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1.
Nat Commun ; 12(1): 24, 2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33402679

RESUMO

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.


Assuntos
Anorexia Nervosa/genética , Glicemia/metabolismo , Intolerância à Glucose/genética , Proteínas Substratos do Receptor de Insulina/genética , Resistência à Insulina/genética , Insulina/sangue , Fatores de Transcrição Kruppel-Like/genética , Adulto , Anorexia Nervosa/sangue , Anorexia Nervosa/etnologia , Anorexia Nervosa/fisiopatologia , Grupo com Ancestrais do Continente Europeu , Jejum/sangue , Feminino , Expressão Gênica , Loci Gênicos , Estudo de Associação Genômica Ampla , Intolerância à Glucose/sangue , Intolerância à Glucose/etnologia , Intolerância à Glucose/fisiopatologia , Humanos , Proteínas Substratos do Receptor de Insulina/sangue , Fatores de Transcrição Kruppel-Like/sangue , Masculino , Pessoa de Meia-Idade , Fenótipo , Caracteres Sexuais , Fatores Sexuais , Relação Cintura-Quadril
2.
J Am Heart Assoc ; : e016808, 2020 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-33287642

RESUMO

Background Caffeine is the most widely consumed psychostimulant and is associated with lower risk of coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM). However, whether these associations are causal remains unknown. This study aimed to identify genetic variants associated with caffeine intake, and to investigate evidence for causal links with CAD or T2DM. In addition, we aimed to replicate previous observational findings. Methods and Results Observational associations were tested within UK Biobank using Cox regression analyses. Moderate observational caffeine intakes from coffee or tea were associated with lower risks of CAD or T2DM, with the lowest risks at intakes of 121 to 180 mg/day from coffee for CAD (hazard ratio [HR], 0.77 [95% CI, 0.73-0.82; P<1×10-16]), and 301 to 360 mg/day for T2DM (HR, 0.76 [95% CI, 0.67-0.86]; P=1.57×10-5). Next, genome-wide association studies were performed on self-reported caffeine intake from coffee, tea, or both in 407 072 UK Biobank participants. These analyses identified 51 novel genetic variants associated with caffeine intake at P<1.67×10-8. These loci were enriched for central nervous system genes. However, in contrast to the observational analyses, 2-sample Mendelian randomization analyses using the identified loci in independent disease-specific cohorts yielded no evidence for causal links between genetically determined caffeine intake and the development of CAD or T2DM. Conclusions Mendelian randomization analyses indicate genetically determined higher caffeine intake might not protect against CAD or T2DM, despite protective associations in observational analyses.

3.
Sci Rep ; 10(1): 14771, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901066

RESUMO

Small-scale studies have suggested a link between the human gut microbiome and highly prevalent diseases. However, the extent to which the human gut microbiome can be considered a determinant of disease and healthy aging remains unknown. We aimed to determine the spectrum of diseases that are linked to the human gut microbiome through the utilization of its genetic determinants as a proxy for its composition. 180 single nucleotide polymorphisms (SNPs) known to influence the human gut microbiome were used to assess the association with health and disease outcomes in 422,417 UK Biobank participants. Potential causal estimates were obtained using a Mendelian randomization (MR) approach. From the total sample analysed (mean age was 57 ± 8 years), 194,567 (46%) subjects were male. Median exposure was 66-person years (interquartile range 59-72). Eleven SNPs were significantly associated with 28 outcomes (Bonferroni corrected P value < 4.63·10-6) including food intake, hypertension, atopy, COPD, BMI, and lipids. Multiple SNP MR pointed to a possible causal link between Ruminococcus flavefaciens and hypertension, and Clostridium and platelet count. Microbiota and their metabolites might be of importance in the interplay between overlapping pathophysiological processes, although challenges remain in establishing causal relationships.

