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Genomic studies in African populations provide unique opportunities to understand disease etiology, human diversity, and population history. In the largest study of its kind, comprising genome-wide data from 6,400 individuals and whole-genome sequences from 1,978 individuals from rural Uganda, we find evidence of geographically correlated fine-scale population substructure. Historically, the ancestry of modern Ugandans was best represented by a mixture of ancient East African pastoralists. We demonstrate the value of the largest sequence panel from Africa to date as an imputation resource. Examining 34 cardiometabolic traits, we show systematic differences in trait heritability between European and African populations, probably reflecting the differential impact of genes and environment. In a multi-trait pan-African GWAS of up to 14,126 individuals, we identify novel loci associated with anthropometric, hematological, lipid, and glycemic traits. We find that several functionally important signals are driven by Africa-specific variants, highlighting the value of studying diverse populations across the region.
Assuntos
População Negra/genética , Predisposição Genética para Doença , Genoma Humano/genética , Genômica , Feminino , Frequência do Gene/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Uganda/epidemiologia , Sequenciamento Completo do GenomaRESUMO
AIMS: We aimed to investigate the association of clinically overt and silent brain lesions with cognitive function in atrial fibrillation (AF) patients. METHODS AND RESULTS: We enrolled 1227 AF patients in a prospective, multicentre cohort study (Swiss-AF). Patients underwent standardized brain magnetic resonance imaging (MRI) at baseline and after 2 years. We quantified new small non-cortical infarcts (SNCIs) and large non-cortical or cortical infarcts (LNCCIs), white matter lesions (WML), and microbleeds (Mb). Clinically, silent infarcts were defined as new SNCI/LNCCI on follow-up MRI in patients without a clinical stroke or transient ischaemic attack (TIA) during follow-up. Cognition was assessed using validated tests. The mean age was 71 years, 26.1% were females, and 89.9% were anticoagulated. Twenty-eight patients (2.3%) experienced a stroke/TIA during 2 years of follow-up. Of the 68 (5.5%) patients with ≥1 SNCI/LNCCI, 60 (88.2%) were anticoagulated at baseline and 58 (85.3%) had a silent infarct. Patients with brain infarcts had a larger decline in cognition [median (interquartile range)] changes in Cognitive Construct score [-0.12 (-0.22; -0.07)] than patients without new brain infarcts [0.07 (-0.09; 0.25)]. New WML or Mb were not associated with cognitive decline. CONCLUSION: In a contemporary cohort of AF patients, 5.5% had a new brain infarct on MRI after 2 years. The majority of these infarcts was clinically silent and occurred in anticoagulated patients. Clinically, overt and silent brain infarcts had a similar impact on cognitive decline. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02105844, https://clinicaltrials.gov/ct2/show/NCT02105844.
Assuntos
Fibrilação Atrial , Ataque Isquêmico Transitório , Acidente Vascular Cerebral , Idoso , Fibrilação Atrial/complicações , Fibrilação Atrial/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Infarto Encefálico , Cognição , Estudos de Coortes , Feminino , Humanos , Ataque Isquêmico Transitório/complicações , Imageamento por Ressonância Magnética , Masculino , Estudos Prospectivos , Acidente Vascular Cerebral/patologiaRESUMO
Three main methods of blood pressure (BP) measurement are routinely used: office-based BP measures (OBPM), 24-hour ambulatory BP measures (ABPM), and home BP measures (HBPM). OBPM can lack precision, ABPM gives exhaustive information but is not comfortable, HBPM requires a device at home and the result is not immediate. The automated (unattended) office blood pressure measurement (AOBP) is a more recent method, simple to implement in the physician's office, permitting to largely avoid the white coat effect. The result is immediate and the readings are similar to those obtained by ABPM, the reference diagnostic method for hypertension. We describe the AOBP for practical application.
