Ronald Moura

Meta-analysis of Brazilian genetic admixture and comparison with other Latin America countries.

This study aims at performing a systematic review and meta‐analysis with the studies of genetic admixture inference of Brazilian population and to compare these results with the genetic admixture levels in other Latin American countries.

Susceptibility to mycobacterium tuberculosis infection in HIV-positive patients is associated with CARD8 genetic variant

Abstract:HLA and other genetic variants, playing an important role in innate and adaptive immunity, are known to influence tuberculosis (TB) development in HIV-1–positive (HIV+) patients. Because inflammasome genes contribute to HIV-1 susceptibility, we investigated the possible association between polymorphisms in inflammasome genes with HIV-1 and Mycobacterium tuberculosis coinfection (HIV+TB+) in a case/control cohort of Brazilian individuals. Nineteen single-nucleotide polymoprhims in 8 inflammasome genes (NLRP1, NLRP3, AIM2, CARD8, CASP1, IL1B, IL1R, and HSP90) were analyzed in HIV+TB+ Brazilian patients (from Recife, Pernambuco). CARD8 rs6509365 polymorphism was associated with HIV+TB+ (P = 5 × 10−5), suggesting a predisposing role of this variant in M. tuberculosis susceptibility in HIV+ subjects (odds ratio = 2.45). This effect is even strong when this allele is combined to CARD8 rs2043211 single-nucleotide polymoprhim. The results of this study support the novel association between CARD8 gene and HIV+TB+ coinfection, demonstrating that inflammasome genetics could influence HIV-1 infection and the development of opportunistic infection.

Interleukin 18 (IL18) gene promoter polymorphisms are associated with type 1 diabetes mellitus in Brazilian patients

Interleukin 18 (IL-18) is a cytokine that plays an important role in the Th1 response, by its ability to induce IFN-γ production in T cells and natural killer cells. Functional variants of IL18 gene has been reported as associated with type 1 diabetes (T1D). In the present study were analyzed three promoter single nucleotide polymorphisms (SNPs), at -656 (rs1946519), -607 (rs1946518) and -137 (rs187238) position, in 181 children and adolescents with T1D and 122 healthy individuals, both from metropolitan area of Recife, Northeast of Brazil. T1D patients were stratified according to the presence autoimmune thyroiditis and celiac disease. Allele and genotype frequencies of IL18 SNPs were Hardy-Weinberg equilibrium in patients and controls. The allele -137G and the haplotype -656G/-607C/-137G were more frequent in T1D patients (OR=1.82 and 1.97, respectively) then in healthy controls. However, those SNPs were not associated with the age of T1D onset as well as with the insurgence of AITD and/or CD in concomitant with T1D patients. Our findings suggest an association between IL18 promoter SNPs and susceptibility to T1D in Brazilian patients.

Iron signature in asbestos-induced malignant pleural mesothelioma: A population-based autopsy study

ABSTRACT Malignant pleural mesothelioma (MPM) is an aggressive cancer with poor prognosis. The development of MPM is frequently linked to inhalation of asbestos fibers. A genetic component of susceptibility to this disease is suggested by the observation that some individuals develop MPM following lower doses of asbestos exposure, whereas others exposed to higher quantities do not seem to be affected. This hypothesis is supported also by frequent reports of MPM familial clustering. Despite the widely recognized role of iron (Fe) in cellular asbestos-induced pulmonary toxicity, the role of the related gene polymorphisms in the etiology of MPM has apparently not been evaluated. Eighty-six single-nucleotide polymorphisms (SNPs) of 10 Fe-metabolism genes were examined by exploiting formalin-fixed paraffin-embedded postmortem samples from 77 patients who died due to MPM (designated AEM) and compared with 48 who were exposed to asbestos but from died in old age of cause other than asbestos (designated AENM). All subjects showed objective signs of asbestos exposure. Three SNPs, localized in the ferritin heavy polypeptide, transferrin, and hephaestin genes, whose frequencies were distributed differently in AEM and AENM populations, were identified. For ferritin and transferrin the C/C and the G/G genotypes, respectively, representing intronic polymorphisms, were significantly associated with protection against MPM and need to be considered as possible genetic markers of protection. Similarly, the C/C hephaestin SNP, a missense variation of this multicopper ferroxidase encoding gene, may be related, also functionally, with protection against MPM. In conclusion, it is proposed that three Fe metabolism-associated genes, significantly associated with protection against development of MPM, may serve as protective markers for this aggressive tumor.

Interferon induced with helicase C domain 1 (IFIH1): trends on helicase domain and type 1 diabetes onset.

The Interferon-induced with helicase C domain 1 (IFIH1) gene has been hypothesized as involved in the viral etiology of type 1 diabetes (T1D) and other autoimmune disorders, since it is implicated in viral recognition. In our study we analyzed IFIH1 rs6432714 and rs10930046 SNPs in T1D patients stratified for the presence of celiac disease and autoimmune thyroid disease. No association with susceptibility to develop the diseases was found. The rs6432714, a tag-SNP that represents part of helicase domain of IF1H1 protein showed a trend of association only with T1D development (P>0.025 after Bonferroni adjustment) in log-additive model (OR=1.45, P=0.0365, power=0.99), indicating that helicase domain of IFIH1 protein could be associated with the susceptibility to T1D.

