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1.
Diabetes Metab Syndr ; 16(1): 102358, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34920192

RESUMO

BACKGROUND AND AIMS: Common variants in fat mass and obesity-associated (FTO) gene have been implicated as a susceptibility locus for obesity and type 2 diabetes in different populations. Here, in an indigenous population-based study, we examined whether FTO rs9939609 has a role in susceptibility to glucose intolerance and obesity. METHODS: The study population comprised 949 full Xavante indigenous people (465 men) aged 18-99 years. The participants were submitted to clinical examination, anthropometrical measures and basal and 2-h post 75g oral glucose load capillary glucose measurements. FTO rs9939609 was genotyped and logistic regression was carried out to test the additive effect of the risk allele. RESULTS: The frequency of the minor allele of the FTO rs9939609 (0.06) was lower in Xavante than observed in some populations. A significant association between the variant and overweight was observed (OR = 1.56 (95% CI:1.06-2.29, p = 0.02), using an additive model of inheritance, adjusted by age and gender and considering the family structure. We found no associations with obesity or glucose intolerance. CONCLUSIONS: The FTO rs9939609 is associated with overweight, but not with obesity or glucose intolerance. The low frequency of the A allele suggests that it is not an important risk determinant for these conditions in Xavante indigenous people.


Assuntos
Diabetes Mellitus Tipo 2 , Intolerância à Glucose , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Índice de Massa Corporal , Brasil , Diabetes Mellitus Tipo 2/complicações , Predisposição Genética para Doença , Genótipo , Intolerância à Glucose/complicações , Intolerância à Glucose/epidemiologia , Intolerância à Glucose/genética , Humanos , Povos Indígenas , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Polimorfismo de Nucleotídeo Único , Adulto Jovem
2.
Stat Appl Genet Mol Biol ; 19(2)2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32374294

RESUMO

Genome wide association study (GWAS) is becoming fundamental in the arduous task of deciphering the etiology of complex diseases. The majority of the statistical models used to address the genes-disease association consider a single response variable. However, it is common for certain diseases to have correlated phenotypes such as in cardiovascular diseases. Usually, GWAS typically sample unrelated individuals from a population and the shared familial risk factors are not investigated. In this paper, we propose to apply a bivariate model using family data that associates two phenotypes with a genetic region. Using generalized estimation equations (GEE), we model two phenotypes, either discrete, continuous or a mixture of them, as a function of genetic variables and other important covariates. We incorporate the kinship relationships into the working matrix extended to a bivariate analysis. The estimation method and the joint gene-set effect in both phenotypes are developed in this work. We also evaluate the proposed methodology with a simulation study and an application to real data.


Assuntos
Simulação por Computador , Estudos de Associação Genética/métodos , Estudo de Associação Genômica Ampla/métodos , Algoritmos , Análise de Variância , Índice de Massa Corporal , Simulação por Computador/estatística & dados numéricos , Bases de Dados Genéticas , Diabetes Mellitus Tipo 2/genética , Família , Feminino , Humanos , Estudos Longitudinais , Masculino , Modelos Estatísticos , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único
3.
Circ Genom Precis Med ; 12(4): e002471, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30897348

RESUMO

BACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk. METHODS: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD. RESULTS: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUS-CHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction <0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09). CONCLUSIONS: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.


Assuntos
Cromossomos Humanos Par 9 , Doença da Artéria Coronariana/patologia , Estudos de Casos e Controles , Doença da Artéria Coronariana/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Razão de Chances , Fatores de Risco
4.
Circ Genom Precis Med ; 12(4): e002470, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30896328

RESUMO

BACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD. METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events. RESULTS: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints. CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.