4.
Cell Syst ; 11(3): 229-238.e5, 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32916098

RESUMO

The electrocardiogram (ECG) is one of the most useful non-invasive diagnostic tests for a wide array of cardiac disorders. Traditional approaches to analyzing ECGs focus on individual segments. Here, we performed comprehensive deep phenotyping of 77,190 ECGs in the UK Biobank across the complete cycle of cardiac conduction, resulting in 500 spatial-temporal datapoints, across 10 million genetic variants. In addition to characterizing polygenic risk scores for the traditional ECG segments, we identified over 300 genetic loci that are statistically associated with the high-dimensional representation of the ECG. We established the genetic ECG signature for dilated cardiomyopathy, associated the BAG3, HSPB7/CLCNKA, PRKCA, TMEM43, and OBSCN loci with disease risk and confirmed this association in an independent cohort. In total, our work demonstrates that a high-dimensional analysis of the entire ECG provides unique opportunities for studying cardiac biology and disease and furthering drug development. A record of this paper's transparent peer review process is included in the Supplemental Information.

5.
J Nutr ; 150(10): 2635-2645, 2020 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-32840624

RESUMO

BACKGROUND: Excess sodium intake and insufficient potassium intake are risk factors for hypertension, but there is limited knowledge regarding genetic factors that influence intake. Twenty-hour or half-day urine samples provide robust estimates of sodium and potassium intake, outperforming other measures such as spot urine samples and dietary self-reporting. OBJECTIVE: The aim of this study was to investigate genomic regions associated with sodium intake, potassium intake, and sodium-to-potassium ratio measured from 24-h or half-day urine samples. METHODS: Using samples of European ancestry (mean age: 54.2 y; 52.3% women), we conducted a meta-analysis of genome-wide association studies in 4 cohorts with 24-h or half-day urine samples (n = 6,519), followed by gene-based analysis. Suggestive loci (P < 10-6) were examined in additional European (n = 844), African (n = 1,246), and Asian (n = 2,475) ancestry samples. RESULTS: We found suggestive loci (P < 10-6) for all 3 traits, including 7 for 24-h sodium excretion, 4 for 24-h potassium excretion, and 4 for sodium-to-potassium ratio. The most significant locus was rs77958157 near cocaine- and amphetamine-regulated transcript prepropeptide (CARTPT) , a gene involved in eating behavior and appetite regulation (P = 2.3 × 10-8 with sodium-to-potassium ratio). Two suggestive loci were replicated in additional samples: for sodium excretion, rs12094702 near zinc finger SWIM-type containing 5 (ZSWIM5) was replicated in the Asian ancestry sample reaching Bonferroni-corrected significance (P = 0.007), and for potassium excretion rs34473523 near sodium leak channel (NALCN) was associated at a nominal P value with potassium excretion both in European (P = 0.043) and African (P = 0.043) ancestry cohorts. Gene-based tests identified 1 significant gene for sodium excretion, CDC42 small effector 1 (CDC42SE1), which is associated with blood pressure regulation. CONCLUSIONS: We identified multiple suggestive loci for sodium and potassium intake near genes associated with eating behavior, nervous system development and function, and blood pressure regulation in individuals of European ancestry. Further research is needed to replicate these findings and to provide insight into the underlying genetic mechanisms by which these genomic regions influence sodium and potassium intake.

6.
Circ Genom Precis Med ; 13(5): 387-395, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32822252

RESUMO

BACKGROUND: The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD. METHODS: Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies. RESULTS: We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci (TTN, CAND2, SCN10A, PITX2, CAV1, SYNPO2L, SOX5, TBX5, MYH6, RPL3L). The top variants at known sarcomere genes (TTN, MYH6) were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, PITX2 and SCN10A) were associated with longer PWD but lower AF risk. CONCLUSIONS: Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.

