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1.
Alzheimers Dement ; 20(9): 6590-6605, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39031528

RESUMO

INTRODUCTION: The apolipoprotein E gene (APOE) is an established central player in the pathogenesis of Alzheimer's disease (AD), with distinct apoE isoforms exerting diverse effects. apoE influences not only amyloid-beta and tau pathologies but also lipid and energy metabolism, neuroinflammation, cerebral vascular health, and sex-dependent disease manifestations. Furthermore, ancestral background may significantly impact the link between APOE and AD, underscoring the need for more inclusive research. METHODS: In 2023, the Alzheimer's Association convened multidisciplinary researchers at the "AAIC Advancements: APOE" conference to discuss various topics, including apoE isoforms and their roles in AD pathogenesis, progress in apoE-targeted therapeutic strategies, updates on disease models and interventions that modulate apoE expression and function. RESULTS: This manuscript presents highlights from the conference and provides an overview of opportunities for further research in the field. DISCUSSION: Understanding apoE's multifaceted roles in AD pathogenesis will help develop targeted interventions for AD and advance the field of AD precision medicine. HIGHLIGHTS: APOE is a central player in the pathogenesis of Alzheimer's disease. APOE exerts a numerous effects throughout the brain on amyloid-beta, tau, and other pathways. The AAIC Advancements: APOE conference encouraged discussions and collaborations on understanding the role of APOE.


Assuntos
Doença de Alzheimer , Apolipoproteínas E , Humanos , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Congressos como Assunto , Animais , Peptídeos beta-Amiloides/metabolismo , Demência/genética , Demência/metabolismo , Pesquisa Biomédica
2.
Mol Psychiatry ; 27(4): 1936-1944, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35136227

RESUMO

The world population is getting older and studies aiming to enhance our comprehension of the underlying mechanisms responsible for health span are of utmost interest for longevity and as a measure for health care. In this review, we summarized previous genetic association studies (GWAS) and next-generation sequencing (NGS) of elderly cohorts. We also present the updated hypothesis for the aging process, together with the factors associated with healthy aging. We discuss the relevance of studying older individuals and build databanks to characterize the presence and resistance against late-onset disorders. The identification of about 2 million novel variants in our cohort of more than 1000 elderly Brazilians illustrates the importance of studying highly admixed populations of non-European ancestry. Finally, the ascertainment of nonagenarians and particularly of centenarians who were recovered from COVID-19 or remained asymptomatic opens new avenues of research aiming to enhance our comprehension of biological mechanisms associated with resistance against pathogens.


Assuntos
COVID-19 , Longevidade , Idoso , Idoso de 80 Anos ou mais , Brasil , Estudos de Coortes , Estudos de Associação Genética , Humanos , Longevidade/genética
3.
Immun Ageing ; 19(1): 57, 2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36384671

RESUMO

BACKGROUND: Although older adults are at a high risk of severe or critical Covid-19, there are many cases of unvaccinated centenarians who had a silent infection or recovered from mild or moderate Covid-19. We studied three Brazilian supercentenarians, older than 110 years, who survived Covid-19 in 2020 before being vaccinated. RESULTS: Despite their advanced age, humoral immune response analysis showed that these individuals displayed robust levels of IgG and neutralizing antibodies (NAbs) against SARS-CoV-2. Enrichment of plasma proteins and metabolites related to innate immune response and host defense was also observed. None presented autoantibodies (auto-Abs) to type I interferon (IFN). Furthermore, these supercentenarians do not carry rare variants in genes underlying the known inborn errors of immunity, including particular inborn errors of type I IFN. CONCLUSION: These observations suggest that their Covid-19 resilience might be a combination of their genetic background and their innate and adaptive immunity.

