ADRB2 and ADCY9 Sequence Variations in Brazilian Asthmatic Patients.

Asthma is a chronic inflammatory respiratory condition, characterized by variable airflow limitation, leading to clinical symptoms such as dyspnea and chest tightness. These symptoms result from an underlying inflammatory process. The ß2 agonists are bronchodilators prescribed for the relief of the disease. Nevertheless, their efficacy exhibits substantial interindividual variability. Currently, there is widespread recognition of the association between specific genetic variants, predominantly located within the ADRB2 and ADCY9 genes and their efficacy. This association, usually represented by the presence of non-synonymous single nucleotide polymorphisms (SNPs) have a strong impact in the protein functionality. The prevalence of these mutations varies based on the ethnic composition of the population and thus understanding the profiles of variability in different populations would contribute significantly to standardizing the use of these medications. In this study, we conducted a sequence-based genotyping of the relevant SNPs within the ADRB2 and ADCY9 genes in patients undergoing treatment with bronchodilators and/or corticosteroids at two healthcare facilities in the state of Rio de Janeiro, Brazil. We investigated the presence of c.46A>G, c.79C>G, c.252G>A, and c.491C>T SNPs within the ADRB2, and c.1320018 A>G within the ADCY9. Our results were in line with existing literature data with both for individuals in Brazil and Latin American.

Cost-Effectiveness of Digital Health Interventions for Asthma or COPD: Systematic Review.

OBJECTIVE: Digital interventions such as remote monitoring of symptoms and physiological measurements have the potential to reduce the economic burden of asthma and chronic obstructive pulmonary disease (COPD) but their cost-effectiveness remains unclear. This systematic review of randomised controlled trials (RCT) aims to assess whether digital health interventions can be cost-effective in these patients. DESIGN: Systematic review of RCTs. Study quality was assessed using RoB2 tool. DATA SOURCES: Systematic search in three databases: PubMed, Scopus and Web of Science. ELIGIBILITY CRITERIA: Studies were eligible if they were RCTs with health economic evaluations assessing participants with asthma and/or COPD and comparing a digital health intervention to standard of care. RESULTS: We included 35 RCTs, of which 21 were related to COPD, 13 to asthma and one to both diseases. Overall, studies assessed four categories of digital health interventions: (i) Electronic patient diaries (n = 4), (ii) real-time monitoring (n = 19), (iii) teleconsultations (n = 6) and (iv) others (n = 6). Eleven studies performed a full economic evaluation analysis, while 24 studies performed a partial economic analysis. Most studies involving real-time monitoring or teleconsultations presented economic results in favour of digital health interventions (indicating them to be cost-effective or less expensive than the standard of care). Mixed results were obtained for electronic patient diaries. In the studies that conducted a full economic analysis, the incremental cost-effectiveness ratio (ICER) ranged from 3530,93€/QALY and 286,369,28€/QALY. In the studies that conducted a partial economic analysis, the cost differences between the intervention group and the control group ranged from 0,12€ and 85,217,86€. Half studies with low risk of bias concluded that the intervention was economically favourable. CONCLUSION: Although costs varied based on intervention type, follow-up period and country, most studies report digital health interventions to be affordable or associated with decreased costs. TRIAL REGISTRATION: PROSPERO: CRD42023439195.

Complete phylogeny of Micrathena spiders suggests multiple dispersal events among Neotropical rainforests, islands and landmasses, and indicates that Andean orogeny promotes speciation.