7.
Nat Commun ; 11(1): 1770, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32317632

RESUMO

Leisure sedentary behaviours are associated with increased risk of cardiovascular disease, but whether this relationship is causal is unknown. The aim of this study is to identify genetic determinants associated with leisure sedentary behaviours and to estimate the potential causal effect on coronary artery disease (CAD). Genome wide association analyses of leisure television watching, leisure computer use and driving behaviour in the UK Biobank identify 145, 36 and 4 genetic loci (P < 1×10-8), respectively. High genetic correlations are observed between sedentary behaviours and neurological traits, including education and body mass index (BMI). Two-sample Mendelian randomization (MR) analysis estimates a causal effect between 1.5 hour increase in television watching and CAD (OR 1.44, 95%CI 1.25-1.66, P = 5.63 × 10-07), that is partially independent of education and BMI in multivariable MR analyses. This study finds independent observational and genetic support for the hypothesis that increased sedentary behaviour by leisure television watching is a risk factor for CAD.


Assuntos
Doença da Artéria Coronariana , Transtornos Mentais/genética , Comportamento Sedentário , Adulto , Idoso , Índice de Massa Corporal , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/etiologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Transtornos Mentais/complicações , Pessoa de Meia-Idade , Fatores de Risco , Reino Unido/epidemiologia
9.
Nat Commun ; 11(1): 163, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31919418

RESUMO

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.


Assuntos
Fibrilação Atrial/genética , Cardiomiopatias/genética , Doença da Artéria Coronariana/genética , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Função Ventricular Esquerda/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Cardiomiopatias/patologia , Proteínas de Transporte/genética , Estudos de Casos e Controles , Inibidor de Quinase Dependente de Ciclina p21/genética , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Proteínas dos Microfilamentos/genética , Proteínas Musculares/genética , Fatores de Risco
10.
Eur J Epidemiol ; 35(2): 123-137, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31773475

RESUMO

The relationship between circulating total bilirubin and incident non-alcoholic fatty liver disease (NAFLD) is uncertain. We aimed to assess the association of total bilirubin with the risk of new-onset NAFLD and investigate any causal relevance to the association using a Mendelian randomization (MR) study. Plasma total bilirubin levels were measured at baseline in the PREVEND prospective study of 3824 participants (aged 28-75 years) without pre-existing cardiovascular disease or NAFLD. Incident NAFLD was estimated using the biomarker-based algorithms, fatty liver index (FLI) and hepatic steatosis index (HSI). Odds ratios (ORs) (95% confidence intervals) for NAFLD were assessed. The genetic variant rs6742078 located in the UDP-glucuronosyltransferase (UGT1A1) locus was used as an instrumental variable. Participants were followed up for a mean duration of 4.2 years. The multivariable adjusted OR (95% CIs) for NAFLD as estimated by FLI (434 cases) was 0.82 (0.73-0.92; p = 0.001) per 1 standard deviation (SD) change in loge total bilirubin. The corresponding adjusted OR (95% CIs) for NAFLD as estimated by HSI (452 cases) was 0.87 (0.78-0.97; p = 0.012). The rs6742078 variant explained 20% of bilirubin variation. The ORs (95% CIs) for a 1 SD genetically elevated total bilirubin level was 0.98 (0.69-1.38; p = 0.900) for FLI and 1.14 (0.81-1.59; p = 0.451) for HSI. Elevated levels of total bilirubin were not causally associated with decreased risk of NAFLD based on MR analysis. The observational association may be driven by biases such as unmeasured confounding and/or reverse causation. However, due to low statistical power, larger-scale investigations are necessary to draw definitive conclusions.


Assuntos
Bilirrubina/sangue , Glucuronosiltransferase/genética , Análise da Randomização Mendeliana , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/genética , Adulto , Idoso , Biomarcadores/sangue , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Estudos Prospectivos , Fatores de Risco
11.
Genes (Basel) ; 10(11)2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31703460

RESUMO

Lower levels of physical activity (PA) have been associated with increased risk of cardiovascular disease. Worldwide, there is a shift towards a lifestyle with less PA, posing a serious threat to public health. One of the suggested mechanisms behind the association between PA and disease development is through systemic inflammation, in which circulating blood cells play a pivotal role. In this study we investigated the relationship between genetically determined PA and circulating blood cells. We used 68 single nucleotide polymorphisms associated with objectively measured PA levels to perform a Mendelian randomization analysis on circulating blood cells in 222,645 participants of the UK Biobank. For inverse variance fixed effects Mendelian randomization analyses, p < 1.85 × 10-3 (Bonferroni-adjusted p-value of 0.05/27 tests) was considered statistically significant. Genetically determined increased PA was associated with decreased lymphocytes (ß = -0.03, SE = 0.008, p = 1.35 × 10-3) and decreased eosinophils (ß = -0.008, SE = 0.002, p = 1.36 × 10-3). Although further mechanistic studies are warranted, these findings suggest increased physical activity is associated with an improved inflammatory state with fewer lymphocytes and eosinophils.