Trois méthodes de mesure de la pression artérielle (PA) sont principalement utilisées : la mesure simple de la PA en clinique (MPAC), la mesure ambulatoire de la PA sur 24 h (MAPA) et l'automesure de la PA (AMPA). La MPAC peut manquer de précision, la MAPA donne des informations exhaustives mais n'est pas très confortable, l'AMPA nécessite un appareil à domicile et l'interprétation du résultat n'est pas immédiate. Une méthode plus récente est la mesure automatique et non observée de la PA (MNPA). Il s'agit d'un procédé simple, qui peut être facilement implémenté au cabinet et qui permet d'éviter en grande partie l'effet blouse blanche. Le résultat est immédiat et les valeurs sont similaires aux mesures par MAPA, la méthode de référence de diagnostic de l'hypertension artérielle. Nous décrivons ici la MNPA pour la pratique.
Assuntos
Hipertensão , Médicos , Humanos , Pressão Sanguínea , Determinação da Pressão Arterial , Hipertensão/diagnóstico , Consultórios MédicosRESUMO
Hundreds of loci have been associated with blood pressure (BP) traits from many genome-wide association studies. We identified an enrichment of these loci in aorta and tibial artery expression quantitative trait loci in our previous work in ~100 000 Genetic Epidemiology Research on Aging study participants. In the present study, we sought to fine-map known loci and identify novel genes by determining putative regulatory regions for these and other tissues relevant to BP. We constructed maps of putative cis-regulatory elements (CREs) using publicly available open chromatin data for the heart, aorta and tibial arteries, and multiple kidney cell types. Variants within these regions may be evaluated quantitatively for their tissue- or cell-type-specific regulatory impact using deltaSVM functional scores, as described in our previous work. We aggregate variants within these putative CREs within 50 Kb of the start or end of 'expressed' genes in these tissues or cell types using public expression data and use deltaSVM scores as weights in the group-wise sequence kernel association test to identify candidates. We test for association with both BP traits and expression within these tissues or cell types of interest and identify the candidates MTHFR, C10orf32, CSK, NOV, ULK4, SDCCAG8, SCAMP5, RPP25, HDGFRP3, VPS37B and PPCDC. Additionally, we examined two known QT interval genes, SCN5A and NOS1AP, in the Atherosclerosis Risk in Communities Study, as a positive control, and observed the expected heart-specific effect. Thus, our method identifies variants and genes for further functional testing using tissue- or cell-type-specific putative regulatory information.
Assuntos
Aterosclerose/genética , Pressão Sanguínea/genética , Locos de Características Quantitativas/genética , Sequências Reguladoras de Ácido Nucleico/genética , Aorta/fisiopatologia , Aterosclerose/fisiopatologia , Pressão Sanguínea/fisiologia , Cromatina , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla , Coração/fisiopatologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Rim/fisiopatologia , Proteínas de Membrana/genética , Artérias da Tíbia/fisiopatologiaRESUMO
BACKGROUND: Lipoprotein(a) [Lp(a)] is an LDL-like molecule that is likely causal for cardiovascular events and Lp(a) variability has been shown to be mostly of genetic origin. Exogenous hormones (hormone replacement therapy) seem to influence Lp(a) levels, but the impact of endogenous hormone levels on Lp(a) is still unknown. The aim of the study was to assess the effect of endogenous steroid hormone metabolites on Lp(a). METHODS: Lipoprotein(a) levels were measured in 1,021 participants from the Swiss Kidney Project on Genes in Hypertension, a family-based, multicentre, population-based prospective cohort study. Endogenous levels of 28 steroid hormone precursors were measured in 24-h urine collections from 883 individuals. Of the participants with Lp(a) data, 1,011 participants had also genotypes available. RESULTS: The participants had an average age of 51 years and 53% were female. Median Lp(a) levels were 62 mg/L, and the 90th percentile was 616 mg/L. The prevalence of a Lp(a) elevation ≥700 mg/L was 3.2%. Forty-three per cent of Lp(a) variability was explained respectively by: age (2%, p < .001), LDL-C (1%, p = .001), and two SNPs (39%, p value<2â 10-16 ). Of the 28 endogenous steroid hormones assessed, androstenetriol, androsterone, 16α-OH-DHEA and estriol were nominatively associated with serum Lp(a) levels in univariable analyses and explained 0.4%-1% of Lp(a) variability, but none of them reached significance in multivariable models. CONCLUSIONS: In this contemporary population-based study, the prevalence of a Lp(a) elevation ≥700 mg/L was 3.2%. The effect of endogenous steroid hormone levels of Lp(a) variability was small at best, suggesting a negligible impact on the wide range of Lp(a) variability.