4.
Am J Med Genet C Semin Med Genet ; 187(3): 357-363, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34189818

RESUMO

Diagnosis of individuals affected by monogenic disorders was significantly improved by next-generation sequencing targeting clinically relevant genes. Whole exomes yield a large number of variants that require several filtering steps, prioritization, and pathogenicity classification. Among the criteria recommended by ACMG, those that rely on population databases critically affect analyses of individuals with underrepresented ancestries. Population-specific allelic frequencies need consideration when characterizing potential deleteriousness of variants. An orthogonal input for classification is annotation of variants previously classified as pathogenic as a criterion that provide supporting evidence widely sourced at ClinVar. We used a whole-genome dataset from a census-based cohort of 1,171 elderly individuals from São Paulo, Brazil, highly admixed, and unaffected by severe monogenic disorders, to investigate if pathogenic assertions in ClinVar are enriched with higher proportions of European ancestry, indicating bias. Potential loss of function (pLOF) variants were filtered from 4,250 genes associated with Mendelian disorders and annotated with ClinVar assertions. Over 1,800 single nucleotide pLOF variants were included, 381 had non-benign assertions. Among carriers (N = 463), average European ancestry was significantly higher than noncarriers (N = 708; p = .011). pLOFs in genomic contexts of non-European local ancestries were nearly three times less likely to have any ClinVar entry (OR = 0.353; p <.0001). Independent pathogenicity assertions are useful for variant classification in molecular diagnosis. However, European overrepresentation of assertions can promote distortions when classifying variants in non-European individuals, even in admixed samples with a relatively high proportion of European ancestry. The investigation and deposit of clinically relevant findings of diverse populations is fundamental improve this scenario.


Assuntos
Variação Genética , Genômica , Idoso , Brasil , Exoma , Sequenciamento de Nucleotídeos em Larga Escala , Humanos
5.
Int J Obes (Lond) ; 45(5): 1017-1029, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33633342

RESUMO

BACKGROUND/OBJECTIVES: Admixed populations are a resource to study the global genetic architecture of complex phenotypes, which is critical, considering that non-European populations are severely underrepresented in genomic studies. Here, we study the genetic architecture of BMI in children, young adults, and elderly individuals from the admixed population of Brazil. SUBJECTS/METHODS: Leveraging admixture in Brazilians, whose chromosomes are mosaics of fragments of Native American, European, and African origins, we used genome-wide data to perform admixture mapping/fine-mapping of body mass index (BMI) in three Brazilian population-based cohorts from Northeast (Salvador), Southeast (Bambuí), and South (Pelotas). RESULTS: We found significant associations with African-associated alleles in children from Salvador (PALD1 and ZMIZ1 genes), and in young adults from Pelotas (NOD2 and MTUS2 genes). More importantly, in Pelotas, rs114066381, mapped in a potential regulatory region, is significantly associated only in females (p = 2.76e-06). This variant is rare in Europeans but with frequencies of ~3% in West Africa and has a strong female-specific effect (95% CI: 2.32-5.65 kg/m2 per each A allele). We confirmed this sex-specific association and replicated its strong effect for an adjusted fat mass index in the same Pelotas cohort, and for BMI in another Brazilian cohort from São Paulo (Southeast Brazil). A meta-analysis confirmed the significant association. Remarkably, we observed that while the frequency of rs114066381-A allele ranges from 0.8 to 2.1% in the studied populations, it attains ~9% among women with morbid obesity from Pelotas, São Paulo, and Bambuí. The effect size of rs114066381 is at least five times higher than the FTO SNPs rs9939609 and rs1558902, already emblematic for their high effects. CONCLUSIONS: We identified six candidate SNPs associated with BMI. rs114066381 stands out for its high effect that was replicated and its high frequency in women with morbid obesity. We demonstrate how admixed populations are a source of new relevant phenotype-associated genetic variants.


Assuntos
Índice de Massa Corporal , Genética Populacional , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Alelos , Brasil , Criança , Pré-Escolar , Mapeamento Cromossômico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Sequências Reguladoras de Ácido Nucleico , Fatores Sexuais , Adulto Jovem
6.
BMC Genomics ; 21(1): 446, 2020 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-32600246