The Neotropical region is the most diverse on the planet, largely owing to its mosaic of tropical rainforests. Multiple tectonic and climatic processes have been hypothesized to contribute to generating this diversity, including Andean orogeny, the closure of the Isthmus of Panama, the GAARlandia land bridge and historical connections among currently isolated forests. Micrathena spiders are diverse and widespread in the region, and thus a complete phylogeny of this genus allows the testing of hypotheses at multiple scales. We estimated a complete, dated phylogeny using morphological data for 117 Micrathena species and molecular data of up to five genes for a subset of 79 species. Employing eventc-based approaches and biogeographic stochastic mapping while considering phylogenetic uncertainty, we estimated ancestral distributions, the timing and direction of dispersal events and diversification rates among areas. The phylogeny is generally robust, with uncertainty in the position of some of the species lacking sequences. Micrathena started diversifying around 25 Ma. Andean cloud forests show the highest in-situ speciation, while the Amazon is the major dispersal source for adjacent areas. The Dry Diagonal generated few species and is a sink of diversity. Species exchange between Central and South America involved approximately 23 dispersal events and started ~20 Ma, which is consistent with a Miocene age for the Isthmus of Panama closure. We inferred four dispersal events from Central America to the Antilles in the last 20 Myr, indicating the spiders did not reach the islands through the GAARlandia land bridge. We identified important species exchange routes among the Amazon, Andean cloud forests and Atlantic forests during the Plio-Pleistocene. Sampling all species of the genus was fundamental to the conclusions above, especially in identifying the Andean forests as the area that generated the majority of species. This highlights the importance of complete taxonomic sampling in biogeographic studies.

Global Diversification of Anelosimus Spiders Driven by Long-Distance Overwater Dispersal and Neogene Climate Oscillations.

Vicariance and dispersal events, combined with intricate global climatic history, have left an imprint on the spatiotemporal distribution and diversity of many organisms. Anelosimus cobweb spiders (Theridiidae), are organisms ranging in behavior from solitary to highly social, with a cosmopolitan distribution in temperate to tropical areas. Their evolutionary history and the discontinuous distribution of species richness suggest that 1) long-distance overwater dispersal and 2) climate change during the Neogene (23-2.6 Ma), may be major factors in explaining their distribution and diversification. Here, we test these hypotheses, and explicitly test if global Miocene/Pliocene climatic cooling in the last 8 Ma affected Anelosimus radiation in parallel in South America and Madagascar. To do so, we investigate the phylogeny and spatiotemporal biogeography of Anelosimus through a culmination of a 20-year comprehensive global sampling at the species level (69 species, including 84% of the known 75 species worldwide, represented by 268 individuals) using nucleotide data from seven loci (5.5 kb). Our results strongly support the monophyly of Anelosimus with an Oligocene ($\sim $30 Ma) South American origin. Major clades on other continents originate via multiple, long-distance dispersal events, of solitary or subsocial-but not social-lineages, from the Americas. These intercontinental dispersals were to Africa, Madagascar (twice), and SE Asia/Australasia. The early diversification of Anelosimus spiders coincides with a sudden thermal increase in the late Oligocene ($\sim $27-25 Ma), though no causal connection can be made. Our results, however, strongly support the hypothesis that global Neogene climatic cooling in the last 8 Ma drove Anelosimus radiation in parallel in South America and Madagascar, offering a rare empirical evidence for diversification of a socially diverse group driven by an interplay between long-distance dispersal and global Neogene climatic changes. [Cobweb spiders; diversification; global biogeography; long-distance dispersal; molecular phylogenetics; neogene climate changes; sociality; vicariance.].

Systematics and evolution of ground spiders revisited (Araneae, Dionycha, Gnaphosidae).

Gnaphosidae Pocock are a very diverse spider family with remarkable spinning organ morphology. Although the family has received intense taxonomic attention in recent years, its intergeneric relationships remain obscure. A phylogenetic analysis of Gnaphosidae genera was performed to untangle the evolutionary history of the family. A matrix of 324 morphological characters, scored for 71 gnaphosid genera and 29 outgroup taxa, was analysed through parsimony and Bayesian phylogenetic inference. Gnaphosidae are not recovered as a monophyletic group, neither were most of the previously proposed intrafamiliar groupings. In accordance with the phylogenetic results obtained, Vectius Simon and Hemicloea Thorell are transferred to Trochanteriidae, and Xenoplectus Schiapelli & Gerschman de Pikelin to Liocranidae. Micaria Westring, Nauhea Forster and Verita Ramírez & Grismado (and some related genera) are probably not gnaphosids, although their phylogenetic placement is uncertain. Gnaphosidae s.s. are defined as spiders with enlarged piriform gland spigots, longer and wider than the major ampullate gland spigots. Within Gnaphosidae s.s., well-supported clades allow the redefinition, on the basis of quantitative phylogenetic evidence, of Gnaphosinae Pocock, Zelotinae Platnick, Herpyllinae Platnick, Drassodinae Simon, Prodidominae Simon rank res. and the newly proposed Leptodrassinae subfam. nov. Many genera are not assigned to subfamily given their poorly supported and unstable relationships. The homology and evolution of structures such as the claw tuft clasper, the spinning organs and the modification of cheliceral promargin are discussed.