Assuntos
Hormônios/fisiologia , Lipoproteína(a)/sangue , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
The recent advent of high-throughput sequencing technologies has allowed exploring the contribution of thousands of genomic, epigenomic, transcriptomic, or proteomic variants to complex phenotypic traits. Here, we sought to conduct large-scale (Epi)Genome-Wide Association Studies (GWAS/EWAS) to investigate the associations between genomic (Single Nucleotide Polymorphism; SNP) and epigenomic (Cytosine-Phospho-Guanine; CpG) markers, with multiple phenotypic traits in a population-based context. We used data from SKIPOGH, a family- and population-based cohort conducted in the cities of Lausanne, Geneva, and Bern (N=1100). We used 7,577,572 SNPs, 420,444 CpGs, and 825 phenotypes, including anthropometric, clinical, blood, urine, metabolite, and metal measures. GWAS analyses assessed the associations between SNPs and metabolites and metals (N=279), using regression models adjusted for age, sex, recruitment center, and familial structure, whereas EWAS analyses explored the relations between CpGs and 825 phenotypes, additionally adjusting for the seasonality of blood sampling and technical nuisance. Following the implementation of GWAS and EWAS analyses, we developed a web-based platform, PhenoExplorer, aimed at providing an open access to the obtained results. Of the 279 phenotypes included in GWAS, 103 displayed significant associations with 2804 SNPs (2091 unique SNPs) at Bonferroni threshold, whereas 109 of the 825 phenotypes included in EWAS analyses were associated with 4893 CpGs (2578 unique CpGs). All of the obtained GWAS and EWAS results were eventually made available using the in-house built web-based PhenoExplorer platform, with the purpose of providing an open-access to the tested associations. In conclusion, we provide a comprehensive outline of GWAS and EWAS associations performed in a Swiss population-based study. Further, we set up a web-based PhenoExplorer platform with the purpose of contributing to the overall understanding of the role of molecular variants in regulating complex phenotypes.
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The latest ESC recommendations propose several interesting new concepts for the practitioner. The recommendations distinguish between the «apparently healthy¼ patient and the patient at specific cardiovascular risk (diabetes, renal failure, and familial hypercholesterolemia). New risk calculation tools are proposed (SCORE2 and SCORE2-OP). The proposed LDL-C targets are specific to each group, as a general rule, < 1.8 mmol/l for individuals at high risk and < 1.4 mmol/l for individuals at very high risk. Presence of risk modifiers, comorbidities and patient preferences modulates therapeutic approach which is usually based on optimizing lifestyle and statin medication when necessary.
Les dernières recommandations de l'European Society of Cardiology (ESC) introduisent plusieurs nouveaux concepts intéressants pour le praticien. Le patient «en bonne santé apparente¼ est différencié de celui à risque spécifique (diabète, insuffisance rénale et hypercholestérolémie familiale). De nouveaux outils de calcul du risque cardiovasculaire sont proposés (SCORE2 et SCORE2-OP). Les cibles de LDL-C proposées sont spécifiques à chaque groupe avec, en règle générale, une valeur < 1,8 mmol/l pour les patients à haut risque et < 1,4 mmol/l pour ceux à très haut risque. La présence de modificateurs de risque, les comorbidités et les préférences du patient modulent l'approche thérapeutique, qui repose habituellement sur le respect des règles hygiénodiététiques et, au besoin, l'administration d'une statine.