Assuntos
Doença das Coronárias/patologia , Adulto , Fatores Etários , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Risco , Fatores Sexuais , Fumar
5.
Eur J Clin Pharmacol ; 74(12): 1555-1566, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30051215

RESUMO

PURPOSE: Interpatient variation of warfarin dose requirements may be explained by genetic variations and general and clinical factors. In this scenario, diverse population-calibrated dosing algorithms, which incorporate the main warfarin dosing influencers, have been widely proposed for predicting supposed warfarin maintenance dose, in order to prevent and reduce adverse events. The aim of the present study was to evaluate the impact of the inclusion of ABCB1 c.3435C>T and CYP4F2 c.1297G>A polymorphisms as additional covariates in a previously developed pharmacogenetic-based warfarin dosing algorithm calibrated for the Brazilian population. METHODS: Two independent cohorts of patients treated with warfarin (n = 832 and n = 133) were included for derivation and replication of the algorithm, respectively. Genotyping of ABCB1 c.3435C>T and CYP4F2 c.1297G>A polymorphisms was performed by polymerase chain reaction followed by melting curve analysis and TaqMan® assay, respectively. A multiple linear regression was performed for the warfarin stable doses as a dependent variable, considering clinical, general, and genetic data as covariates. RESULTS: The inclusion of ABCB1 and CYP4F2 polymorphisms was able to improve the algorithm's coefficient of determination (R2) by 2.6%. In addition, the partial determination coefficients of these variants revealed that they explained 3.6% of the warfarin dose variability. We also observed a marginal improvement of the linear correlation between observed and predicted doses (from 59.7 to 61.4%). CONCLUSION: Although our study indicates that the contribution of the combined ABCB1 and CYP4F2 genotypes in explaining the overall variability in warfarin dose is not very large, we demonstrated that these pharmacogenomic data are statistically significant. However, the clinical relevance and cost-effective impact of incorporating additional variants in warfarin dosing algorithms should be carefully evaluated.


Assuntos
Algoritmos , Anticoagulantes/administração & dosagem , Família 4 do Citocromo P450/genética , Farmacogenética , Polimorfismo Genético/genética , Varfarina/administração & dosagem , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Idoso , Anticoagulantes/farmacocinética , Brasil , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Varfarina/farmacocinética
6.
Sci Rep ; 7(1): 5697, 2017 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-28720787

RESUMO

The well-established negative health outcomes of sleep deprivation, and the suggestion that availability of electricity may enable later bed times without compensating sleep extension in the morning, have stimulated interest in studying communities whose sleep pattern may resemble a pre-industrial state. Here, we describe sleep and activity in two neighbouring communities, one urban (Milange) and one rural (Tengua), in a region of Mozambique where urbanisation is an ongoing process. The two communities differ in the amount and timing of daily activity and of light exposure, with later bedtimes (≈1 h) associated with more evening and less daytime light exposure seen in the town of Milange. In contrast to previous reports comparing communities with and without electricity, sleep duration did not differ between Milange (7.28 h) and Tengua (7.23 h). Notably, calculated sleep quality was significantly poorer in rural Tengua than in Milange, and poor sleep quality was associated with a number of attributes more characteristic of rural areas, including more intense physical labour and less comfortable sleeping arrangements. Thus, whilst our data support the hypothesis that access to electricity delays sleep timing, the higher sleep quality in the urban population also suggests that some aspects of industrialisation are beneficial to sleep.


Assuntos
Iluminação , Sono/fisiologia , Urbanização , Vigília/fisiologia , Adolescente , Adulto , Ritmo Circadiano/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Moçambique , Fatores de Tempo
7.
Chronobiol Int ; 34(2): 269-272, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28055282

RESUMO

Significant questions remain unanswered regarding the genetic versus environmental contributions to racial/ethnic differences in sleep and circadian rhythms. We addressed this question by investigating the association between diurnal preference, using the morningness-eveningness questionnaire (MEQ), and genetic ancestry within the Baependi Heart Study cohort, a highly admixed Brazilian population based in a rural town. Analysis was performed using measures of ancestry, using the Admixture program, and MEQ from 1,453 individuals. We found an association between the degree of Amerindian (but not European of African) ancestry and morningness, equating to 0.16 units for each additional percent of Amerindian ancestry, after adjustment for age, sex, education, and residential zone. To our knowledge, this is the first published report identifying an association between genetic ancestry and MEQ, and above all, the first one based on ancestral contributions within individuals living in the same community. This previously unknown ancestral dimension of diurnal preference suggests a stratification between racial/ethnic groups in an as yet unknown number of genetic polymorphisms.


