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1.
Nat Genet ; 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31659325

RESUMO

Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P < 5.0 × 10-8). No SNPs were associated with thoracic aortic calcification at the genome-wide threshold. Increased expression of HDAC9 in human aortic smooth muscle cells promoted calcification and reduced contractility, while inhibition of HDAC9 in human aortic smooth muscle cells inhibited calcification and enhanced cell contractility. In matrix Gla protein-deficient mice, a model of human vascular calcification, mice lacking HDAC9 had a 40% reduction in aortic calcification and improved survival. This translational genomic study identifies the first genetic risk locus associated with calcification of the abdominal aorta and describes a previously unknown role for HDAC9 in the development of vascular calcification.

2.
Nat Commun ; 10(1): 4267, 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31537805

RESUMO

Identifying methylation quantitative trait loci (meQTLs) and integrating them with disease-associated variants from genome-wide association studies (GWAS) may illuminate functional mechanisms underlying genetic variant-disease associations. Here, we perform GWAS of >415 thousand CpG methylation sites in whole blood from 4170 individuals and map 4.7 million cis- and 630 thousand trans-meQTL variants targeting >120 thousand CpGs. Independent replication is performed in 1347 participants from two studies. By linking cis-meQTL variants with GWAS results for cardiovascular disease (CVD) traits, we identify 92 putatively causal CpGs for CVD traits by Mendelian randomization analysis. Further integrating gene expression data reveals evidence of cis CpG-transcript pairs causally linked to CVD. In addition, we identify 22 trans-meQTL hotspots each targeting more than 30 CpGs and find that trans-meQTL hotspots appear to act in cis on expression of nearby transcriptional regulatory genes. Our findings provide a powerful meQTL resource and shed light on DNA methylation involvement in human diseases.

3.
Nat Commun ; 10(1): 2581, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31197173

RESUMO

Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation in the crosstalk between the adaptive immune system and glucose homeostasis. The differential methylation explains at least 16.9% of the association between obesity and insulin. Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D.


Assuntos
Metilação de DNA/fisiologia , Diabetes Mellitus Tipo 2/genética , Glucose/metabolismo , Insulina/metabolismo , Obesidade/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Simulação por Computador , Ilhas de CpG/genética , Diabetes Mellitus Tipo 2/metabolismo , Epigênese Genética/fisiologia , Epigenômica/métodos , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Homeostase/genética , Humanos , Masculino , Redes e Vias Metabólicas/genética , Pessoa de Meia-Idade , Obesidade/metabolismo , Polimorfismo de Nucleotídeo Único/fisiologia , Adulto Jovem
4.
Hypertension ; 73(2): 497-503, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30624993

RESUMO

Genetic variants at SH2B3 are associated with blood pressure and circulating ß2M (ß-2 microglobulin), a well-characterized kidney filtration biomarker. We hypothesize that circulating ß2M is an independent risk predictor of hypertension and may causally contribute to its development. The study sample consisted of 7 065 Framingham Heart Study participants with measurements of plasma ß2M. Generalized estimating equations were used to test the association of ß2M with prevalent and new-onset hypertension. There were 2 145 (30%) cases of prevalent hypertension at baseline and 886 (21%) cases of incident hypertension during 6 years of follow-up. A 1-SD increase in baseline plasma ß2M was associated with a greater risk of prevalent (odds ratio 1.14, 95% CI 1.05-1.24) and new-onset (odds ratio 1.18, 95% CI 1.07-1.32) hypertension. Individuals within the top ß2M quartile had a greater risk than the bottom quartile for prevalent (odds ratio 1.29, 95% CI 1.05-1.57) and new-onset (odds ratio 1.59, 95% CI 1.20-2.11) hypertension. These associations remained essentially unchanged in analyses restricted to participants free of albuminuria and chronic kidney disease. Mendelian randomization demonstrated that lower SH2B3 expression is causal for increased circulating ß2M levels, and in a hypertensive mouse model, knockout of Sh2b3 increased ß 2 M gene expression. In a community-based study of healthy individuals, higher plasma ß2M levels are associated with increased risk of prevalent and incident hypertension independent of chronic kidney disease status. Overlapping genetic signals for hypertension and ß2M, in conjunction with mouse knockout experiments, suggest that the SH2B3-ß2M axis plays a causal role in hypertension.