Assuntos
Eosinofilia/genética , Exercício Físico , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Contagem de Células Sanguíneas , Eosinofilia/epidemiologia , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade
12.
JCI Insight ; 4(23)2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31600170

RESUMO

BACKGROUNDThe presence of an early repolarization pattern (ERP) on the surface ECG is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait, but molecular genetic determinants are unknown.METHODSTo identify genetic susceptibility loci for ERP, we performed a GWAS and meta-analysis in 2,181 cases and 23,641 controls of European ancestry.RESULTSWe identified a genome-wide significant (P < 5 × 10-8) locus in the potassium voltage-gated channel subfamily D member 3 (KCND3) gene that was successfully replicated in additional 1,124 cases and 12,510 controls. A subsequent joint meta-analysis of the discovery and replication cohorts identified rs1545300 as the lead SNP at the KCND3 locus (OR 0.82 per minor T allele, P = 7.7 × 10-12) but did not reveal additional loci. Colocalization analyses indicate causal effects of KCND3 gene expression levels on ERP in both cardiac left ventricle and tibial artery.CONCLUSIONSIn this study, we identified for the first time to our knowledge a genome-wide significant association of a genetic variant with ERP. Our findings of a locus in the KCND3 gene provide insights not only into the genetic determinants but also into the pathophysiological mechanism of ERP, discovering a promising candidate for functional studies.FUNDINGThis project was funded by the German Center for Cardiovascular Research (DZHK Shared Expertise SE081 - STATS). For detailed funding information per study, see the Supplemental Acknowledgments.


Assuntos
Eletrocardiografia/métodos , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Canais de Potássio Shal/genética , Fibrilação Ventricular/genética , Alelos , Morte Súbita Cardíaca , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Loci Gênicos , Genótipo , Ventrículos do Coração , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Transcriptoma
13.
Hypertension ; 74(4): 826-832, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31476911

RESUMO

We aimed to estimate the effects of a lifelong exposure to high systolic blood pressure (SBP) on left ventricular (LV) structure and function using Mendelian randomization. A total of 5596 participants of the UK Biobank were included for whom cardiovascular magnetic resonance imaging and genetic data were available. Major exclusion criteria included nonwhite ethnicity, major cardiovascular disease, and body mass index >30 or <18.5 kg/m2. A genetic risk score to estimate genetically predicted SBP (gSBP) was constructed based on 107 previously established genetic variants. Manual cardiovascular magnetic resonance imaging postprocessing analyses were performed in 300 individuals at the extremes of gSBP (150 highest and lowest). Multivariable linear regression analyses of imaging biomarkers were performed using gSBP as continuous independent variable. All analyses except myocardial strain were validated using previously derived imaging parameters in 2530 subjects. The mean (SD) age of the study population was 62 (7) years, and 52% of subjects were female. Corrected for age, sex, and body surface area, each 10 mm Hg increase in gSBP was significantly (P<0.0056) associated with 4.01 g (SE, 1.28; P=0.002) increase in LV mass and with 2.80% (SE, 0.97; P=0.004) increase in LV global radial strain. In the validation cohort, after correction for age, sex, and body surface area, each 10 mm Hg increase in gSBP was associated with 5.27 g (SE, 1.50; P<0.001) increase in LV mass. Our study provides a novel line of evidence for a causal relationship between SBP and increased LV mass and with increased LV global radial strain.