Assuntos
Anticolesterolemiantes , Doenças Cardiovasculares , Inibidores de Hidroximetilglutaril-CoA Redutases , Hiperlipoproteinemia Tipo II , Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Estilo de Vida , Fatores de RiscoRESUMO
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
Assuntos
Tecido Adiposo/metabolismo , Distribuição da Gordura Corporal , Estudo de Associação Genômica Ampla , Insulina/metabolismo , Locos de Características Quantitativas/genética , Adipócitos/metabolismo , Adipogenia/genética , Fatores Etários , Índice de Massa Corporal , Epigênese Genética , Europa (Continente)/etnologia , Feminino , Genoma Humano/genética , Humanos , Resistência à Insulina/genética , Masculino , Modelos Biológicos , Neovascularização Fisiológica/genética , Obesidade/genética , Polimorfismo de Nucleotídeo Único/genética , Grupos Raciais/genética , Caracteres Sexuais , Transcrição Gênica/genética , Relação Cintura-QuadrilRESUMO
Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for â¼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
Assuntos
Índice de Massa Corporal , Estudo de Associação Genômica Ampla , Obesidade/genética , Obesidade/metabolismo , Adipogenia/genética , Adiposidade/genética , Fatores Etários , Metabolismo Energético/genética , Europa (Continente)/etnologia , Feminino , Predisposição Genética para Doença/genética , Ácido Glutâmico/metabolismo , Humanos , Insulina/metabolismo , Secreção de Insulina , Masculino , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Grupos Raciais/genética , Sinapses/metabolismoRESUMO
PURPOSE: Poor adherence to drug therapy and inadequate drug regimens are two frequent factors responsible for the poor blood pressure (BP) control observed in patients with apparent resistant hypertension. We evaluated the efficacy of an antihypertensive management strategy combining a standardised therapy with three long acting drugs and electronic monitoring of drug adherence in patients with apparent resistant hypertension. MATERIALS AND METHODS: In this multicentric observational study, adult patients with residual hypertension on 24 h ambulatory BP monitoring (ABMP) despite the use of three or more antihypertensive drugs could be included. Olmesartan/amlodipine (40/10 mg, single pill fixed-dose combination) and chlorthalidone (25 mg) were prescribed for 3 months in two separated electronic pills boxes (EPB). The primary outcome was 24 h ambulatory systolic BP (SBP) control at 3 months, defined as mean SBP <130 mmHg. RESULTS: We enrolled 48 patients (36.0% women) of whom 35 had complete EPB data. After 3 months, 52.1% of patients had 24 h SBP <130 mmHg. 24 h SBP decreased by respectively -9.1 ± 15.5 mmHg, -22.8 ± 30.6 mmHg and -27.7 ± 16.6 mmHg from the tertile with the lowest adherence to the tertile with the highest adherence to the single pill combination (p = 0.024). A similar trend was observed with tertiles of adherence to chlorthalidone. Adherence superior to 90% was associated with 24 h systolic and diastolic blood pressure control in multiple logistic regression analysis (odds ratio = 14.1 (95% confidence interval 1.1-173.3, p = 0.039). CONCLUSIONS: A simplified standardised antihypertensive therapy combined with electronic monitoring of adherence normalises SBP in about half of patients with apparent resistant hypertension. Such combined management strategy enables identifying patients who need complementary investigations and those who rather need a long-term support of their adherence.
