.012). CONCLUSIONS/SIGNIFICANCE: These results represent the first report on CM genetic risk factors in Angolan children and suggest the novel hypothesis that genetic variants of the TGFB2 and HMOX1 genes may contribute to confer a specific risk of developing the CM syndrome in patients with severe P. falciparum malaria. This work may provide motivation for future studies aiming to replicate our findings in larger populations and to confirm a role for these genes in determining the clinical course of malaria

Caracterização genética de São Tomé e Príncipe com base em marcadores do cromossoma Y e DNA mitocondrial

Tese de doutoramento em Antropologia (Antropologia Biológica) apresentada à Fac. de Ciências e Tecnologia da Universidade de CoimbraNeste trabalho, por recurso a técnicas de PCR, PCR/RFLP e/ou sequenciação directa, analisaram-se os padrões de distribuição de 7 STRs (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392 e DYS393) e 14 marcadores bialélicos (YAP, SRY8299, 92R7, SRY1532, SRY2627, Tat, sY81, M9, LLy22g, 12f2, M109, M112, M150 e M168) do cromossoma Y e de variações de sequência em HVS-I e HVS-II do mtDNA, em amostras de Angolares, Forros e Tongas, três grupos populacionais de São Tomé e Príncipe, uma ex-colónia portuguesa localizada no Golfo da Guiné. Os níveis de diversidade registados no arquipélago são elevados e enquadram-se na gama de valores que caracteriza a maioria das populações continentais Africanas. O seu fundo genético é preponderantemente de origem subsariana (Centro/Ocidente), o que atesta o forte impacto da contribuição de escravos no povoamento do arquipélago. A presença de 20.4% de linhagens definidas por marcadores bialélicos do cromossoma Y de presumível origem europeia e a ausência de sequências com a mesma origem no conjunto de linhagens femininas, revela que é considerável o componente europeu na população actual de São Tomé e Príncipe e que a sua introdução foi essencialmente veiculada por indivíduos do sexo masculino. Não se encontraram indícios de diferenciação genética entre Forros e Tongas. Os Angolares apresentam relativamente a Tongas ou Forros, sinais de alguma diferenciação genética que atinge significância estatística quando averiguada com STRs do Y ou mtDNA. O grau de subestruturação detectado é mais acentuado nas linhagens definidas por STRs do Y que nas de mtDNA, indicando que entre os Angolares e outros sãotomenses, foram menores as restrições ao fluxo génico mediado pelo sexo feminino que ao fluxo mediado pelo sexo masculino. Apesar dos níveis de diversidade reduzidos comparativamente a Forros ou Tongas, não se encontraram entre os Angolares sinais claros da presença de “linhagens fundadoras”In this study PCR, PCR/RFLP and/or sequenciation direct methods were used to analyse the distribution patterns of 7 STRs (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392 and DYS393) and 14 biallelic markers (YAP, SRY8299, 92R7, SRY1532, SRY2627, Tat, sY81, M9, LLy22g, 12f2, M109, M112, M150 and M168) of the Y- chromosome and sequence variation in HVS-I and HVS-II of mtDNA, in samples from Angolares, Forros and Tongas, three ethnic groups from the archipelago of São Tomé e Príncipe, a former Portuguese colony located in the Gulf of Guinea. Levels of diversity in the archipelago of São Tomé e Príncipe, are high and fits the range of values that characterizes the majority of African continental populations. The Santomean genetic background is preponderantly of subsariana origin (Central/Southwestern substratum), testifying the strong impact of the contribution of slaves in the settlement of the archipelago. The absence of any lineages of putative European descent means that the European impact at the mitochondrial pool was virtually nil. The presence of 20.4% of lineages defined for Y-biallelics markers of presumable European origin and the absence of sequences with the same origin in the set of female lineages, reveal that the European component in the present day São Tomé e Príncipe population is high although its introduction was basically mediated by male individuals. Indications of genetic differentiation between Forros and Tongas had not been found. The Angolares presents relatively to Tongas or Forros, signals of genetic differentiation that attained statistical significance with Y-STRs or mtDNA. The level of detected substructuring was more accented in the lineages defined by Y-STRs than in the ones of mtDNA, indicating that among Angolares and other santomean, had been smaller the restrictions to the genetic flow mediated by the female that to the flow mediated for the male sex. In spite of the reduced levels of diversity comparatively to Forros or Tongas, the Angolares do not show clear signs of “founding lineages

STR data from S. Tomé e Príncipe (Gulf of Guinea, West Africa)

Allele frequencies for eight STRs (CD4, FES/FPS, MBPB, TH01, TP53, TPO, F13A1, VWA) were estimated from samples (sized between 279 and 328) of unrelated individuals born in S. Tomé e Príncipe (Gulf of Guinea, West Africa).http://www.sciencedirect.com/science/article/B6T6W-41WJBSP-8/1/a84a6eb4f309df8255225fa49f985dd

Insights from pattern of mtDNA variation into the genetic history of São Tomé e Príncipe

Sequence data from the hypervariable segments I (HVS-I) and II (HVS-II) was obtained for 30 Angolares, 35 Forros and 38 Tongas, three self-reported ethnic groups from São Tomé e Príncipe, an African archipelago (Gulf of Guinea) whose settlement begun in the late 15th century. The repertory of mtDNA lineages denoted a fully African maternal pool primarily arisen from a Central/Southwestern substratum. The absence of any lineages of putative European descent means that the European impact at the mitochondrial pool was virtually nil. Angolares showed a clear reduction of mtDNA diversity and a slight genetic differentiation relatively to Tongas or Forros, whereas the two last groups did not present any signs of genetic boundaries between each other. The data now obtained reinforce the depiction of genetic substructuring in São Tomé e Príncipe previously derived from Y-chromosome STRs.http://www.sciencedirect.com/science/article/B7581-4C4WDDP-4F/1/820043d2aef5dc67577eadeb2c4c328

Population Genetics of Four PKLR Intragenic Polymorphisms in Portugal and São Tomé e Príncipe (Gulf of Guinea)

Four intragenic PKLR polymorphisms [1705A/C, 1738C/T, T10/19, and (ATT)n microsatellite] were studied in normal population samples of Central Portugal and São Tomé e Príncipe, a small archipelago located in the Gulf of Guinea, West Africa. For all loci, the observed genotype distributions do not deviate from Hardy-Weinberg equilibrium. The allele frequencies found in the Portuguese population are similar to those previously described in Caucasian populations. Mother-child pair analysis for the (ATT)n microsatellite does not show deviations to the Mendelian rules. In São Tomé e Príncipe the biallelic polymorphisms 1705A/C, 1738C/T, and T10/19 presented inverse allelic frequencies when compared with the Portuguese population. Two new alleles were found at the (ATT)n microsatellite. Significant statistical differences were found between both populations. The results showed that São Tomeans had higher haplotype diversity and lower linkage disequilibrium among the polymorphic sites. The PKLR intragenic polymorphisms, commonly used in haplotype analysis with the gene mutations in PK-deficient patients, can thus be successfully employed in anthropological genetics