Assuntos
Ritmo Circadiano , Indígenas Norte-Americanos/genética , Adulto , População Negra/genética , Brasil , Estudos de Coortes , Etnicidade , Feminino , Frequência do Gene , Homeostase , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , População Rural , Sono , Inquéritos e Questionários , População Urbana , População Branca/genética
8.
BMJ Open ; 6(10): e011598, 2016 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-27797990

RESUMO

PURPOSE: Cardiovascular disease (CVD) is a major challenge to global health. The same epidemiological transition scenario is replayed as countries develop, but with variations based on environment, culture and ethnic mixture. The Baependi Heart Study was set up in 2005 to develop a longitudinal family-based cohort study that reflects on some of the genetic and lifestyle-related peculiarities of the Brazilian populations, in order to evaluate genetic and environmental influences on CVD risk factor traits. PARTICIPANTS: Probands were recruited in Baependi, a small rural town in the state of Minas Gerais, Brazil, following by first-degree and then increasingly more distant relatives. The first follow-up wave took place in 2010, and the second in 2016. At baseline, the study evaluated 1691 individuals across 95 families. Cross-sectional data have been collected for 2239 participants. FINDINGS TO DATE: Environmental and lifestyle factors and measures relevant to cardiovascular health have been reported. Having expanded beyond cardiovascular health outcomes, the phenotype datasets now include genetics, biochemistry, anthropometry, mental health, sleep and circadian rhythms. Many of these have yielded heritability estimates, and a shared genetic background of anxiety and depression has recently been published. In spite of universal access to electricity, the population has been found to be strongly shifted towards morningness compared with metropolitan areas. FUTURE PLANS: A new follow-up, marking 10 years of the study, is ongoing in 2016, in which data are collected as in 2010 (with the exception of the neuropsychiatric protocol). In addition to this, a novel questionnaire package collecting information about intelligence, personality and spirituality is being planned. The data set on circadian rhythms and sleep will be amended through additional questionnaires, actimetry, home sleep EEG recording and dim light melatonin onset (DLMO) analysis. Finally, the anthropometric measures will be expanded by adding three-dimensional facial photography, voice recording and anatomical brain MRI.


Assuntos
Doenças Cardiovasculares/etiologia , Conjuntos de Dados como Assunto , População Rural , Adulto , Antropometria , Brasil/epidemiologia , Doenças Cardiovasculares/etnologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/psicologia , Ritmo Circadiano , Estudos de Coortes , Estudos Transversais , Etnicidade , Família , Feminino , Nível de Saúde , Humanos , Estilo de Vida , Masculino , Saúde Mental , Pessoa de Meia-Idade , Fenótipo , Fatores de Risco , Sono , Meio Social , Inquéritos e Questionários
9.
PLoS One ; 10(12): e0144255, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26650098

RESUMO

To investigate the phenotypic and genetic overlap between anxiety and depression symptoms in an admixed population from extended family pedigrees. Participants (n = 1,375) were recruited from a cohort of 93 families (mean age±SD 42±16.3, 57% female) in the rural town of Baependi, Brazil. The Hospital Anxiety and Depression Scale (HADS) was used to assess depression and anxiety symptoms. Heritability estimates were obtained by an adjusted variance component model. Bivariate analyses were performed to obtain the partition of the covariance of anxiety and depression into genetic and environmental components, and to calculate the genetic contribution modulating both sets of symptoms. Anxiety and depression scores were 7.49±4.01 and 5.70±3.82, respectively. Mean scores were affected by age and were significantly higher in women. Heritability for depression and anxiety, corrected for age and sex, were 0.30 and 0.32, respectively. Significant genetic correlations (ρg = 0.81) were found between anxiety and depression scores; thus, nearly 66% of the total genetic variance in one set of symptoms was shared with the other set. Our results provided strong evidence for a genetic overlap between anxiety and depression symptoms, which has relevance for our understanding of the biological basis of these constructs and could be exploited in genome-wide association studies.