Assuntos
Pressão Sanguínea/fisiologia , Coração/fisiopatologia , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda/fisiologia , Idoso , Índice de Massa Corporal , Feminino , Coração/diagnóstico por imagem , Humanos , Hipertensão/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade
14.
Circ Genom Precis Med ; 12(7): e002384, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31306056

RESUMO

BACKGROUND: Lipids are increasingly involved in cardiovascular risk prediction as potential proarrhythmic influencers. However, knowledge is limited about the specific mechanisms connecting lipid alterations with atrial conduction. METHODS: To shed light on this issue, we conducted a broad assessment of 151 sphingo- and phospholipids, measured using mass spectrometry, for association with atrial conduction, measured by P wave duration (PWD) from standard electrocardiograms, in the MICROS study (Microisolates in South Tyrol) (n=839). Causal pathways involving lipidomics, body mass index (BMI), and PWD were assessed using 2-sample Mendelian randomization analyses based on published genome-wide association studies of lipidomics (n=4034) and BMI (n=734 481), and genetic association analysis of PWD in 5 population-based studies (n=24 236). RESULTS: We identified an association with relative phosphatidylcholine 38:3 (%PC 38:3) concentration, which was replicated in the ORCADES (Orkney Complex Disease Study; n=951), with a pooled association across studies of 2.59 (95% CI, 1.3-3.9; P=1.1×10-4) ms PWD per mol% increase. While being independent of cholesterol, triglycerides, and glucose levels, the %PC 38:3-PWD association was mediated by BMI. Results supported a causal effect of BMI on both PWD ( P=8.3×10-5) and %PC 38:3 ( P=0.014). CONCLUSIONS: Increased %PC 38:3 levels are consistently associated with longer PWD, partly because of the confounding effect of BMI. The causal effect of BMI on PWD reinforces evidence of BMI's involvement into atrial electrical activity.


Assuntos
Artérias/fisiopatologia , Índice de Massa Corporal , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Lipídeos/química , Adulto , Idoso , Artérias/metabolismo , Eletrocardiografia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Metabolismo dos Lipídeos , Lipidômica , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Fatores de Risco
15.
Sci Rep ; 9(1): 9439, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31263163

RESUMO

Type 2 diabetes (T2D) affects the health of millions of people worldwide. The identification of genetic determinants associated with changes in glycemia over time might illuminate biological features that precede the development of T2D. Here we conducted a genome-wide association study of longitudinal fasting glucose changes in up to 13,807 non-diabetic individuals of European descent from nine cohorts. Fasting glucose change over time was defined as the slope of the line defined by multiple fasting glucose measurements obtained over up to 14 years of observation. We tested for associations of genetic variants with inverse-normal transformed fasting glucose change over time adjusting for age at baseline, sex, and principal components of genetic variation. We found no genome-wide significant association (P < 5 × 10-8) with fasting glucose change over time. Seven loci previously associated with T2D, fasting glucose or HbA1c were nominally (P < 0.05) associated with fasting glucose change over time. Limited power influences unambiguous interpretation, but these data suggest that genetic effects on fasting glucose change over time are likely to be small. A public version of the data provides a genomic resource to combine with future studies to evaluate shared genetic links with T2D and other metabolic risk traits.


Assuntos
Glicemia/genética , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla , Glicemia/análise , Diabetes Mellitus Tipo 2/genética , Feminino , Variação Genética , Genótipo , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único
16.
Cell Mol Life Sci ; 76(12): 2391-2409, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30919020

