Antonio Victor Campos Coelho

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.

Mannose binding lectin gene (MBL2) functional polymorphisms are associated with systemic lupus erythematosus in southern Brazilians

Susceptibility to systemic lupus erythematosus (SLE) has been associated with immunologic, environmental, and genetic factors. To uncover a possible association between MBL2 gene polymorphisms and SLE, we analyzed functional polymorphisms in the promoter and first exon of the MBL2 gene in 134 Brazilian SLE patients and 101 healthy controls. Genotype and allele frequencies of MBL2 A/O polymorphism were significantly different between patients and controls, and the O allele was associated with an increased risk of SLE. An association between low mannose binding lectin (MBL) producer combined genotypes and increased risk for SLE was also reported. Furthermore, when stratifying SLE patients according to clinical and laboratory data, an association between the A/O genotype and nephritic disorders and between the X/Y genotype and antiphospholipid syndrome was evident. Combined genotypes responsible for low MBL production were more frequently observed in SLE patients with nephritis. Our results indicate MBL2 polymorphisms as possible risk factors for SLE development and disease-related clinical manifestations.

ABCB1 and ABCC1 variants associated with virological failure of first‐line protease inhibitors antiretroviral regimens in Northeast Brazil patients

The present study aims at evaluating the association between seven single nucleotide polymorphisms (SNPs) in five genes involved on antiretroviral pharmacokinetic pathways and virological failure in first line highly active antiretroviral therapy. Seven candidate polymorphisms (rs3842 and rs1045642 in ABCB1, rs212091 and rs3743527 in ABCC1, rs3745274 in CYP2B6, rs628031 in SLC22A1 and rs1517618 in SLCO3A1) were evaluated if they were associated with virological failure through logistic regression analysis. The study design was a retrospective cohort, analyzing 187 patients from Recife metropolitan region (Pernambuco, Brazil): among these 160 obtained complete suppression of HIV‐1 replication (responders) and were compared to 27 non‐responders, which underwent virological failure. There was no association between CYP2B6, SLC22A1, and SLCO3A1 SNPs and virological failure. Using logistic regression analysis, a significant association was detected between rs1045642 (3435C>T, ABCB1) and rs212091 (198217T>C; 3′‐UTR, ABCC1) with virological failure of first‐line antiretroviral regimens containing protease inhibitors, when controlled by clinical factors, such as sex, age and race. The present results could contribute to unravel the influence of genetic background in anti‐HIV‐1 therapy outcome and help in treatment personalization of Northeast Brazil HIV infected patients.

Mannose binding lectin and mannose binding lectin-associated serine protease-2 genes polymorphisms in human T-lymphotropic virus infection

Variations in genes involved in the immune response pathways may influence the interaction between viruses (such as Human T‐lymphotropic virus, HTLV‐1) and the host. The mannose binding lectin (MBL) and its associated serine protease type 2 (MASP‐2) promote the activation of the lectin pathway of the complement system. As the interaction of complement system with HTLV‐1 is not well understood, the MBL2 promoter/exon 1 polymorphisms and a MASP2 missense polymorphism were examined in a Northeast Brazilian population, looking for a possible relationship between these variations and the susceptibility to HTLV‐1 infection. The present study describes an association between a polymorphism in the MASP2 gene and susceptibility to HTLV‐1 infection, and provides further evidence of an association between the MBL2 gene and HTLV‐1 infection. These findings suggest an important role of the complement system activation, via the lectin pathway, in the susceptibility to HTLV‐1 infection. J Med. Virol. 85:1829–1835, 2013.

Microcephaly prevalence in infants born to zika virus-infected women: A systematic review and meta-analysis

Zika virus is an emergent flavivirus transmitted by Aedes genus mosquitoes that recently reached the Americas and was soon implicated in an increase of microcephaly incidence. The objective of the present study is to systematically review the published data and perform a meta-analysis to estimate the prevalence of microcephaly in babies born to Zika virus-infected women during pregnancy. We searched PubMed and Cochrane databases, included cohort studies, and excluded case reports and case series publications. We extracted sample sizes and the number of microcephaly cases from eight studies, which permitted a calculation of prevalence rates that are pooled in a random-effects model meta-analysis. We estimated the prevalence of microcephaly of 2.3% (95% CI = 1.0–5.3%) among all pregnancies. Limitations include mixed samples of women infected at different pregnancy times, since it is known that infection at the first trimester is associated with higher risk to congenital anomalies. The estimates are deceptively low, given the devastating impact the infection causes over children and their families. We hope our study contributes to public health knowledge to fight Zika virus epidemics to protect mothers and their newborns.