Spider species richness and sampling effort at Cracraft´S Belém Area of Endemism.

A list of spider species is presented for the Belém Area of Endemism, the most threatened region in the Amazon Basin, comprising portions of eastern State of Pará and western State of Maranhão, Brazil. The data are based both on records from the taxonomic and biodiversity survey literature and on scientific collection databases. A total of 319 identified species were recorded, with 318 occurring in Pará and only 22 in Maranhão. About 80% of species are recorded at the vicinities of the city of Belém, indicating that sampling effort have been strongly biased. To identify potentially high-diversity areas, discounting the effect of variations in sampling effort, the residues of a linear regression between the number of records and number of species mapped in each 0.25°grid cells were analyzed. One grid, representing the Alto Turiaçu Indigenous land, had the highest deviation from the expected from the linear regression, indicating high expected species richness. Several other grid cells showed intermediate values of the regression residuals, indicating species richness moderately above to the expected from the model.

Strong spatial structure, Pliocene diversification and cryptic diversity in the Neotropical dry forest spider Sicarius cariri.

The Brazilian Caatinga is part of the seasonally dry tropical forests, a vegetation type disjunctly distributed throughout the Neotropics. It has been suggested that during Pleistocene glacial periods, these dry forests had a continuous distribution, so that these climatic shifts may have acted as important driving forces of the Caatinga biota diversification. To address how these events affected the distribution of a dry forest species, we chose Sicarius cariri, a spider endemic to the Caatinga, as a model. We studied the phylogeography of one mitochondrial and one nuclear gene and reconstructed the paleodistribution of the species using modelling algorithms. We found two allopatric and deeply divergent clades within S. cariri, suggesting that this species as currently recognized might consist of more than one independently evolving lineage. Sicarius cariri populations are highly structured, with low haplotype sharing among localities, high fixation index and isolation by distance. Models of paleodistribution, Bayesian reconstructions and coalescent simulations suggest that this species experienced a reduction in its population size during glacial periods, rather than the expansion expected by previous hypotheses on the paleodistribution of dry forest taxa. In addition to that, major splits of intraspecific lineages of S. cariri took place in the Pliocene. Taken together, these results indicate S. cariri has a complex diversification history dating back to the Tertiary, suggesting the history of dry forest taxa may be significantly older than previously thought.

Three new species and new records of the orb-weaving spider genus Philoponella (Araneae, Uloboridae) from Brazil and Ecuador.

Three new species of the spider genus Philoponella Mello-Leitão, 1917 are described: Philoponella opelli n. sp. from Brazil and Ecuador, and Philoponella fluviidulcifis n. sp. , and Philoponella duopunctata n. sp. from Brazil. New records for Philoponella vittata (Keyserling, 1881), P. republicana (Simon, 1891), P. fasciata (Mello-Leitão, 1917) and P. divisa Opell, 1979 are provided for Brazil and Ecuador.

Two new species of Fernandezina Birabn, 1951 (Araneae, Palpimanidae) from cave and epigean habitats in Brazil.

The South American palpimanid genus Fernandezina Birabn currently comprises 15 described species, all known from epigean environments. Representatives of Fernandezina are easily recognized by the unexpanded femora I in both sexes and by the dorsally extended opisthosomal scutum in males. Herein, F. fernandoi sp. nov. is described based on males and females from hypogean environments and F. angeloi sp. nov. is described based on a single male from a nearby epigean environment, both in Brazil. Additionally, we provide an identification key for the species of the genus.