GRID2 a novel gene possibly associated with mevalonate kinase deficiency

Abstract Mevalonate kinase deficiency (MKD) is a rare autosomal disease caused by mutations in the mevalonate kinase gene (MVK). The genotype–phenotype correlation is sometimes problematic due to the great genetic and clinical heterogeneity; so we hypothesize that genes other than MVK are able to modulate MKD clinical phenotypes. This hypothesis was tested by analyzing the exome of 22 patients with MKD all carrying MVK gene mutations, and 20 patients with recurrent fevers (RF) not carrying MVK mutations. Our preliminary findings suggest a possible role of GRID2 in the susceptibility to develop MKD. GRID2 gene (4q22.2), encoding for human glutamate receptor delta-2, associated with MKD: The rs1450500 SNP was differently distributed in patients with MKD with respect to those with RF. Being aware of the small number of patients analyzed, we hypothesized a possible role for GRID2 as possible phenotype modifier in MKD patients, especially in those with severe phenotypes.

Exome analysis of HIV patients submitted to dendritic cells therapeutic vaccine reveals an association of CNOT1 gene with response to the treatment

With the aim of searching genetic factors associated with the response to an immune treatment based on autologous monocyte‐derived dendritic cells pulsed with autologous inactivated HIV, we performed exome analysis by screening more than 240,000 putative functional exonic variants in 18 HIV‐positive Brazilian patients that underwent the immune treatment.

Host genomic HIV restriction factors modulate the response to dendritic cell-based treatment against HIV-1

Host genome is still poorly investigated in the context of vaccine or immunotherapy, however recently findings emphasized that it may affect the response to those treatments. In our retrospective study we evaluated the effect of HIV-1 genetic restriction factors on the response to dendritic cell (DC)-based immunotherapy in a Brazilian cohort of HIV positive (HIV+) patients that underwent a phase I clinical trial in 2004. Genomic DNA from 18 HIV+ individuals that underwent DC-based immunotherapy was analyzed for selected polymorphisms known to be associated with susceptibility to HIV-1 infection and/or AIDS progression. Allelic and genotypic distribution of the 22 polymorphisms was evaluated considering the response to the treatment. The rs11884476 SNP in PARD3B resulted associated with good response to immune treatment according to an over-dominant model. Even if functional effect of this variation is still unknown, our data suggested that it could play a role in the control of viral replication. Our findings, being aware of the limitation represented by the small number of subjects analyzed, suggest that genetic factors involved in AIDS progression could affect the response to immunotherapy, reinforcing the idea that deeper investigation on host genetic variations will be fundamental for a rational vaccine development.

Association of TNF-α, CTLA4, and PTPN22 polymorphisms with type 1 diabetes and other autoimmune diseases in Brazil.

Type 1 diabetes mellitus (T1D) is a complex disorder characterized by an autoimmune response against human pancreatic beta-cells. Patients with T1D can also develop a response toward one or more other factors, such as in autoimmune thyroiditis (AITD) and celiac disease (CD). In the presence of T1D + AITD, the patient is diagnosed with autoimmune polyglandular syndrome type III (APSIII); patients with APSIII may also present with CD. These diseases have a strong genetic component and share many susceptibility genes, suggesting potentially overlapping pathogenic pathways. Polymorphisms in the TNF-α(rs1800629), CTLA-4 (rs231775), and PTPN22 (rs2476601) genes have been previous associated with T1D; however, there is no consensus regarding their role in T1D and scarce literature focusing on AIDT and/or CD. Thus, we analyzed these genetic variants in 205 Northeast Brazilian patients with T1D and with/without AITD and/or CD, and in 308 healthy controls. The PTPN22 gene variants were associated with T1D susceptibility and APSIII [odds ratio (OR) = 2.57 and 2.77, respectively]. CTLA4 rs231775 and TNF-αrs1800629 were not associated with T1D onset in the Brazilian population. However, when comparing APSIII individuals in the T1D only group, we observed an association of the TNF-αSNP in the allelic (P = 0.0442; OR = 0.44) and dominant models (P = 0.0387; OR = 0.40). This study reinforces the importance of CTLA-4 and other variants in unraveling the pathogenic mechanisms of T1D in different populations and in understanding their relationships with the development of other T1D-related autoimmune diseases.

DEFB1 polymorphisms are involved in susceptibility to human papillomavirus infection in Brazilian gynaecological patients

The human beta defensin 1 (hBD-1) antimicrobial peptide is a member of the innate immune system known to act in the first line of defence against microorganisms, including viruses such as human papillomavirus (HPV). In this study, five functional polymorphisms (namely g-52G>A, g-44C>G and g-20G>A in the 5’UTR and c.*5G>A and c.*87A>G in the 3’UTR) in the DEFB1 gene encoding for hBD-1 were analysed to investigate the possible involvement of these genetic variants in susceptibility to HPV infection and in the development of HPV-associated lesions in a population of Brazilian women. The DEFB1 g-52G>A and c.*5G>A single-nucleotide polymorphisms (SNPs) and the GCAAA haplotype showed associations with HPV-negative status; in particular, the c.*5G>A SNP was significantly associated after multiple test corrections. These findings suggest a possible role for the constitutively expressed beta defensin-1 peptide as a natural defence against HPV in the genital tract mucosa.