Assuntos
Monitorização Ambulatorial da Pressão Arterial , Hipertensão , Adulto , Anlodipino , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Feminino , Humanos , Hipertensão/tratamento farmacológico , Masculino , Adesão à Medicação , Resultado do TratamentoRESUMO
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is responsible for the degradation of the LDL-receptor. Inclisiran is a new synthetic interfering ribonucleic acid (siRNA) lowers LDL-cholesterol (LDL-C) levels in the blood by using RNA silencing technology to reduce the production of PCSK9. Inclisiran administered subcutaneously at 0 and 3 months, and then every 6 months has been shown to reduce LDL-C by approximately 50 % in patients at high and very-high cardiovascular risk, or with a diagnosis of familial hypercholesterolemia, but also in patients intolerant to statins. New data are expected, in particular with cardiovascular clinical endpoints, as well as safety for use in adolescents.
La proprotéine convertase subtilisine/kexine de type 9 (PCSK9) est responsable de la dégradation du LDL (Low Density Lipoprotein)-récepteur. L'inclisiran est un nouveau petit ARN interférent synthétique qui baisse les taux de LDL-cholestérol (LDL-C) circulant en utilisant la technologie de silençage ARN pour réduire la production de PCSK9. Administré par voie sous-cutanée à 0 et 3 mois, puis tous les 6 mois, l'inclisiran a démontré une réduction du LDL-C d'environ 50 % chez des patients à haut et très haut risque cardiovasculaire ou avec un diagnostic d'hypercholestérolémie familiale, mais aussi chez des patients intolérants aux statines. De nouvelles données sont attendues, notamment sur les critères de jugement cliniques cardiovasculaires, ainsi que la sécurité d'emploi chez les adolescents.
Assuntos
Anticolesterolemiantes , Inibidores de Hidroximetilglutaril-CoA Redutases , Hiperlipoproteinemia Tipo II , Adolescente , Anticolesterolemiantes/uso terapêutico , LDL-Colesterol , Humanos , Pró-Proteína Convertase 9RESUMO
BACKGROUND: High-intensity interval training (HIIT) has been shown to be more effective than moderate-intensity continuous training (MICT) for the physical rehabilitation. However, data on its suitability for older hospitalized patients is scarce. METHODS: Randomized controlled trial in a hospital setting. Inclusion of 100 patients, ≥65 years old, hospitalized for rehabilitation after an acute medical condition, in a two-week rehabilitation program of either four HIIT or three MICT sessions per week. Completion was defined as participation in all but two planned sessions accomplishing ≥50% of each session. We assessed: upper-limb muscle strength (handgrip isometric strength test), lower-limb muscle strength (quadriceps and ankle flexion and extension tests); gait speed and spatio-temporal parameters (instrumented walkway), and exercise capacity (6-min walk test). All adverse events were recorded as safety endpoints. RESULTS: An intention-to-treat analysis showed a 44% completion rate for the HIIT group (95% CI, 30-59) and 77% for MICT (95% CI, 55-82). A modified intention-to-treat analysis restricted to patients who participated in ≥1 session showed an 88% completion rate in the HIIT group (95%CI, 69-97) and an 80% completion rate in MICT (95%CI, 65-90). The exercises most frequently undertaken were the pedal exerciser (54%) and the NuStep (32%). There were no significant differences in the various measures. No serious adverse events occurred. CONCLUSION: A HIIT rehabilitation program for this population was feasible, safe and had a high adherence rate. TRIAL REGISTRATION NUMBER: Clinicatrials.gov ID: NCT02318459. Trial registration date: November 7th, 2014. Retrospectively registered. This study adheres to the CONSORT guidelines.
Assuntos
Treinamento Intervalado de Alta Intensidade , Idoso , Estudos de Viabilidade , Força da Mão , Humanos , Pacientes Internados , Projetos PilotoRESUMO
[This corrects the article DOI: 10.1371/journal.pgen.1005378.].