The desert wolf-spider genus Xenoctenus: two endemic species from the Brazilian Caatinga, and a redescription of the type-species, X. unguiculatus (Araneae: Xenoctenidae).

The Caatinga is a nucleus of seasonally dry tropical forest (SDTF) known as a hotspot of diversification and endemism. Despite its importance, this biome is still insufficiently sampled, resulting in extensive knowledge gaps regarding its species richness and composition. In this study we report two species of Xenoctenidae that are endemic to, and widely distributed in the Caatinga. We redescribe and illustrate Odo vittatus (Mello-Leito, 1936), the only xenoctenid species previously known from the Caatinga. We transfer this species to Xenoctenus Mello-Leito,1938, a genus currently known from six species restricted to Argentina, Bolivia, and Colombia. We also newly describe the male of Xenoctenus vittatus comb. nov. and provide new records of this species, which was hitherto known only from the type-locality, throughout the Caatinga and nearby semiarid vegetation formations. We also describe and illustrate a new species, Xenoctenus kaatinga sp. nov., based on males and female specimens collected throughout the Caatinga. Additionally, we propose diagnostic characters for Xenoctenus and redescribe the type-species, X. unguiculatus.

Determination of NAT2 Genotypes in a Cohort of Patients with Suspected TB in the State of Rio de Janeiro.

The human N-acetyltransferase 2 enzyme, encoded by the NAT2 gene, plays an important role in the metabolism of isoniazid, the main drug used to treat tuberculosis. The interindividual variation in the response of patients to drug treatment for tuberculosis may be responsible for the occurrence of unfavorable outcomes. The presence of polymorphisms in genes associated with the metabolism and transport of drugs, receptors, and therapeutic targets has been identified as a major determinant of this variability. The objective of this study was to identify the genetic profile of NAT2 in the study population. Using the obtained genomic DNA followed by PCR amplification and sequencing, the frequency of nine SNPs as well as alleles associated with slow (47.9%), intermediate (38.7%), and fast acetylation phenotypes (11.3%), in addition to those whose phenotype has not yet been characterized (2.1%), was estimated. The NAT2*5B allele was identified more frequently (31.3%). The description of SNPs in pharmacogenes and the establishment of their relationship with the pharmacokinetics of an individual offer an individualized approach that allows us to reduce the unfavorable outcomes of a therapy, ensure better adherence to treatment, prevent the emergence of MDR strains, reduce the cost of treatment, and improve the quality of patients' lives.

Factors Affecting Usage of a Digital Asthma Monitoring Application by Old-Age Asthmatics Living in Inner Central Portugal.

Purpose: To analyse factors affecting the ability to use the digital asthma monitoring application Mask-Air® in old-age individuals living in inland Portugal. Patients and Methods: In this observational study, patients with medically confirmed asthma who agreed to participate were interviewed and subdivided into Non-users Group: those who could not use the application and Users Group: those who could. Sociodemographic and psychological data, comorbidities, and asthma status were compared between groups. Assessment of reasons for refusal was based on a 6-item questionnaire. Results: Among the 72 sequentially recruited patients (mean age±SD 73.26±5.43 yrs; 61 women; 11 men), 44 (61.1%; mean age±SD 74.64±5.68 yrs; 38 women; 6 men)) were included in Non-users Group and 28 (38.9%; mean age±SD 71.11±4.26 yrs; 23 women; 5 men) in Users Group. Non-users Group patients were significantly older, had lower socioeconomic level, and more frequently had severe asthma (25% vs 3.6%; Odds ratio=0.08 (95% CI=0.01-0.81; p=0.033)) and diabetes (32.6% vs 7.4%; Odds ratio=0.17 (95% CI=0.03-0.80; p=0.025)) than Users Group. The main reasons for not using the App were "Lack of required hardware" (n=35) and "Digital illiteracy" (n=26), but lack of interest to use the App among those who had conditions to use it was uncommon. Conclusion: Most old-age asthmatics living in Beira Interior either lack a smartphone or digital skills, which are significant obstacles to implementing app-based monitoring studies.