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.

Tumor necrosis factor (TNF) alpha and interleukin (IL) 18 genes polymorphisms are correlated with susceptibility to HPV infection in patients with and without cervical intraepithelial lesion

Abstract Background: The Human Papillomavirus (HPV) predisposes 500 000 women to cervical cancer. Host genetic background may facilitate virus persistence in the uterine cervix. Polymorphisms in regulatory and coding regions of cytokine genes have been associated with susceptibility to some human diseases. Aim: This study aims at investigating whether TNFA -308 G/A and IL18 -137 G/C and -607 C/A polymorphisms are associated with susceptibility to HPV infection/progression to high-grade squamous intraepithelial lesion (HSIL). Subjects and methods: One hundred and twenty-two HPV infected and 132 HPV negative women (the latter used as healthy controls) were analysed. TNFA -308 G/A and IL18 (-137G/C and -607 C/A) polymorphisms were analysed using specific sequence polymorphism PCR (SSP-PCR). Univariate statistical analysis and a logistic regression were performed. Results: The TNFA -308A allele was associated with susceptibility to HPV infection (p = 0.0008), while the IL18 -607A allele conferred protection against HPV infection (p = 0.0043). TNFA -308 G/A and IL18 (-137G/C and -607 C/A) polymorphisms were not associated with development of cervical lesions (p > 0.05). An association was also observed between smoking and susceptibility to the development of HSIL. Conclusion: The findings suggest an association between two TNFA SNPs and susceptibility to HPV infection in women from Northeast Brazil. The results need to be functionally validated and replicated in other populations with different ethnic backgrounds.

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.

Frequency of the CCR5-delta32 allele in Brazilian populations: A systematic literature review and meta-analysis

The CCR5 is a chemokine receptor widely expressed by several immune cells that are engaged in inflammatory responses. Some populations have individuals exhibiting a 32bp deletion in the CCR5 gene (CCR5-delta32) that produces a truncated non-functional protein not expressed on the cell surface. This polymorphism, known to be associated with susceptibility to infectious and inflammatory diseases, such as osteomyelitis, pre-eclampsia, systemic lupus erythematous, juvenile idiopathic arthritis, rheumatoid arthritis and HIV/AIDS, is more commonly found in European populations with average frequency of 10%. However, it is also possible to observe a significant frequency in other world populations, such as the Brazilian one. We performed a systematic review and meta-analysis of CCR5-delta32 genetic association studies in Brazilian populations throughout the country to estimate the frequency of this polymorphism. We also compared CCR5-delta32 frequencies across Brazilian regions. The systematic literature reviewed studies involving delta32 allele in Brazilian populations published from 1995 to 2015. Among the reviewed literature, 25 studies including 30 Brazilian populations distributed between the North, Northeast, South and Southeast regions were included in our meta-analysis. We observed an overall allelic frequency of 4% (95%-CI, 0.03-0.05), that was considered moderate and, notably, higher than some European populations, such as Cyprus (2.8%), Italy (3%) and Greece (2.4%). Regarding the regional frequency comparisons between North-Northeast (N-NE) and South-Southeast (S-SE) regions, we observed an allelic frequency of 3% (95%-CI, 0.02-0.04) and 4% (95%-CI, 0.03-0.05), respectively. The populations from S-SE regions had a slightly higher CCR5-delta32 frequency than N-NE regions (OR=1.41, p=0.002). Although there are several studies about the CCR5-delta32 polymorphism and its effect on the immune response of some infectious diseases, this report is the first meta-analysis study that provides a descriptive study of the distribution of CCR5-delta32 allele in Brazilian population.