5.
Hum Genet ; 138(2): 199-210, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30671673

RESUMO

In this study, we investigated low-frequency and rare variants associated with blood pressure (BP) by focusing on a linkage region on chromosome 16p13. We used whole genome sequencing (WGS) data obtained through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program on 395 Cleveland Family Study (CFS) European Americans (CFS-EA). By analyzing functional coding variants and non-coding rare variants with CADD score > 10 residing within the chromosomal region in families with linkage evidence, we observed 25 genes with nominal statistical evidence (burden or SKAT p < 0.05). One of the genes is RBFOX1, an evolutionarily conserved RNA-binding protein that regulates tissue-specific alternative splicing that we previously reported to be associated with BP using exome array data in CFS. After follow-up analysis of the 25 genes in ten independent TOPMed studies with individuals of European, African, and East Asian ancestry, and Hispanics (N = 29,988), we identified variants in SLX4 (p = 2.19 × 10-4) to be significantly associated with BP traits when accounting for multiple testing. We also replicated the associations previously reported for RBFOX1 (p = 0.007). Follow-up analysis with GTEx eQTL data shows SLX4 variants are associated with gene expression in coronary artery, multiple brain tissues, and right atrial appendage of the heart. Our study demonstrates that linkage analysis of family data can provide an efficient approach for detecting rare variants associated with complex traits in WGS data.


Assuntos
Pressão Sanguínea/genética , Cromossomos Humanos Par 16/genética , Exoma , Ligação Genética , Variação Genética , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Processamento Alternativo/genética , Feminino , Seguimentos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Fatores de Processamento de RNA/genética , Recombinases/genética
6.
Arterioscler Thromb Vasc Biol ; 39(1): 107-115, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30580566

RESUMO

Objective- Mechanisms of early and late improvements in cardiovascular risk after bariatric surgery and applicability to larger, at-risk populations remain unclear. We aimed to identify proteins altered after bariatric surgery and their relations to metabolic syndrome and diabetes mellitus. Approach and Results- We identified 19 proteins altered in 32 nonfasting plasma samples from a study of patients undergoing bariatric surgery who were evaluated preoperatively (visit 1) versus both early (visit 2; ≈3 months) and late (visit 3; ≈12 months) postoperative follow-up using predefined protein panels (Olink). Using in silico methods and publicly available gene expression repositories, we found that genes encoding 8 out of 19 proteins had highest expression in liver relative to other assayed tissues, with the top biological and disease processes, including major obesity-related vascular diseases. Of 19 candidate proteins in the surgical cohort, 6 were previously measured in >3000 FHS (Framingham Heart Study) participants (IGFBP [insulin-like growth factor binding protein]-1, IGFBP-2, P-selectin, CD163, LDL (low-density lipoprotein)-receptor, and PAI [plasminogen activator inhibitor]-1). A higher concentration of IGFBP-2 at baseline was associated with a lower risk of incident metabolic syndrome (odds ratio per log-normal unit, 0.45; 95% CI, 0.32-0.64; P=7.7×10-6) and diabetes mellitus (odds ratio, 0.63; 95% CI, 0.49-0.79; P=0.0001) after multivariable adjustment. Conclusions- Using a directed protein quantification platform (Olink), we identified known and novel proteins altered after surgical weight loss, including IGFBP-2. Future efforts in well-defined obesity intervention settings may further define and validate novel targets for the prevention of vascular disease in obesity.

7.
Nat Commun ; 9(1): 5141, 2018 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-30510157

RESUMO

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

8.
Eur Heart J ; 39(44): 3961-3969, 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30169657

RESUMO

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.

9.
Nat Commun ; 9(1): 3853, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30228274

RESUMO

In the originally published version of this Article, financial support was not fully acknowledged. The sentence "KS was supported by the 'Biomedical Research Program' funds at Weill Cornell Medicine in Qatar, a program funded by the Qatar Foundation" has been added to the acknowledgement section in both the PDF and HTML versions of the Article.