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Magnesium (Mg2+) homeostasis is critical for metabolism. However, the genetic determinants of the renal handling of Mg2+, which is crucial for Mg2+ homeostasis, and the potential influence on metabolic traits in the general population are unknown. We obtained plasma and urine parameters from 9099 individuals from seven cohorts, and conducted a genome-wide meta-analysis of Mg2+ homeostasis. We identified two loci associated with urinary magnesium (uMg), rs3824347 (P=4.4×10-13) near TRPM6, which encodes an epithelial Mg2+ channel, and rs35929 (P=2.1×10-11), a variant of ARL15, which encodes a GTP-binding protein. Together, these loci account for 2.3% of the variation in 24-hour uMg excretion. In human kidney cells, ARL15 regulated TRPM6-mediated currents. In zebrafish, dietary Mg2+ regulated the expression of the highly conserved ARL15 ortholog arl15b, and arl15b knockdown resulted in renal Mg2+ wasting and metabolic disturbances. Finally, ARL15 rs35929 modified the association of uMg with fasting insulin and fat mass in a general population. In conclusion, this combined observational and experimental approach uncovered a gene-environment interaction linking Mg2+ deficiency to insulin resistance and obesity.
Assuntos
Fatores de Ribosilação do ADP/genética , Homeostase/genética , Rim/metabolismo , Magnésio/sangue , Magnésio/urina , Canais de Cátion TRPM/genética , Adiposidade/genética , Animais , Proteínas de Ligação ao GTP/genética , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Humanos , Insulina/sangue , Resistência à Insulina/genética , Magnésio/administração & dosagem , Camundongos , Obesidade/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/metabolismo , Peixe-Zebra , Proteínas de Peixe-Zebra/genéticaRESUMO
Aims: Sudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. We aim to identify potential loci associated with SCA and to identify risk factors causally associated with SCA. Methods and results: We carried out a large genome-wide association study (GWAS) for SCA (n = 3939 cases, 25 989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization (MR) methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. No variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (i) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (ii) height and BMI, and (iii) electrical instability traits (QT and atrial fibrillation), suggesting aetiologic roles for these traits in SCA risk. Conclusions: Our findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in high-risk populations and the general community.
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Arritmias Cardíacas/genética , Morte Súbita Cardíaca/etiologia , Arritmias Cardíacas/fisiopatologia , Índice de Massa Corporal , Doença da Artéria Coronariana/genética , Feminino , Estudo de Associação Genômica Ampla , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Masculino , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Medição de Risco/métodos , Fatores de Risco , Fatores SexuaisRESUMO
Caffeine is the most widely consumed psychoactive substance in the world and presents with wide interindividual variation in metabolism. This variation may modify potential adverse or beneficial effects of caffeine on health. We conducted a genome-wide association study (GWAS) of plasma caffeine, paraxanthine, theophylline, theobromine and paraxanthine/caffeine ratio among up to 9,876 individuals of European ancestry from six population-based studies. A single SNP at 6p23 (near CD83) and several SNPs at 7p21 (near AHR), 15q24 (near CYP1A2) and 19q13.2 (near CYP2A6) met GW-significance (P < 5 × 10-8) and were associated with one or more metabolites. Variants at 7p21 and 15q24 associated with higher plasma caffeine and lower plasma paraxanthine/caffeine (slow caffeine metabolism) were previously associated with lower coffee and caffeine consumption behavior in GWAS. Variants at 19q13.2 associated with higher plasma paraxanthine/caffeine (slow paraxanthine metabolism) were also associated with lower coffee consumption in the UK Biobank (n = 94 343, P < 1.0 × 10-6). Variants at 2p24 (in GCKR), 4q22 (in ABCG2) and 7q11.23 (near POR) that were previously associated with coffee consumption in GWAS were nominally associated with plasma caffeine or its metabolites. Taken together, we have identified genetic factors contributing to variation in caffeine metabolism and confirm an important modulating role of systemic caffeine levels in dietary caffeine consumption behavior. Moreover, candidate genes identified encode proteins with important clinical functions that extend beyond caffeine metabolism.
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Antígenos CD/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Cafeína/genética , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP2A6/genética , Imunoglobulinas/genética , Glicoproteínas de Membrana/genética , Receptores de Hidrocarboneto Arílico/genética , Cafeína/sangue , Café/genética , Café/metabolismo , Citocromo P-450 CYP1A2/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Teobromina/sangue , Teofilina/sangue , População Branca , Antígeno CD83RESUMO
Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.