This study was done to see whether it was possible to use a mobile phone application (App) to help old-age asthmatics living in inner Central Portugal better monitor and self-manage their disease. The researchers interviewed a group of 72 patients with proven asthma who agreed to participate in the study. This group was subdivided into two subgroups: Non-users Group (44 patients) included those who could not use the App because they did not have a smartphone; Users Group (28 patients) included those who had all the conditions to use the App. Patients were helped to download the App (called MASK-Air), were given a thorough explanation about it, and about how it should be used on a daily basis to monitor their asthma symptoms. The researchers found that patients in Non-users Group were significantly older, had worse socioeconomic conditions, and more often had severe asthma and diabetes. They also discovered that the main reasons for not using the App were lack of a smartphone and not knowing how to use a smartphone. These results show that lacking a smartphone and not knowing how to use digital tools are frequent situations in old-age asthmatics living in inner Central Portugal, and these may be obstacles for patients in monitoring their own asthma symptoms.

Extensive low-density Plasmodium falciparum reservoir in the island of Príncipe, an isolated malaria pre-elimination setting.

OBJECTIVES: The isolated Príncipe is at the malaria pre-elimination stage. Autochthonous clinical cases have been reported sporadically on the island, signaling the possibility of a sizable subpatent (i.e., rapid diagnostic test- and microscopy-negative and polymerase chain reaction [PCR]-positive) parasite reservoir. METHODS: Asymptomatic low-density infections were detected by quantitative PCR (qPCR) targeting Plasmodium falciparum multicopy genes (pfr364 and varATS). Positivity rates were assayed for samples surveyed by active case detection (n = 112) and reactive case detection (n = 221) in 2022. RESULTS: qPCR unveiled 70% of low parasitemia carriers, reaching >90% in reactive case detection. The high P. falciparum prevalence was confirmed by the two high-sensitivity qPCR protocols. Higher positivity rates were observed in the localities where most malaria cases were reported in 2022. Most parasitemias were very low (<2 Pf /µl). CONCLUSIONS: These findings suggest that pre-elimination surveillance can benefit from the routine application of highly sensitive tools to unveil otherwise invisible but potentially relevant parasite populations.

Genetic ancestry proportion influences risk of adverse events from tuberculosis treatment in Brazil.

Tuberculosis (TB) treatment is highly effective, but response to therapy can vary by geography, race, and ethnicity. We assessed for differences in TB treatment response in a representative and heterogeneous Brazilian population. We estimated genetic ancestry proportion according to major ancestry groups (African, European, and Amerindian ancestry) in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil cohort. RePORT-Brazil is an observational prospective cohort study of individuals with newly-diagnosed, culture-confirmed, pulmonary TB. TB treatment outcomes that were attributed to TB treatment included Grade 2 or higher adverse drug reaction (ADR), Grade 3 or higher ADR, hepatic ADR, and failure/recurrence. Ancestry proportion was the main predictor in logistic regression for each outcome, with adjustments for candidate confounders. There were 941 pulmonary TB patients included in this study. We observed a decreased risk of Grade 2+ ADR when African ancestry proportion increased by 10% (Odds Ratio [OR] 0.41, 95% Confidence Interval [CI] 0.20 -0.85) and an increased risk for Grade 2+ ADR with increasing European ancestry (OR 2.84, 95% CI 1.47 - 5.48). We then performed the same analysis adding HIV status as an interaction term. The decreased risk for Grade 2+ ADR seen for African ancestry proportion did not hold for persons living with HIV; we observed increased risk for Grade 2+ ADR with increasing African ancestry proportion. There were no associations with Amerindian ancestry or for other treatment outcomes. In this Brazilian TB cohort, toxicity risk was associated with African and European ancestry, divergent, and affected by HIV. #RePORT-Brazil Consortium members include: Aline Benjamin and Flavia M. Sant'Anna Instituto Nacional de Infectologia Evandro Chagas, Fiocruz, Rio de Janeiro, Brazil Jamile Garcia de Oliveira and João Marine Clínica de Saúde Rinaldo Delmare, Rio de Janeiro, Brazil Adriana Rezende and Anna Cristina Carvalho Secretaria de Saúde de Duque de Caxias, Rio de Janeiro, Brazil Michael Rocha and Betânia Nogueira Instituto Brasileiro para Investigação da Tuberculose, Fundação José Silveira, Salvador, Brazil Alexandra Brito and Renata Spener Fundação Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Brazil Megan Turner Vanderbilt University Medical Center, Nashville, USA.

