Genetic Admixture in Brazilians Exposed to Infection with <i>Leishmania chagasi</i>

Ettinger, Nicholas; Duggal, Priya; Braz, Regina F. S.; Nascimento, Eliana T.; Beaty, Terri H.; Jerônimo, Selma M. B.; Pearson, Richard D.; Blackwell, Jenefer M.; Moreno, Lina M.; Wilson, Mary E.

doi:10.1111/j.1469-1809.2009.00510.x

Cited by 20 publications

(30 citation statements)

References 29 publications

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“…Informed written consent for sample collection was obtained from adults, and from parents of children <18 years old. The Brazilian populations studied are long-term (>200 years) admixtures of Caucasian, Negroid and Native Indian ethnic backgrounds, as confirmed in recent analysis of the Natal families 11 .…”

Section: Methodssupporting

confidence: 62%

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Common variants in the HLA-DRB1–HLA-DQA1 HLA class II region are associated with susceptibility to visceral leishmaniasis

Fakiola¹,

Strange²,

Cordell³

et al. 2013

Nat Genet

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To identify susceptibility loci for visceral leishmaniasis we undertook genome-wide association studies in two populations; 989 cases and 1089 controls from India, and 357 cases in 308 Brazilian families (1970 individuals). The HLA-DRB1-HLA-DQA1 locus was the only region to show strong evidence of association in both populations. Replication at this region was undertaken in a second Indian population comprising 941 cases and 990 controls, resulting in Pcombined=2.76×10−17 and OR(95%CI)=1.41(1.30-1.52) across the three cohorts at rs9271858. A conditional analysis provided evidence for multiple associations within the HLA-DRB1-HLA-DQA1 region, and a model in which risk differed between three groups of haplotypes better explained the signal and was significant in the Indian discovery and replication cohorts. In conclusion the HLA-DRB1-HLA-DQA1 HLA class II region contributes to visceral leishmaniasis susceptibility in India and Brazil, suggesting shared genetic risk factors for visceral leishmaniasis that cross the epidemiological divides of geography and parasite species.

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Section: Methodssupporting

confidence: 62%

“…Patients and controls were matched for self-reported age, sex, religion, caste and geographic region of recruitment. The Brazilian family-based sample was collected as part of the Belém Family Study and from study sites near Natal 6,10,11 (Supplementary Table 1, online methods).…”

mentioning

confidence: 99%

Common variants in the HLA-DRB1–HLA-DQA1 HLA class II region are associated with susceptibility to visceral leishmaniasis

Fakiola¹,

Strange²,

Cordell³

et al. 2013

Nat Genet

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“…The variable degrees of susceptibility or natural resistance to VL have been the focus of intense studies in the mice and dog models [6,7] and in humans [8] since the 70’s. A genetic basis for the susceptibility to VL was described in mice, dogs and humans [7,9-11]. It is well known that innate immunity plays a pivotal role in host resistance to VL.…”

Section: Resultsmentioning

confidence: 99%

Resistance to visceral leishmaniasis is severely compromised in mice deficient of bradykinin B2-receptors

et al. 2012

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BackgroundKinins liberated from plasma–borne kininogens, are potent innate stimulatory signals. We evaluated whether resistance to infection by Leishmania (L.) chagasi depends on activation of G-protein coupled bradykinin B2 receptors (B2R).FindingsB2R −/− C57BL/6 knock-out (KOB2) and B2R+/+ C57BL/6-wild type control mice (C57) were infected with amastigotes of Leishmania (L.) chagasi. Thirty days after infection, the KOB2 mice showed 14% and 32% relative increases of liver (p< 0.017) and spleen weights (p<0.050), respectively, whereas liver parasite load increased 65% (p< 0.011) in relation to wild type mice. The relative weight increases of liver and spleen and the parasite load were positively correlated (R = 0.6911; p< 0.007 to R = 0.7629; p< 0.001, respectively). Conversely, we found a negative correlation between the increased liver relative weight and the weakened DTH response (a strong correlate to protection or natural resistance to VL) or the decreased levels of IgG2b antibodies to leishmanial antigen. Finally, we also found that IFN-γ secretion by splenocytes, an adaptive response that was significantly decreased in KOB2 mice (p< 0.002), was (i) negatively correlated to the increase in liver LDU (R = −0.6684; p = 0.035) and liver/body relative weight (R = −0.6946; p = 0.026) and (ii) positively correlated to serum IgG2b levels (R = 0.8817; p = 0.001).ConclusionsWe found that mice lacking B2R display increased susceptibility to the infection by Leishmania (L.) chagasi. Our findings suggest that activation of the bradykinin/B2R pathway contributes to development of host resistance to visceral leishmaniasis.

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“…Based on our knowledge of admixture in the region of northeast Brazil (Ettinger et al, 2009), tagging SNPs (minor allele frequency > 0.05) were selected from LD blocks using the CEU and YRI populations in HapMap (Table S1). SNP selection was based on >1 SNP per LD block with r 2 > 0.8.…”

Section: Methodsmentioning

confidence: 99%

Fine mapping under linkage peaks for symptomatic or asymptomatic outcomes of Leishmania infantum infection in Brazil

Weirather

Duggal

Nascimento

et al. 2016

Infection, Genetics and Evolution

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Infection with the protozoan Leishmania infantum can lead to asymptomatic infection and protective immunity, or to the progressive and potentially fatal disease visceral leishmaniasis (VL). Published studies show host genetic background determines in part whether infected individuals will develop a symptomatic or asymptomatic outcome. The purpose of the current study was to fine map chromosome regions previously linked with risk for symptomatic (chromosome 9) or asymptomatic (chromosomes 15 and 19) manifestations of L. infantum infection. We conducted a family-based genetic study of VL and asymptomatic infection (detected by a DTH skin test) with a final post quality control sample of 961 individuals with full genotype and phenotype information from highly endemic neighborhoods of northeast Brazil. A total of 5485 SNPs under the linkage peaks on chromosomes 9, 15 and 19 were genotyped. No strong SNP associations were observed for the DTH phenotype. The most significant associations with the VL phenotype were with SNP rs1470217 (p = 5.9e−05; pcorrected = 0.057) on chromosome 9, and with SNP rs8107014 (p = 1.4e−05; pcorrected = 0.013) on chromosome 19. SNP rs1470217 is situated in a 180 kb intergenic region between TMEM215 (Transmembrane protein 215) and APTX (Aprataxin). SNP rs8107014 lies in the intron between exons 26 and 27 of a 34 exon transcript (ENST00000204005) of LTBP4, (Latent transforming growth factor-beta-binding protein 4a). The latter supports growing evidence that the transforming growth factor-beta pathway is important in the immunopathogenesis of VL.

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Genetic Admixture in Brazilians Exposed to Infection with Leishmania chagasi

Cited by 20 publications

References 29 publications

Common variants in the HLA-DRB1–HLA-DQA1 HLA class II region are associated with susceptibility to visceral leishmaniasis

Common variants in the HLA-DRB1–HLA-DQA1 HLA class II region are associated with susceptibility to visceral leishmaniasis

Resistance to visceral leishmaniasis is severely compromised in mice deficient of bradykinin B2-receptors

Fine mapping under linkage peaks for symptomatic or asymptomatic outcomes of Leishmania infantum infection in Brazil

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