RESUMO

BACKGROUND: Approximately 5% of the human genome shows common structural variation, which is enriched for genes involved in the immune response and cell-cell interactions. A well-established region of extensive structural variation is the glycophorin gene cluster, comprising three tandemly-repeated regions about 120 kb in length and carrying the highly homologous genes GYPA, GYPB and GYPE. Glycophorin A (encoded by GYPA) and glycophorin B (encoded by GYPB) are glycoproteins present at high levels on the surface of erythrocytes, and they have been suggested to act as decoy receptors for viral pathogens. They are receptors for the invasion of the protist parasite Plasmodium falciparum, a causative agent of malaria. A particular complex structural variant, called DUP4, creates a GYPB-GYPA fusion gene known to confer resistance to malaria. Many other structural variants exist across the glycophorin gene cluster, and they remain poorly characterised. RESULTS: Here, we analyse sequences from 3234 diploid genomes from across the world for structural variation at the glycophorin locus, confirming 15 variants in the 1000 Genomes project cohort, discovering 9 new variants, and characterising a selection of these variants using fibre-FISH and breakpoint mapping at the sequence level. We identify variants predicted to create novel fusion genes and a common inversion duplication variant at appreciable frequencies in West Africans. We show that almost all variants can be explained by non-allelic homologous recombination and by comparing the structural variant breakpoints with recombination hotspot maps, confirm the importance of a particular meiotic recombination hotspot on structural variant formation in this region. CONCLUSIONS: We identify and validate large structural variants in the human glycophorin A-B-E gene cluster which may be associated with different clinical aspects of malaria.


Assuntos
Variação Estrutural do Genoma , Glicoforinas/genética , Malária Falciparum/genética , Pontos de Quebra do Cromossomo , Mapeamento Cromossômico , Bases de Dados Genéticas , Resistência à Doença , Humanos , Hibridização in Situ Fluorescente , Alinhamento de Sequência , Sequenciamento Completo do Genoma
8.
Hum Mol Genet ; 23(15): 4103-10, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-24647604

RESUMO

Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetically determined muscle disorders with a primary or predominant involvement of the pelvic or shoulder girdle musculature. More than 20 genes with autosomal recessive (LGMD2A to LGMD2Q) and autosomal dominant inheritance (LGMD1A to LGMD1H) have been mapped/identified to date. Mutations are known for six among the eight mapped autosomal dominant forms: LGMD1A (myotilin), LGMD1B (lamin A/C), LGMD1C (caveolin-3), LGMD1D (desmin), LGMD1E (DNAJB6), and more recently for LGMD1F (transportin-3). Our group previously mapped the LGMD1G gene at 4q21 in a Caucasian-Brazilian family. We now mapped a Uruguayan family with patients displaying a similar LGMD1G phenotype at the same locus. Whole genome sequencing identified, in both families, mutations in the HNRPDL gene. HNRPDL is a heterogeneous ribonucleoprotein family member, which participates in mRNA biogenesis and metabolism. Functional studies performed in S. cerevisiae showed that the loss of HRP1 (yeast orthologue) had pronounced effects on both protein levels and cell localizations, and yeast proteome revealed dramatic reorganization of proteins involved in RNA-processing pathways. In vivo analysis showed that hnrpdl is important for muscle development in zebrafish, causing a myopathic phenotype when knocked down. The present study presents a novel association between a muscular disorder and a RNA-related gene and reinforces the importance of RNA binding/processing proteins in muscle development and muscle disease. Understanding the role of these proteins in muscle might open new therapeutic approaches for muscular dystrophies.


Assuntos
Músculo Esquelético/metabolismo , Distrofia Muscular do Cíngulo dos Membros/genética , Mutação , Ribonucleoproteínas/genética , Adulto , Animais , Mapeamento Cromossômico , Feminino , Expressão Gênica , Loci Gênicos , Humanos , Masculino , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Distrofia Muscular do Cíngulo dos Membros/patologia , Linhagem , Fenótipo , Processamento Pós-Transcricional do RNA , Ribonucleoproteínas/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Peixe-Zebra/genética , Fatores de Poliadenilação e Clivagem de mRNA/genética , Fatores de Poliadenilação e Clivagem de mRNA/metabolismo
9.
HLA ; 103(1): e15282, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37950640

RESUMO

Human genomics has quickly evolved, powering genome-wide association studies (GWASs). SNP-based GWASs cannot capture the intense polymorphism of HLA genes, highly associated with disease susceptibility. There are methods to statistically impute HLA genotypes from SNP-genotypes data, but lack of diversity in reference panels hinders their performance. We evaluated the accuracy of the 1000 Genomes data as a reference panel for imputing HLA from admixed individuals of African and European ancestries, focusing on (a) the full dataset, (b) 10 replications from 6 populations, and (c) 19 conditions for the custom reference panels. The full dataset outperformed smaller models, with a good F1-score of 0.66 for HLA-B. However, custom models outperformed the multiethnic or population models of similar size (F1-scores up to 0.53, against up to 0.42). We demonstrated the importance of using genetically specific models for imputing populations, which are currently underrepresented in public datasets, opening the door to HLA imputation for every genetic population.