The spider genus Kukulcania in South America (Araneae: Filistatidae): a redescription of K. brevipes (Keyserling) and new records of K. hibernalis (Hentz).

Two species of the spider genus Kukulcania are known from South America. Kukulcania brevipes (Keyserling), originally described from Peru, is here diagnosed, illustrated and redescribed, with several new records provided for eastern Peru and northern Chile. The synanthropic Kukulcania hibernalis (Hentz) is illustrated and diagnosed, with several new records extending the distribution of this species from northern Venezuela to southern Brazil.

The six-eyed sand spiders of the genus Sicarius (Araneae: Haplogynae: Sicariidae) from the Brazilian Caatinga.

In this paper we revise the species of Sicarius (Araneae: Sicariidae) from the Brazilian Caatinga, the largest tropical dry forest nucleus in the world. We redescribe, designate a neotype and provide new records for Sicarius tropicus (Mello- Leitão, 1936), the only species previously known from the region, and describe three new species: S. cariri n. sp., S. diadorim n. sp. and S. ornatus n. sp. We report high intraspecific variation in the genitalic morphology of these species, especially in females. We also provide anecdotal observations on natural history and behavior of these species, including diet, mating behavior and clutch size. We include an identification key for Brazilian Caatinga species of Sicarius.

Frequencies of Cytochrome P450 2B6 and 2C8 Allelic Variants in the Mozambican Population.

BACKGROUND: The cytochrome P450 enzymes (CYP) play an important role in the metabolism of many therapeutic agents. The activities of different enzymes exhibit variability in different populations, which causes variations in drug response or toxicity. The CYP2B6 and CYP2C8 enzymes are encoded by polymorphic genes characterised by different single nucleotide polymorphisms (SNPs). Several of these CYP variants are often associated with slow metabolism phenotypes. This study aimed to analyse the frequencies of allelic variants of CYP2B6 and CYP2C8 in the Mozambican population. METHODS: Using a polymerase chain reaction and restriction fragment length polymorphism assay (PCR-RFLP), the frequencies of the allelic variants of CYP2B6 (c.64C>T, c.516G>T, c.777C>A, c.785A>G, c.1459C>T) and CYP2C8 (c.805A>T, c.416G>A, c.1196A>G, c.792C>G) were determined in 360 Mozambican blood donors. RESULTS: The frequencies of the allelic variants of the CYP2B6 gene were 0.057, 0.426, 0.0, 0.410, and 0.004. For the CYP2C8 gene, the frequencies of the allelic variants were 0.160, 0.048, 0.0, and 0.005. No significant differences were observed between the gender and geographic distribution of volunteers around the country. CONCLUSION: The frequencies of the allelic variants of the CYP2B6 and CYP2C8 genes were found to be homogeneously distributed in the Mozambican population and were comparable to other African populations. Further studies are required to explore the impact of these variants on the clinical response (efficacy and toxicity) of drugs, including antimalarials.

Pharmacogenetics of tuberculosis treatment toxicity and effectiveness in a large Brazilian cohort.