RESUMO

The acute heart rate response to exercise, i.e., heart rate increase during and heart rate recovery after exercise, has often been associated with all-cause and cardiovascular mortality. The long-term response of heart rate to exercise results in favourable changes in chronotropic function, including decreased resting and submaximal heart rate as well as increased heart rate recovery. Both the acute and long-term heart rate response to exercise have been shown to be heritable. Advances in genetic analysis enable researchers to investigate this hereditary component to gain insights in possible molecular mechanisms underlying interindividual differences in the heart rate response to exercise. In this review, we comprehensively searched candidate gene, linkage, and genome-wide association studies that investigated the heart rate response to exercise. A total of ten genes were associated with the acute heart rate response to exercise in candidate gene studies. Only one gene (CHRM2), related to heart rate recovery, was replicated in recent genome-wide association studies (GWASs). Additional 17 candidate causal genes were identified for heart rate increase and 26 for heart rate recovery in these GWASs. Nine of these genes were associated with both acute increase and recovery of the heart rate during exercise. These genes can be broadly categorized into four categories: (1) development of the nervous system (CCDC141, PAX2, SOX5, and CAV2); (2) prolongation of neuronal life span (SYT10); (3) cardiac development (RNF220 and MCTP2); (4) cardiac rhythm (SCN10A and RGS6). Additional 10 genes were linked to long-term modification of the heart rate response to exercise, nine with heart rate increase and one with heart rate recovery. Follow-up will be essential to get functional insights in how candidate causal genes affect the heart rate response to exercise. Future work will be required to translate these findings to preventive and therapeutic applications.


Assuntos
Doenças Cardiovasculares/genética , Exercício Físico , Frequência Cardíaca , Animais , Sistema Nervoso Autônomo/metabolismo , Sistema Nervoso Autônomo/fisiopatologia , Doenças Cardiovasculares/fisiopatologia , Regulação da Expressão Gênica , Ligação Genética , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único
17.
Am J Nephrol ; 49(3): 193-202, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30808845

RESUMO

BACKGROUND: Serum urea level is a heritable trait, commonly used as a diagnostic marker for kidney function. Genome-wide association studies (GWAS) in East-Asian populations identified a number of genetic loci related to serum urea, however there is a paucity of data for European populations. METHODS: We performed a two-stage meta-analysis of GWASs on serum urea in 13,312 participants, with independent replication in 7,379 participants of European ancestry. RESULTS: We identified 6 genome-wide significant single nucleotide polymorphisms (SNPs) in or near 6 loci, of which 2 were novel (POU2AF1 and ADAMTS9-AS2). Replication of East-Asian and Scottish data provided evidence for an additional 8 loci. SNPs tag regions previously associated with anthropometric traits, serum magnesium, and urinary albumin-to-creatinine ratio, as well as expression quantitative trait loci for genes preferentially expressed in kidney and gastro-intestinal tissues. CONCLUSIONS: Our findings provide insights into the genetic underpinnings of urea metabolism, with potential relevance to kidney function.


Assuntos
Grupo com Ancestrais do Continente Europeu/genética , Rim/metabolismo , Locos de Características Quantitativas , Ureia/sangue , Biologia Computacional , Estudo de Associação Genômica Ampla , Humanos , Redes e Vias Metabólicas/genética , Polimorfismo de Nucleotídeo Único , Valores de Referência , Ureia/metabolismo
18.
JAMA Cardiol ; 4(2): 144-152, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30673084