Assuntos
Genética Populacional , Estudo de Associação Genômica Ampla , Humanos , Alelos , Genótipo , Antígenos HLA-B , Polimorfismo de Nucleotídeo Único
10.
JAMA Netw Open ; 7(7): e2423377, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-39052291

RESUMO

Importance: Race differences in dementia prevalence and incidence have previously been reported, with higher dementia burden in Black decedents. However, previous neuropathological studies were conducted mostly in convenience samples with White participants; conducting clinicopathological studies across populations is crucial for understanding the underlying dementia causes in individuals from different racial backgrounds. Objective: To compare the frequencies of neuropathological lesions and cognitive abilities between Black and White Brazilian adults in an autopsy study. Design, Setting, and Participants: This cross-sectional study used samples from the Biobank for Aging Studies, a population-based autopsy study conducted in Sao Paulo, Brazil. Participants were older adults whose family members consented to the brain donations; Asian participants and those with missing data were excluded. Samples were collected from 2004 to 2023. Neuropathologists were masked to cognitive outcomes. Exposure: Race as reported by the deceased's family member. Main Outcomes and Measures: The frequencies of neurodegenerative and cerebrovascular lesions were evaluated in 13 selected cerebral areas. Cognitive and functional abilities were examined with the Clinical Dementia Rating Scale. Results: The mean (SD) age of the 1815 participants was 74.0 (12.5) years, 903 (50%) were women, 617 (34%) were Black, and 637 (35%) had cognitive impairment. Small vessel disease (SVD) and siderocalcinosis were more frequent in Black compared with White participants (SVD: odds ratio [OR], 1.74; 95% CI, 1.29-2.35; P < .001; siderocalcinosis: OR, 1.70; 95% CI, 1.23-2.34; P = .001), while neuritic plaques were more frequent in White compared with Black participants (OR, 0.61; 95% CI, 0.44-0.83; P = .002). Likewise, Alzheimer disease neuropathological diagnosis was more frequent in White participants than Black participants (198 [39%] vs 77 [33%]), while vascular dementia was more common among Black participants than White participants (76 [32%] vs 121 [24%]). Race was not associated with cognitive abilities, nor did it modify the association between neuropathology and cognition. Conclusions and Relevance: In this cross-sectional study of Brazilian older adults, Alzheimer disease pathology was more frequent in White participants while vascular pathology was more frequent in Black participants. Further neuropathological studies in diverse samples are needed to understand race disparities in dementia burden.


Assuntos
População Branca , Humanos , Brasil/epidemiologia , Feminino , Masculino , Idoso , Estudos Transversais , População Branca/estatística & dados numéricos , População Branca/psicologia , Idoso de 80 Anos ou mais , Cognição , Demência/epidemiologia , Demência/etnologia , Encéfalo/patologia , Autopsia , População Negra/estatística & dados numéricos , População Negra/psicologia
11.
Gene ; : 149025, 2024 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-39437899

RESUMO

The effects of aging on the organism manifest in various ways, including profound and complex changes in functioning patterns, responses to stimuli, and regenerative capacity. Nevertheless, it is remarkable that some elderly individuals maintain their health and functionality despite advanced age, showing resilience to environmental adversities, such as SARS-CoV-2 infection. In this study, we examined a unique cohort of 100 individuals older than 90 years, including centenarians, who recovered from COVID-19 before the availability of vaccines in Brazil. We performed whole-exome analyses and identified incidental findings in four participants. These findings included pathogenic variants associated with serious conditions, such as cancer predisposition and cardiovascular diseases. Specifically, variants were found in the RYR1, DSP, BRCA2, BRCA1, and TTN genes. Also, other two individuals were homozygous for rare variants in the TYK2 gene, related to primary immunodeficiencies. The significance of these findings is underscored by the fact that, despite carrying these rare variants, these individuals surpassed 90 years of age and survived the COVID-19 pandemic. This suggests the presence of genetic protective factors that contribute to longevity and resilience. Therefore, this study provides new insights into interpreting incidental findings in long-lived populations and raises important questions for clinical practice and the genetics of longevity.