10.
Nat Commun ; 9(1): 3268, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30111768

RESUMO

Identifying genetic variants associated with circulating protein concentrations (protein quantitative trait loci; pQTLs) and integrating them with variants from genome-wide association studies (GWAS) may illuminate the proteome's causal role in disease and bridge a knowledge gap regarding SNP-disease associations. We provide the results of GWAS of 71 high-value cardiovascular disease proteins in 6861 Framingham Heart Study participants and independent external replication. We report the mapping of over 16,000 pQTL variants and their functional relevance. We provide an integrated plasma protein-QTL database. Thirteen proteins harbor pQTL variants that match coronary disease-risk variants from GWAS or test causal for coronary disease by Mendelian randomization. Eight of these proteins predict new-onset cardiovascular disease events in Framingham participants. We demonstrate that identifying pQTLs, integrating them with GWAS results, employing Mendelian randomization, and prospectively testing protein-trait associations holds potential for elucidating causal genes, proteins, and pathways for cardiovascular disease and may identify targets for its prevention and treatment.

11.
J Am Heart Assoc ; 7(14)2018 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-30006491

RESUMO

BACKGROUND: The discovery of novel and highly predictive biomarkers of cardiovascular disease (CVD) has the potential to improve risk-stratification methods and may be informative regarding biological pathways contributing to disease. METHODS AND RESULTS: We used a discovery proteomic platform that targeted high-value proteins for CVD to ascertain 85 circulating protein biomarkers in 3523 Framingham Heart Study participants (mean age, 62 years; 53% women). Using multivariable-adjusted Cox models to account for clinical variables, we found 8 biomarkers associated with incident atherosclerotic CVD, 18 with incident heart failure, 38 with all-cause mortality, and 35 with CVD death (false discovery rate, q<0.05 for all; P-value ranges, 9.8×10-34 to 3.6×10-2). Notably, a number of regulators of metabolic and adipocyte homeostasis were associated with cardiovascular events, including insulin-like growth factor 1 (IGF1), insulin-like growth factor binding protein 1 (IGFBP1), insulin-like growth factor binding protein 2 (IGFBP2), leptin, and adipsin. In a multimarker approach that accounted for clinical factors, growth differentiation factor 15 (GDF15) was associated with all outcomes. In addition, N-terminal pro-b-type natriuretic peptide, C-reactive protein, and leptin were associated with incident heart failure, and C-type lectin domain family 3 member B (CLEC3B; tetranectin), N-terminal pro-b-type natriuretic peptide, arabinogalactan protein 1 (AGP1), soluble receptor for advanced glycation end products (sRAGE), peripheral myelin protein 2 (PMP2), uncarboxylated matrix Gla protein (UCMGP), kallikrein B1 (KLKB1), IGFBP2, IGF1, leptin receptor, and cystatin-C were associated with all-cause mortality in a multimarker model. CONCLUSIONS: We identified numerous protein biomarkers that predicted cardiovascular outcomes and all-cause mortality, including biomarkers representing regulators of metabolic homeostasis and inflammatory pathways. Further studies are needed to validate our findings and define clinical utility, with the ultimate goal of improving strategies for CVD prevention.

12.
J Am Heart Assoc ; 7(5)2018 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-29502103

RESUMO

BACKGROUND: Platelet function is associated with adverse events in patients with cardiovascular disease (CVD). METHODS AND RESULTS: We examined associations of baseline platelet function with incident CVD events in the community-based FHS (Framingham Heart Study). Participants free of prevalent CVD and without recent aspirin treatment with available data in the Framingham Offspring cohort (1991-1995) and Omni cohort (1994-1998) were included. Platelet function was measured with light transmission aggregometry using collagen (1.9 µg/mL), ADP (0.05-15 µmol/L), and epinephrine (0.01-15 µmol/L). We used proportional hazards models to analyze incident outcomes (myocardial infarction/stroke, CVD, and CVD mortality) with respect to platelet measures. The study sample included 2831 participants (average age, 54.3 years; 57% women). During follow-up (median, 20.4 years), we observed 191 composite incident myocardial infarction or stroke events, 432 incident CVD cases, and 117 CVD deaths. Hyperreactivity to ADP and platelet aggregation at ADP concentration of 1.0 µmol/L were significantly associated with incident myocardial infarction/stroke in a multivariable model (hazard ratio, 1.68 [95% confidence interval, 1.13-2.50] [P=0.011] for hyperreactivity across ADP doses; and hazard ratio, 1.16 [95% confidence interval, 1.02-1.33] [P=0.029] for highest quartile of ADP response at 1.0 µmol/L versus others). No association was observed for collagen lag time or any epinephrine measures with incident myocardial infarction or stroke. CONCLUSIONS: Intrinsic hyperreactivity to low-dose ADP in our community-based sample, who were free of CVD and any antiplatelet therapy, is associated with future arterial thrombosis during a 20-year follow-up. These findings reinforce ADP activation inhibition as a critical treatment paradigm and encourage further study of ADP inhibitor-refractive populations.

13.
Circ Cardiovasc Imaging ; 11(1): e006209, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29305347

RESUMO

BACKGROUND: Ideal cardiovascular health (CVH) is associated with a lower risk of cardiovascular disease and freedom from coronary artery calcium (CAC). Prospective data on the association between maintenance of optimal CVH and the progression of subclinical coronary atherosclerosis are limited. We assessed the influence of unfavorable versus favorable CVH on the incidence of CAC progression. METHODS AND RESULTS: The study population consisted of 1119 FHS (Framingham Heart Study) participants who attended the serial FHS MDCT I and MDCT II study (Multi-Detector Computed Tomography) and had a zero Agatston CAC score at baseline. CVH status was defined using 6 CVH metrics from the American Heart Association definition. CAC progression was defined by an increase in Agatston CAC score to ≥3.4. Generalized estimating equations were applied to identify significant associations of CAC progression with both the baseline measurement of CVH and the longitudinal maintenance of CVH. After follow-up (mean, 6.1 years), we observed CAC progression in 191 participants (17.1%). Participants with unfavorable CVH at baseline had a greater risk of CAC progression (odds ratio, 2.43; 95% confidence interval, 1.40-4.23; P=0.0017). In addition, each unit decrease in ideal CVH metric was associated with an increase in CAC progression (odds ratio, 1.15; 95% confidence interval, 0.99-1.34; P=0.067), after adjustment for baseline ideal CVH metrics. CONCLUSIONS: Significant associations between an unfavorable CVH profile and CAC progression support public health measures that seek to prevent cardiovascular disease by promoting favorable CVH profiles in persons free of clinical and subclinical cardiovascular disease.

14.
Intern Med J ; 48(4): 414-421, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29193523

RESUMO

BACKGROUND: In the elderly, impaired cognition may weaken medication adherence and compromise treatment for cardiovascular disease (CVD). AIM: We examined risk factors for medication adherence and the relationship between adherence and levels of CVD risk factors among older participants with hypertension, dyslipidaemia and diabetes in the Framingham Heart Study. METHODS: The four-item Morisky Medication Adherence Scale was administered to 1559 participants, median age 70 years, 53% women. We created an adherence score, ranging from 0 to 4, with low adherence defined as a score ≥2. CVD risk factors were assessed using standard protocols. Cognition was measured using the Mini-Mental State Examination (MMSE) and depressive symptoms were measured using the Center for Epidemiologic Studies of Depression (CES-D) scale. RESULTS: Among participants who self-reported taking antihypertensive, lipid-lowering and/or hyperglycaemic medication(s), 12% (n = 191) had low medication adherence. The risk of low adherence increased by 45% (95% confidence interval (CI): 25-68%, P < 0.001) per five-unit increase in CES-D score. In participants taking antihypertensive medication (n = 1017), low adherence was associated with higher mean diastolic blood pressure (73 mmHg, 95% CI: 71-75 vs 71 mmHg, 95% CI: 70-71; P = 0.04) after adjusting for covariates. Among participants taking lipid-lowering medication (n = 937), low adherence was associated with higher mean low-density lipoprotein cholesterol (92 mg/dL, 95% CI: 87-96 vs 86 mg/dL, 95% CI: 84-88; P = 0.03). Low adherence was not associated with fasting plasma glucose (P = 0.10) or haemoglobin A1c (P = 0.68) in the subgroup of participants (n = 192) taking hypoglycaemic medication. CONCLUSIONS: Depressive symptoms might act as a barrier for medication adherence, which exacerbates CVD risk factors in older-aged adults.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/psicologia , Depressão/psicologia , Adesão à Medicação/psicologia , Autorrelato , Idoso , Anti-Hipertensivos/uso terapêutico , Doenças Cardiovasculares/epidemiologia , Estudos de Coortes , Estudos Transversais , Depressão/epidemiologia , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Hipolipemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Fatores de Risco
15.
Nat Commun ; 8(1): 1286, 2017 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-29097680

RESUMO

Chronic kidney disease (CKD) is defined by reduced estimated glomerular filtration rate (eGFR). Previous genetic studies have implicated regulatory mechanisms contributing to CKD. Here we present epigenome-wide association studies of eGFR and CKD using whole-blood DNA methylation of 2264 ARIC Study and 2595 Framingham Heart Study participants to identify epigenetic signatures of kidney function. Of 19 CpG sites significantly associated (P < 1e-07) with eGFR/CKD and replicated, five also associate with renal fibrosis in biopsies from CKD patients and show concordant DNA methylation changes in kidney cortex. Lead CpGs at PTPN6/PHB2, ANKRD11, and TNRC18 map to active enhancers in kidney cortex. At PTPN6/PHB2 cg19942083, methylation in kidney cortex associates with lower renal PTPN6 expression, higher eGFR, and less renal fibrosis. The regions containing the 243 eGFR-associated (P < 1e-05) CpGs are significantly enriched for transcription factor binding sites of EBF1, EP300, and CEBPB (P < 5e-6). Our findings highlight kidney function associated epigenetic variation.


Assuntos
Metilação de DNA/genética , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/fisiopatologia , Idoso , Sítios de Ligação/genética , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Ilhas de CpG , Progressão da Doença , Proteína p300 Associada a E1A/genética , Proteína p300 Associada a E1A/metabolismo , Epigênese Genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular/genética , Humanos , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
17.
Hypertension ; 2017 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-28739976

RESUMO

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

18.
Nat Commun ; 8: 15805, 2017 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-28613276

RESUMO

Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74

19.
Hum Mol Genet ; 26(12): 2346-2363, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28379579

RESUMO

Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. Genome-wide association study analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation. This study aims to discover new genetic loci associated with heart rate from Exome Chip meta-analyses.Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104 452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134 251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods.We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2 and SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long-range regulatory chromatin interactions in heart tissue (SCD, SLF2 and MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants.Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.


Assuntos
Frequência Cardíaca/genética , Adulto , Alelos , Grupo com Ancestrais do Continente Europeu/genética , Exoma , Feminino , Frequência do Gene/genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Genótipo , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
20.
Aging (Albany NY) ; 9(4): 1130-1142, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28394764

RESUMO

An ongoing debate in demography has focused on whether the human lifespan has a maximal natural limit. Taking a mechanistic perspective, and knowing that short telomeres are associated with diminished longevity, we examined whether telomere length dynamics during adult life could set a maximal natural lifespan limit. We define leukocyte telomere length of 5 kb as the 'telomeric brink', which denotes a high risk of imminent death. We show that a subset of adults may reach the telomeric brink within the current life expectancy and more so for a 100-year life expectancy. Thus, secular trends in life expectancy should confront a biological limit due to crossing the telomeric brink.


Assuntos
Longevidade/fisiologia , Encurtamento do Telômero , Telômero/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Algoritmos , Southern Blotting , Estudos de Coortes , Feminino , Humanos , Leucócitos/ultraestrutura , Expectativa de Vida , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Caracteres Sexuais , Telômero/ultraestrutura
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