Background: Genetic polymorphisms have been associated with risk of anti-tuberculosis treatment toxicity. We characterized associations with adverse events and treatment failure/recurrence among adults treated for tuberculosis in Brazil. Methods: Participants were followed in Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil. We included persons with culture-confirmed drug-susceptible pulmonary tuberculosis who started treatment between 2015-2019, and who were evaluable for pharmacogenetics. Treatment included 2 months of isoniazid, rifampin or rifabutin, pyrazinamide, and ethambutol, then 4 months of isoniazid and rifampin or rifabutin, with 24 month follow-up. Analyses included 43 polymorphisms in 20 genes related to anti-tuberculosis drug hepatotoxicity or pharmacokinetics. Whole exome sequencing was done in a case-control toxicity subset. Results: Among 903 participants in multivariable genetic association analyses, NAT2 slow acetylator status was associated with increased risk of treatment-related grade 2 or greater adverse events, including hepatotoxicity. Treatment failure/recurrence was more likely among NAT2 rapid acetylators, but not statistically significant at the 5% level. A GSTM1 polymorphism (rs412543) was associated with increased risk of treatment-related adverse events, including hepatotoxicity. SLCO1B1 polymorphisms were associated with increased risk of treatment- related hepatoxicity and treatment failure/recurrence. Polymorphisms in NR1/2 were associated with decreased risk of adverse events and increased risk of failure/recurrence. In whole exome sequencing, hepatotoxicity was associated with a polymorphism in VTI1A , and the genes METTL17 and PRSS57 , but none achieved genome-wide significance. Conclusions: In a clinical cohort representing three regions of Brazil, NAT2 acetylator status was associated with risk for treatment-related adverse events. Additional significant polymorphisms merit investigation in larger study populations.

Human N-acetyltransferase 2 (NAT2) gene variability in Brazilian populations from different geographical areas.

Introduction: Several polymorphisms altering the NAT2 activity have already been identified. The geographical distribution of NAT2 variants has been extensively studied and has been demonstrated to vary significantly among different ethnic population. Here, we describe the genetic variability of human N-acetyltransferase 2 (NAT2) gene and the predominant genotype-deduced acetylation profiles of Brazilians. Methods: A total of 964 individuals, from five geographical different regions, were genotyped for NAT2 by sequencing the entire coding exon. Results: Twenty-three previously described NAT2 single nucleotide polymorphisms (SNPs) were identified, including the seven most common ones globally (c.191G>A, c.282C>T, c.341T>C, c.481C>T, c.590G>A, c.803A>G and c.857G>A). The main allelic groups were NAT2*5 (36%) and NAT2*6 (18.2%), followed to the reference allele NAT2*4 (20.4%). Combined into genotypes, the most prevalent allelic groups were NAT2*5/*5 (14.6%), NAT2*5/*6 (11.9%) and NAT2*6/*6 (6.2%). The genotype deduced NAT2 slow acetylation phenotype was predominant but showed significant variability between geographical regions. The prevalence of slow acetylation phenotype was higher in the Northeast, North and Midwest (51.3%, 45.5% and 41.5%, respectively) of the country. In the Southeast, the intermediate acetylation phenotype was the most prevalent (40.3%) and, in the South, the prevalence of rapid acetylation phenotype was significantly higher (36.7%), when compared to other Brazilian states (p < 0.0001). Comparison of the predicted acetylation profile among regions showed homogeneity among the North and Northeast but was significantly different when compared to the Southeast (p = 0.0396). The Southern region was significantly different from all other regions (p < 0.0001). Discussion: This study contributes not only to current knowledge of the NAT2 population genetic diversity in different geographical regions of Brazil, but also to the reconstruction of a more accurate phenotypic picture of NAT2 acetylator profiles in those regions.

TNF -308G>A single nucleotide polymorphism is associated with leprosy among Brazilians: a genetic epidemiology assessment, meta-analysis, and functional study.

Leprosy is an infectious disease caused by Mycobacterium leprae. Tumor necrosis factor (TNF) plays a key role in the host response. Some association studies have implicated the single nucleotide polymorphism TNF -308G>A in leprosy susceptibility, but these results are still controversial. We first conducted 4 association studies (2639 individuals) that showed a protective effect of the -308A allele (odds ratio [OR] = 0.77; P = .005). Next, results of a meta-analysis reinforced this association after inclusion of our new data (OR = 0.74; P = .04). Furthermore, a subgroup analysis including only Brazilian studies suggested that the association is specific to this population (OR = 0.63; P = .005). Finally, functional analyses using whole blood cultures showed that patients carrying the -308A allele produced higher TNF levels after lipopolysaccharide (LPS) (6 hours) and M. leprae (3 hours) stimulation. These results reinforce the association between TNF and leprosy and suggest the -308A allele as a marker of disease resistance, especially among Brazilians.