12.
Forensic Sci Int Genet ; 74: 103161, 2024 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-39418769

RESUMO

Insertion/deletion polymorphisms, or InDels, are widely present in the human genome. They have been considered as potential markers for forensic analysis because they can be genotyped using the CE platform and compatible typing techniques used in forensic laboratories. Additionally, InDels have lower mutation rates and often short amplicon sizes, making them ideal for detecting degraded samples. However, most InDels are bi-allelic; therefore, their discrimination power is relatively low. A new set of genetic marker called multi-InDels was reported to improve InDel's informativeness. Multi-InDel markers are generally designated as microhaplotypes encompassing two or more InDels within a short distance, usually less than 200 bp. In this study, we evaluated the applicability of three previously proposed panels of multi-InDel markers, designed for Asian populations, for human identification in Brazil. We assessed all the multi-InDel markers using high-coverage whole-genome sequencing data from a census-based cohort of 1171 Brazilians residing in São Paulo, the largest Brazilian capital. The results showed that most markers are informative for Brazilian individuals since they present more than three frequent haplotypes with different sizes. However, most markers are prone to amplification/sequencing errors due to repetitive or low-complexity regions. Among the tested panels, the one from Huang et al. (2014) is the most promising for forensic use in Brazil, with a combined match probability and cumulative power of exclusion of 4.92 ×10-14 and 0.9991, respectively. Nevertheless, these values are low compared to the ones obtained with CODIS STRs (short tandem repeats) and larger SNP (single nucleotide polymorphisms) panels. Therefore, new attempts to scan the human genome for highly polymorphic multi-InDel markers are still necessary to obtain a suitable panel of multi-InDels for worldwide populations.

13.
HLA ; 103(6): e15543, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38837862

RESUMO

The MHC class I region contains crucial genes for the innate and adaptive immune response, playing a key role in susceptibility to many autoimmune and infectious diseases. Genome-wide association studies have identified numerous disease-associated SNPs within this region. However, these associations do not fully capture the immune-biological relevance of specific HLA alleles. HLA imputation techniques may leverage available SNP arrays by predicting allele genotypes based on the linkage disequilibrium between SNPs and specific HLA alleles. Successful imputation requires diverse and large reference panels, especially for admixed populations. This study employed a bioinformatics approach to call SNPs and HLA alleles in multi-ethnic samples from the 1000 genomes (1KG) dataset and admixed individuals from Brazil (SABE), utilising 30X whole-genome sequencing data. Using HIBAG, we created three reference panels: 1KG (n = 2504), SABE (n = 1171), and the full model (n = 3675) encompassing all samples. In extensive cross-validation of these reference panels, the multi-ethnic 1KG reference exhibited overall superior performance than the reference with only Brazilian samples. However, the best results were achieved with the full model. Additionally, we expanded the scope of imputation by developing reference panels for non-classical, MICA, MICB and HLA-H genes, previously unavailable for multi-ethnic populations. Validation in an independent Brazilian dataset showcased the superiority of our reference panels over the Michigan Imputation Server, particularly in predicting HLA-B alleles among Brazilians. Our investigations underscored the need to enhance or adapt reference panels to encompass the target population's genetic diversity, emphasising the significance of multiethnic references for accurate imputation across different populations.


Assuntos
Alelos , Etnicidade , Frequência do Gene , Polimorfismo de Nucleotídeo Único , Humanos , Brasil , Etnicidade/genética , Antígenos HLA/genética , Desequilíbrio de Ligação , Estudo de Associação Genômica Ampla/métodos , Genótipo , Genética Populacional/métodos , Antígenos de Histocompatibilidade Classe I/genética , Biologia Computacional/métodos
14.
J Mol Diagn ; 26(9): 825-831, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38972593

RESUMO

Polygenic risk scores (PRSs) for breast cancer have a clear clinical utility in risk prediction. PRS transferability across populations and ancestry groups is hampered by population-specific factors, ultimately leading to differences in variant effects, such as linkage disequilibrium and differences in variant frequency (allele frequency differences). Thus, locally sourced population-based phenotypic and genomic data sets are essential to assess the validity of PRSs derived from signals detected across populations. This study assesses the transferability of a breast cancer PRS composed of 313 risk variants (313-PRS) in a Brazilian trihybrid admixed ancestries (European, African, and Native American) whole-genome sequenced cohort, the Rare Genomes Project. 313-PRS was computed in the Rare Genomes Project (n = 853) using the UK Biobank (UKBB; n = 264,307) as reference. The Brazilian cohorts have a high European ancestry (EA) component, with allele frequency differences and to a lesser extent linkage disequilibrium patterns similar to those found in EA populations. The 313-PRS distribution was found to be inflated when compared with that of the UKBB, leading to potential overestimation of PRS-based risk if EA is taken as a standard. However, case controls lead to equivalent predictive power when compared with UKBB-EA samples with area under the receiver operating characteristic curve values of 0.66 to 0.62 compared with 0.63 for UKBB.


Assuntos
Neoplasias da Mama , Predisposição Genética para Doença , Herança Multifatorial , Humanos , Neoplasias da Mama/genética , Feminino , Brasil/epidemiologia , Herança Multifatorial/genética , Medição de Risco/métodos , Estudos de Coortes , Frequência do Gene , Desequilíbrio de Ligação , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Estudos de Casos e Controles , Estratificação de Risco Genético
15.
Front Pharmacol ; 14: 1178715, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37234706

RESUMO

Introduction: Research in the field of pharmacogenomics (PGx) aims to identify genetic variants that modulate response to drugs, through alterations in their pharmacokinetics (PK) or pharmacodynamics (PD). The distribution of PGx variants differs considerably among populations, and whole-genome sequencing (WGS) plays a major role as a comprehensive approach to detect both common and rare variants. This study evaluated the frequency of PGx markers in the context of the Brazilian population, using data from a population-based admixed cohort from Sao Paulo, Brazil, which includes variants from WGS of 1,171 unrelated, elderly individuals. Methods: The Stargazer tool was used to call star alleles and structural variants (SVs) from 38 pharmacogenes. Clinically relevant variants were investigated, and the predicted drug response phenotype was analyzed in combination with the medication record to assess individuals potentially at high-risk of gene-drug interaction. Results: In total, 352 unique star alleles or haplotypes were observed, of which 255 and 199 had a frequency < 0.05 and < 0.01, respectively. For star alleles with frequency > 5% (n = 97), decreased, loss-of-function and unknown function accounted for 13.4%, 8.2% and 27.8% of alleles or haplotypes, respectively. Structural variants (SVs) were identified in 35 genes for at least one individual, and occurred with frequencies >5% for CYP2D6, CYP2A6, GSTM1, and UGT2B17. Overall 98.0% of the individuals carried at least one high risk genotype-predicted phenotype in pharmacogenes with PharmGKB level of evidence 1A for drug interaction. The Electronic Health Record (EHR) Priority Result Notation and the cohort medication registry were combined to assess high-risk gene-drug interactions. In general, 42.0% of the cohort used at least one PharmGKB evidence level 1A drug, and 18.9% of individuals who used PharmGKB evidence level 1A drugs had a genotype-predicted phenotype of high-risk gene-drug interaction. Conclusion: This study described the applicability of next-generation sequencing (NGS) techniques for translating PGx variants into clinically relevant phenotypes on a large scale in the Brazilian population and explores the feasibility of systematic adoption of PGx testing in Brazil.

16.
Int J Infect Dis ; 129: 207-215, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36758851

RESUMO

OBJECTIVES: The X-chromosome contains the largest number of immune-related genes, which play a major role in COVID-19 symptomatology and susceptibility. Here, we had a unique opportunity to investigate, for the first time, COVID-19 outcomes in six unvaccinated young Brazilian patients with Turner syndrome (TS; 45, X0), including one case of critical illness in a child aged 10 years, to evaluate their immune response according to their genetic profile. METHODS: A serological analysis of humoral immune response against SARS-CoV-2, phenotypic characterization of antiviral responses in peripheral blood mononuclear cells after stimuli, and the production of cytotoxic cytokines of T lymphocytes and natural killer cells were performed in blood samples collected from the patients with TS during the convalescence period. Whole exome sequencing was also performed. RESULTS: Our volunteers with TS showed a delayed or insufficient humoral immune response to SARS-CoV-2 (particularly immunoglobulin G) and a decrease in interferon-γ production by cluster of differentiation (CD)4+ and CD8+ T lymphocytes after stimulation with toll-like receptors 7/8 agonists. In contrast, we observed a higher cytotoxic activity in the volunteers with TS than the volunteers without TS after phorbol myristate acetate/ionomycin stimulation, particularly granzyme B and perforin by CD8+ and natural killer cells. Interestingly, two volunteers with TS carry rare genetic variants in genes that regulate type I and III interferon immunity. CONCLUSION: Following previous reports in the literature for other conditions, our data showed that patients with TS may have an impaired immune response against SARS-CoV-2. Furthermore, other medical conditions associated with TS could make them more vulnerable to COVID-19.