Assuntos
Índice de Massa Corporal , Tamanho Corporal/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Adulto , Fatores Etários , Idoso , Mapeamento Cromossômico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Caracteres Sexuais , Relação Cintura-Quadril , População BrancaRESUMO
The handling of electrolytes by the kidney is essential for homeostasis. However, the heritability of these processes, the first step in gene discovery, is poorly known. To help clarify this, we estimated the heritability of serum concentration, urinary excretion, renal clearance, and fractional excretion of sodium, potassium, magnesium, calcium, phosphate, and chloride in a population-based study. Nuclear families were randomly selected from the general population in Lausanne, Geneva, and Bern, Switzerland, and urine collected over 24-hour periods. We used the ASSOC program (S.A.G.E.) to estimate narrow sense heritability, including sex, age, body mass index, and study center as covariates in the model. The 1128 participants, from 273 families, had a mean age of 47 years, body mass index of 25.0 kg/m2, and an estimated glomerular filtration rate (CKD-EPI) of 98 mL/min/1.73 m2. The heritability of serum concentration was highest for calcium, 37% and lowest for sodium, 13%. The heritability of 24-hour urine clearances, excretions, and fractional excretions ranged from 15%, 10%, and 16%, respectively, for potassium to 45%, 44%, and 51%, respectively, for calcium. All probability values were significant. The heritability for phosphate-related phenotypes was lower than that for calcium. Thus, the serum and urine concentrations as well as urinary excretion and renal handling of electrolytes are heritable in the general adult population. The phenotypic variance attributable to additive genetic factors was variable and was higher for calcium. These results pave the way for identifying genetic variants involved in electrolyte homeostasis in the general population.
Assuntos
Eletrólitos/metabolismo , Homeostase/genética , Rim/fisiopatologia , Eliminação Renal/genética , Adulto , Estudos de Coortes , Biologia Computacional , Eletrólitos/sangue , Eletrólitos/urina , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Software , SuíçaRESUMO
Most body mass index (BMI) genetic loci have been identified in studies of primarily European ancestries. The effect of these loci in other racial/ethnic groups is less clear. Thus, we aimed to characterize the generalizability of 170 established BMI variants, or their proxies, to diverse US populations and trans-ethnically fine-map 36 BMI loci using a sample of >102,000 adults of African, Hispanic/Latino, Asian, European and American Indian/Alaskan Native descent from the Population Architecture using Genomics and Epidemiology Study. We performed linear regression of the natural log of BMI (18.5-70 kg/m2) on the additive single nucleotide polymorphisms (SNPs) at BMI loci on the MetaboChip (Illumina, Inc.), adjusting for age, sex, population stratification, study site, or relatedness. We then performed fixed-effect meta-analyses and a Bayesian trans-ethnic meta-analysis to empirically cluster by allele frequency differences. Finally, we approximated conditional and joint associations to test for the presence of secondary signals. We noted directional consistency with the previously reported risk alleles beyond what would have been expected by chance (binomial p < 0.05). Nearly, a quarter of the previously described BMI index SNPs and 29 of 36 densely-genotyped BMI loci on the MetaboChip replicated/generalized in trans-ethnic analyses. We observed multiple signals at nine loci, including the description of seven loci with novel multiple signals. This study supports the generalization of most common genetic loci to diverse ancestral populations and emphasizes the importance of dense multiethnic genomic data in refining the functional variation at genetic loci of interest and describing several loci with multiple underlying genetic variants.
Assuntos
Índice de Massa Corporal , Etnicidade/genética , Genética Populacional , Humanos , Obesidade/epidemiologia , Obesidade/genéticaRESUMO
Although age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p ≤ 5 × 10(-8)) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 × 10(-4)) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations.