Identification of Genomic Variants Associated with the Risk of Acute Lymphoblastic Leukemia in Native Americans from Brazilian Amazonia.

A number of genomic variants related to native American ancestry may be associated with an increased risk of developing Acute Lymphoblastic Leukemia (ALL), which means that Latin American and hispanic populations from the New World may be relatively susceptible to this disease. However, there has not yet been any comprehensive investigation of the variants associated with susceptibility to ALL in traditional Amerindian populations from Brazilian Amazonia. We investigated the exomes of the 18 principal genes associated with susceptibility to ALL in samples of 64 Amerindians from this region, including cancer-free individuals and patients with ALL. We compared the findings with the data on populations representing five continents available in the 1000 Genomes database. The variation in the allele frequencies found between the different groups was evaluated using Fisher's exact test. The analyses of the exomes of the Brazilian Amerindians identified 125 variants, seven of which were new. The comparison of the allele frequencies between the two Amerindian groups analyzed in the present study (ALL patients vs. cancer-free individuals) identified six variants (rs11515, rs2765997, rs1053454, rs8068981, rs3764342, and rs2304465) that may be associated with susceptibility to ALL. These findings contribute to the identification of genetic variants that represent a potential risk for ALL in Amazonian Amerindian populations and might favor precision oncology measures.

Association of the rs4646994 in ACE gene with susceptibility to tuberculosis in a region of the Brazilian Amazon.

Background: Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacterium tuberculosis and represents an important global public health issue. Single-nucleotide polymorphisms and INDELs are common genetic variations that can be located in genes associated with immune response and, therefore, they may have direct implications over the phenotype of susceptibility to infections like tuberculosis. This study aimed to investigate the association between the 17 genetic polymorphisms and susceptibility to tuberculosis in a Brazilian population. Methods: This case-control study enrolled 283 individuals with active tuberculosis and 145 health care workers. Four INDELs and 13 single nucleotide polymorphisms and were genotyped using Multiplex PCR method and TaqMan SNP Genotyping Assays. Group comparisons for categorical variables were performed using the chi-squared test, whilst the t-Student test was used to analyze the continuous variables. Multiple logistic regression analyses were performed to estimate the odds ratio (OR) with 95% confidence intervals (CI). Deviation from Hardy-Weinberg equilibrium was assessed using chi-squared tests with Bonferroni correction. The results were analyzed comparing the genotypic distributions adopting the dominant model and the estimated values ​​of p corrected for multiple tests through FDR (False Discovery Rate) test. Results: The HWE test confirmed that the genotypic frequencies for polymorphisms were balanced. The frequency of Del allele was 73 and 75%, in cases and controls respectively. Frequency of Del allele was significantly higher in the control group than TB group. The homozygous Del/Del genotype was present in 51.6% of cases and 58.6% of controls. The rare Ins/Ins genotype was present in only 7.6% of controls and 6% of cases. The ACE Del/Del genotype was significantly higher in the cases than in controls revealing significant protection for TB in the domain model (OR = 0.465; p < 0.005). Conclusions: The Del/Del genotype of the rs4646994 in ACE gene was associated with susceptibility to tuberculosis. The identification of genetic variants responsible for susceptibility to tuberculosis will allow the development of new diagnostic tools for tuberculosis infection. These studies will help improve control and the future eradication of this disease.

Exome Evaluation of Autism-Associated Genes in Amazon American Populations.

Autism spectrum disorder is a neurodevelopmental disorder, affecting one in 160 children worldwide. The causes of autism are still poorly understood, but research shows the relevance of genetic factors in its pathophysiology, including the CHD8, SCN2A, FOXP1 and SYNGAP1 genes. Information about the genetic influence on various diseases, including autism, in the Amerindian population from Amazon, is still scarce. We investigated 35 variants of the CHD8, SCN2A, FOXP1, and SYNGAP1 gene in Amazonian Amerindians in comparison with publicly available population frequencies from the 1000 Genomes Project database. Our study identified 16 variants in the Amerindian population of the Amazon with frequencies significantly different from the other populations. Among them, the SCN2A (rs17183814, rs75109281, and rs150453735), FOXP1 (rs56850311 and rs939845), and SYNGAP1 (rs9394145 and rs115441992) variants presented higher frequency than all other populations analyzed. In addition, nine variants were found with lower frequency among the Amerindians: CHD8 (rs35057134 and rs10467770), SCN2A (rs3769951, rs2304014, rs1838846, and rs7593568), FOXP1 (rs112773801 and rs56850311), and SYNGAP1 (rs453590). These data show the unique genetic profile of the indigenous population of the Brazilian Amazon. Knowledge of these variants can help to understand the pathophysiology and diagnosis of autism among Amerindians, Brazilians, and in admixed populations that have contributions from this ethnic group.

Influence of Polymorphism on the NFkB1 Gene (rs28362491) on the Susceptibility to Sarcopenia in the Elderly of the Brazilian Amazon.

BACKGROUND: Sarcopenia is a disease characterized by progressive reduction in muscle mass and strength or function. Although it is known that sarcopenia may be associated with environmental factors, studies suggest the identification of genes related to skeletal muscle maintenance that explain the susceptibility to the disease. OBJECTIVE: To analyze the influence of NFkB1 gene polymorphism on susceptibility to sarcopenia in the elderly. METHODS: This is a case-control study, which included 219 elderly people, 74 elderly people with sarcopenia, and 145 without sarcopenia. Samples were analyzed for NFkB1 gene polymorphism (rs28362491), genotyped in PCR, and followed by fragment analysis. To avoid misinterpretation due to population substructure, we applied a previously developed set of 61 informative ancestral markers that were genotyped by multiplex PCR. We used logistic regression to identify differences in genotypic frequencies between elderly people with and without sarcopenia. RESULTS: It was observed that the NFkB1 gene polymorphism presented frequencies of 24%, 50%, and 26% for the genotype DEL/DEL, DEL/INS, and INS/INS, respectively. Furthermore, elderly individuals with the INS/INS genotype had increased chances (p = 0.010; OR:2.943; 95%CI:1.301-6.654) for the development of sarcopenia. CONCLUSION: The INDEL polymorphism of the NFkB1 gene (rs28362491) may influence the susceptibility to sarcopenia in the elderly in elderly people in the Amazon.

Polymorphisms in the CYP2A6 and ABCC4 genes are associated with a protective effect on chronic myeloid leukemia in the Brazilian Amazon population.

BACKGROUND: Susceptibility to Chronic Myeloid Leukemia (CML) may be modulated by genetic variables. However, the majority of previous investigations have focused on genetically homogeneous populations, resulting in a lack of evidence on how genetic factors may influence the development of CML in miscegenated populations. We analyzed 30 polymorphisms in genes related to DNA repair, folate metabolism, transmembrane transport, xenobiotic metabolism, and pyrimidine synthesis in relation to their potential role in the susceptibility of the individual to CML. METHODS: This case-control study included 126 healthy individuals and 143 patients diagnosed with CML from the admixed population of the Brazilian Amazon. The samples were genotyped by real-time PCR and the genetic ancestry analysis was based on a panel of 61 ancestry informative markers. RESULTS: The results indicated a protective effect against the development of CML in carriers of the C allele of the rs28399433 (CYP2A6) gene and the CC genotype of the rs3742106 (ABCC4) gene. CONCLUSION: Our findings suggest that the rs3742106 (ABCC4) and rs28399433 (CYP2A6) polymorphisms may modulate susceptibility to CML in a population of the Brazilian Amazon region.

High Frequency of Hb E-Saskatoon (HBB: c.67G > A) in Brazilians: A New Genetic Origin?

Hb E-Saskatoon [ß22(B4)Glu→Lys, HBB: c.67G > A] is a rare, nonpathological ß-globin variant that was first described in a Canadian woman of Scottish and Dutch ancestry and has since then been detected in several populations. The aim of the present study was to identify the origin of Hb E-Saskatoon in Brazil using ß-globin haplotypes and genetic ancestry in carriers of this hemoglobin (Hb) variant. Blood samples were investigated by isoelectric focusing (IEF) and high performance liquid chromatography (HPLC) using commercial kits. Hb E-Saskatoon was confirmed by amplification of the HBB gene, followed by sequence analysis. Haplotypes of the ß-globin gene were determined by polymerase chain reaction (PCR), followed by digestion with specific restriction enzymes. Individual ancestry was estimated with 48 biallelic insertion/deletions using three 16-plex PCR amplifications. The IEF pattern was similar to Hbs C (HBB: c.19G > A) and Hb E (HBB: c.79G > A) [isoelectric point (pI): 7.59-7.65], and HPLC results showed an elution in the Hb S (HBB: c.20A > T) window [retention time (RT): 4.26-4.38]. DNA sequencing of the amplified ß-globin gene showed a mutation at codon 22 (GAA>AAA) corresponding to Hb E-Saskatoon. A total of 11 cases of this variant were identified. In nine unrelated individuals, Hb E-Saskatoon was in linkage disequilibrium with haplotype 2 [+ - - - -]. All subjects showed a high degree of European contribution (mean = 0.85). Hb E-Saskatoon occurred on the ß-globin gene of haplotype 2 in all Brazilian carriers. These findings suggest a different genetic origin for this Hb variant from that previously described.

Does ethnic ancestry play a role in smoking?