RESUMO

Importance: Increased free thyroxine (FT4) and decreased thyrotropin are associated with increased risk of atrial fibrillation (AF) in observational studies, but direct involvement is unclear. Objective: To evaluate the potential direct involvement of thyroid traits on AF. Design, Setting, and Participants: Study-level mendelian randomization (MR) included 11 studies, and summary-level MR included 55 114 AF cases and 482 295 referents, all of European ancestry. Exposures: Genomewide significant variants were used as instruments for standardized FT4 and thyrotropin levels within the reference range, standardized triiodothyronine (FT3):FT4 ratio, hypothyroidism, standardized thyroid peroxidase antibody levels, and hyperthyroidism. Mendelian randomization used genetic risk scores in study-level analysis or individual single-nucleotide polymorphisms in 2-sample MR for the summary-level data. Main Outcomes and Measures: Prevalent and incident AF. Results: The study-level analysis included 7679 individuals with AF and 49 233 referents (mean age [standard error], 62 [3] years; 15 859 men [29.7%]). In study-level random-effects meta-analysis, the pooled hazard ratio of FT4 levels (nanograms per deciliter) for incident AF was 1.55 (95% CI, 1.09-2.20; P = .02; I2 = 76%) and the pooled odds ratio (OR) for prevalent AF was 2.80 (95% CI, 1.41-5.54; P = .003; I2 = 64%) in multivariable-adjusted analyses. The FT4 genetic risk score was associated with an increase in FT4 by 0.082 SD (standard error, 0.007; P < .001) but not with incident AF (risk ratio, 0.84; 95% CI, 0.62-1.14; P = .27) or prevalent AF (OR, 1.32; 95% CI, 0.64-2.73; P = .46). Similarly, in summary-level inverse-variance weighted random-effects MR, gene-based FT4 within the reference range was not associated with AF (OR, 1.01; 95% CI, 0.89-1.14; P = .88). However, gene-based increased FT3:FT4 ratio, increased thyrotropin within the reference range, and hypothyroidism were associated with AF with inverse-variance weighted random-effects OR of 1.33 (95% CI, 1.08-1.63; P = .006), 0.88 (95% CI, 0.84-0.92; P < .001), and 0.94 (95% CI, 0.90-0.99; P = .009), respectively, and robust to tests of horizontal pleiotropy. However, the subset of hypothyroidism single-nucleotide polymorphisms involved in autoimmunity and thyroid peroxidase antibodies levels were not associated with AF. Gene-based hyperthyroidism was associated with AF with MR-Egger OR of 1.31 (95% CI, 1.05-1.63; P = .02) with evidence of horizontal pleiotropy (P = .045). Conclusions and Relevance: Genetically increased FT3:FT4 ratio and hyperthyroidism, but not FT4 within the reference range, were associated with increased AF, and increased thyrotropin within the reference range and hypothyroidism were associated with decreased AF, supporting a pathway involving the pituitary-thyroid-cardiac axis.


Assuntos
Fibrilação Atrial/genética , Análise da Randomização Mendeliana/métodos , Glândula Tireoide/metabolismo , Glândula Tireoide/patologia , Idoso , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Hipertireoidismo/sangue , Hipertireoidismo/epidemiologia , Hipertireoidismo/genética , Hipotireoidismo/sangue , Hipotireoidismo/epidemiologia , Hipotireoidismo/genética , Iodeto Peroxidase/imunologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Testes de Função Tireóidea/métodos , Glândula Tireoide/fisiopatologia , Tireotropina/sangue , Tireotropina/genética , Tiroxina/sangue , Tiroxina/genética , Tri-Iodotironina/sangue , Tri-Iodotironina/genética
19.
Eur J Hum Genet ; 27(6): 952-962, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30679814

RESUMO

Genome-wide association studies (GWAS) of quantitative electrocardiographic (ECG) traits in large consortia have identified more than 130 loci associated with QT interval, QRS duration, PR interval, and heart rate (RR interval). In the current study, we meta-analyzed genome-wide association results from 30,000 mostly Dutch samples on four ECG traits: PR interval, QRS duration, QT interval, and RR interval. SNP genotype data was imputed using the Genome of the Netherlands reference panel encompassing 19 million SNPs, including millions of rare SNPs (minor allele frequency < 5%). In addition to many known loci, we identified seven novel locus-trait associations: KCND3, NR3C1, and PLN for PR interval, KCNE1, SGIP1, and NFKB1 for QT interval, and ATP2A2 for QRS duration, of which six were successfully replicated. At these seven loci, we performed conditional analyses and annotated significant SNPs (in exons and regulatory regions), demonstrating involvement of cardiac-related pathways and regulation of nearby genes.


Assuntos
Eletrocardiografia , Loci Gênicos , Polimorfismo de Nucleotídeo Único , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Países Baixos
20.
Nat Genet ; 51(1): 51-62, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30578418

RESUMO

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.


Assuntos
Pressão Sanguínea/genética , Grupos Étnicos/genética , Adolescente , Animais , Feminino , Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Túbulos Renais/fisiologia , Masculino , Camundongos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Transcriptoma/genética , Regulação para Cima/genética
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