Assuntos
COVID-19 , Síndrome de Turner , Criança , Humanos , SARS-CoV-2 , Síndrome de Turner/complicações , Síndrome de Turner/genética , Leucócitos Mononucleares , Linfócitos T CD8-Positivos , Anticorpos Antivirais
18.
Sci Rep ; 12(1): 21240, 2022 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-36481695

RESUMO

The inference of genetic ancestry plays an increasingly prominent role in clinical, population, and forensic genetics studies. Several genotyping strategies and analytical methodologies have been developed over the last few decades to assign individuals to specific biogeographic regions. However, despite these efforts, ancestry inference in populations with a recent history of admixture, such as those in Brazil, remains a challenge. In admixed populations, proportion and components of genetic ancestry vary on different levels: (i) between populations; (ii) between individuals of the same population, and (iii) throughout the individual's genome. The present study evaluated 1171 admixed Brazilian samples to compare the genetic ancestry inferred by tri-/tetra-hybrid admixture models and evaluated different marker sets from those with small numbers of ancestry informative markers panels (AIMs), to high-density SNPs (HDSNP) and whole-genome-sequence (WGS) data. Analyses revealed greater variation in the correlation coefficient of ancestry components within and between admixed populations, especially for minority ancestral components. We also observed positive correlation between the number of markers in the AIMs panel and HDSNP/WGS. Furthermore, the greater the number of markers, the more accurate the tri-/tetra-hybrid admixture models.


Assuntos
Genética Populacional , Humanos , Brasil , Grupos Minoritários , Polimorfismo de Nucleotídeo Único , População da América do Sul/genética , Sequenciamento Completo do Genoma
19.
iScience ; 25(3): 103861, 2022 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-35198912

RESUMO

The question of whether host genetics plays a role in the development of the infant gut microbiota does not, as yet, have a clear answer. In order to throw additional light on this question, we have analyzed 16S rRNA amplicon sequences from 99 valid fecal samples of five sets of dichorionic triplet babies born by C-section from 1 to 36 months of age. Beta diversity analysis showed that monozygotic twins were more similar to each other than their dizygotic siblings. Monozygotic twins also tended to share more amplicon sequence variants between them. Heritability analysis showed that the genera Bacteroides and Veillonella are particularly susceptible to host genetics. We conclude that infant gut microbiota development is influenced by host genetics, but this effect is subtle and may affect only certain bacterial taxa during a limited time period early in life.

20.
Discov Ment Health ; 2(1): 1, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35174362

RESUMO

BACKGROUND: COVID-19 has affected millions of people worldwide. Clinical manifestations range from severe cases with lethal outcome to mild or asymptomatic cases. Although the proportion of infected individuals does not differ between sexes, men are more susceptible to severe COVID-19, with a higher risk of death than women. Also, men are pointed out as more lax regarding protective measures, mask wearing and vaccination. Thus, we questioned whether sex-bias may be explained by biological pathways and/or behavioral aspects or both. METHODS: Between July 2020 and July 2021, we performed an epidemiological survey including 1744 unvaccinated adult Brazilian couples, with there was at least one infected symptomatic member, who were living together during the COVID-19 infection without protective measures. Presence or absence of infection was confirmed by RT-PCR and/or serology results. Couples were divided into two groups: (1) both partners were infected (concordant couples) and (2) one partner was infected and the spouse remained asymptomatic despite the close contact with the COVID-19 symptomatic partner (discordant couples). Statistical analysis of the collected data was performed aiming to verify a differential transmission potential between genders in couples keeping contact without protective measures. RESULTS: The combination of our collected data showed that the man is the first (or the only) affected member in most cases when compared to women and that this difference may be explained by biological and behavioral factors. CONCLUSIONS: The present study confirmed the existence of gender differences not only for susceptibility to infection and resistance to COVID-19 but also in its transmission rate.

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