Assuntos
Ansiedade/genética , Depressão/genética , Adulto , Ansiedade/epidemiologia , Brasil/epidemiologia , Estudos de Coortes , Depressão/epidemiologia , Relações Familiares , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Fatores Sexuais , Meio Social
10.
Proc Natl Acad Sci U S A ; 112(28): 8696-701, 2015 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-26124090

RESUMO

While South Americans are underrepresented in human genomic diversity studies, Brazil has been a classical model for population genetics studies on admixture. We present the results of the EPIGEN Brazil Initiative, the most comprehensive up-to-date genomic analysis of any Latin-American population. A population-based genome-wide analysis of 6,487 individuals was performed in the context of worldwide genomic diversity to elucidate how ancestry, kinship, and inbreeding interact in three populations with different histories from the Northeast (African ancestry: 50%), Southeast, and South (both with European ancestry >70%) of Brazil. We showed that ancestry-positive assortative mating permeated Brazilian history. We traced European ancestry in the Southeast/South to a wider European/Middle Eastern region with respect to the Northeast, where ancestry seems restricted to Iberia. By developing an approximate Bayesian computation framework, we infer more recent European immigration to the Southeast/South than to the Northeast. Also, the observed low Native-American ancestry (6-8%) was mostly introduced in different regions of Brazil soon after the European Conquest. We broadened our understanding of the African diaspora, the major destination of which was Brazil, by revealing that Brazilians display two within-Africa ancestry components: one associated with non-Bantu/western Africans (more evident in the Northeast and African Americans) and one associated with Bantu/eastern Africans (more present in the Southeast/South). Furthermore, the whole-genome analysis of 30 individuals (42-fold deep coverage) shows that continental admixture rather than local post-Columbian history is the main and complex determinant of the individual amount of deleterious genotypes.


Assuntos
Genética Populacional , Mutação , População Negra/genética , Brasil , Humanos , População Branca/genética
11.
Sci Rep ; 5: 9214, 2015 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-25782397

RESUMO

Diurnal preference (chronotype) is a useful instrument for studying circadian biology in humans. It harbours trait-like dimensions relating to circadian period and sleep homeostasis, but also has ontogenetic components (morningness increases with age). We used the Morningness-Eveningness questionnaire (MEQ) in the Baependi study, a family-based cohort study based in a small town in Minas Gerais, Brazil. The population is highly admixed and has a cohesive and conservative lifestyle. 825 individuals (497 female) aged 18-89 years (average ± SD = 46.4 ± 16.3) and belonging to 112 different families participated in this study. The average MEQ score was 63.5 ± 11.2 with a significant (P < 0.0001) linear increase with age. Morningness was significantly (P < 0.0001) higher in the rural (70.2 ± 9.8) than in the municipal zone (62.6 ± 11.1), and was also significantly (P = 0.025) higher in male (64.6 ± 10.9) than in female (62.8 ± 11.2) participants. Thus, in spite of universal access to electricity, the Baependi population was strongly shifted towards morningness, particularly in the rural zone. Heritability of MEQ score was 0.48 when adjusted for sex and age, or 0.38 when adjusted for sex, age, and residential zone. The reported MEQ score heritability is more akin to those of previous twin studies than previous family studies.


Assuntos
Ritmo Circadiano/fisiologia , Sono/fisiologia , Vigília/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil , Estudos de Coortes , Demografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , População Rural , Fatores Sexuais , Privação do Sono/diagnóstico , Privação do Sono/patologia , Inquéritos e Questionários , Adulto Jovem
12.
Stat Appl Genet Mol Biol ; 13(3): 359-78, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24864303

RESUMO

Effective analytical tools are highly desirable for data analysis and for making the biological link between genotypic and phenotypic measures. In family data it is important to reconcile the methods that explain the phenotypic variability through fixed genetic effects and ones that estimate variance components using classical heritability methods. Thus, in this paper, we propose a method based on added-variable plot for polygenic linear mixed models applied to genome wide association studies in family-based designs. Our goal is to be able to discriminate genetic predictor variables in effects due to random polygenic and residual components. We also propose an index to detect influential families for each predictor variable identified with genetic effect. We assess the performance of our proposed method using our own family simulated data and the Genetic Analysis Workshop 17 family simulated data.


Assuntos
Modelos Genéticos , Estatística como Assunto , Simulação por Computador , Família , Humanos , Modelos Lineares , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
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