The higher proportion of smokers among Black people in Brazil has been attributed to socioeconomic disparities, but genetic factors could also contribute for this finding. This study aimed at investigating associations between smoking status with genetically defined ethnic ancestry and socioeconomic features in Brazilians. Blood samples were collected from 448 volunteers (66.7% male; age: 37.1 ± 11.4 years) classified as current smokers (CS: 60.9%), former smokers (FS: 8.9%) and never smokers (NS: 30.1%). Individual interethnic admixtures were determined using a 48 insertion-deletion polymorphisms ancestry-informative-marker panel. CS showed a lower amount of European ancestry than NS (0.837 ± 0.243 X 0.883 ± 0.194, p ≤ 0.05) and FS (0.837 ± 0.243 X 0.864 ± 0.230, p ≤ 0.05), and a higher proportion of African Sub-Saharan ancestry than FS (0.128 ± 0.222 X 0.07 ± 0.174, p ≤ 0.05) and NS (0.128 ± 0.222 X 0.085 ± 0.178, p ≤ 0.05). NS reported a higher number of years in school than CS (11.2 ± 3.7 X 8.9 ± 3.8, p ≤ 0.001). CS were less common in economic Class A (30%) and more common in Class B (56.8%). In multivariate analysis, only lower number of school years and lower economic class were associated with higher chances for CS. The use of genetic molecular markers for characterizing ethnic background confirmed that socioeconomic disparities are the main determinants of higher smoking rates among Blacks in Brazil.

Autosome STRs in native South America-Testing models of association with geography and language.

Information on one Ecuadorian and three Peruvian Amerindian populations for 11 autosomal short tandem repeat (STR) loci is presented and incorporated in analyses that includes 26 other Native groups spread all over South America. Although in comparison with other studies we used a reduced number of markers, the number of populations included in our analyses is currently unmatched by any genome-wide dataset. The genetic polymorphisms indicate a clear division of the populations into three broad geographical areas: Andes, Amazonia, and the Southeast, which includes the Chaco and southern Brazil. The data also show good agreement with proposed hypotheses of splitting and dispersion of major language groups over the last 3,000 years. Therefore, relevant aspects of Native American history can be traced using as few as 11 STR autosomal markers coupled with a broad geographic distribution of sampled populations.

Autosomal STR analyses in native Amazonian tribes suggest a population structure driven by isolation by distance.

Eleven short tandem repeat loci (CSF1PO, D3S1358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51, D21S11, TH01, and TPOX) were investigated in 232 individuals from 6 Amazonian native tribes (Tiriyó, Waiãpi, Zoé, Urubu-Kaapor, Awa-Guajá, and Parakanã). We added the new data to a database that included five previously typed native populations from the same area (Wai Wai, Gavião, Zoró, Suruí, and Xavante). The results presented here concern this new data set, which accounts for 526 individuals in total. We tested whether major geographic or linguistic barriers to gene flow exist among such human groups and tried to find a possible anthropological or ethnological explanation for such patterns. We measured the average heterozygosity (H) and the number of alleles (N(A) ) and found that both are lower than values observed in populations of different ethnic backgrounds, such as European or African descendants. Despite such a result, we found high between-population variation; lower H and/or N(A) values were obtained from four isolated tribes that came into contact with external nonnative populations in recent times (1921-1989). By applying analysis of molecular variance, generalized hierarchical modeling, and the Structure Bayesian analysis, we were not able to detect any significant geographic or linguistic barrier to gene flow. Geographic autocorrelation analysis suggests that the genetic structure of native Amazonian tribes is better explained by isolation by distance because the level of genetic similarity decreases according to linear geographic distance, reaching null or negative values at a scale of 300 km.

Serological and molecular evidence of HTLV-I infection among Japanese immigrants living in the Amazon region of Brazil.

Human T-lymphotropic virus type I (HTLV-I) infection was investigated in 168 Japanese immigrants (64 males and 104 females) living in the Tome-Acu county located in the State of Para, Brazil. The serological screening was performed using an enzyme-linked immunosorbent assay, and showed the presence of anti-HTLV in four women whose ages ranged from 50 to 88. Confirmation of infection and discrimination HTLV typing was performed using a nested PCR on the extracted DNA targeting the pX region. In three of the samples, infection was confirmed to be HTLV-I. Sequencing HTLV-I 5'LTR and the RFLP pattern using DraI and SacI endonucleases indicated that the virus is a member of the Cosmopolitan group. These three women originated from the Kyushu region, though two of the corresponding HTLV-I strains were phylogenetically related to the Japanese subgroup and the third to the Transcontinental subgroup, which probably reflects the geographical origin of the infected individuals. The Japanese community residing in the northern Brazil apparently have not contributed to increase the prevalence of HTLV-I in the country.