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1.
Nat Rev Cardiol ; 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33219353

RESUMO

The known genetic architecture of blood pressure now comprises >30 genes, with rare variants resulting in monogenic forms of hypertension or hypotension and >1,477 common single-nucleotide polymorphisms (SNPs) being associated with the blood pressure phenotype. Monogenic blood pressure syndromes predominantly involve the renin-angiotensin-aldosterone system and the adrenal glucocorticoid pathway, with a smaller fraction caused by neuroendocrine tumours of the sympathetic and parasympathetic nervous systems. The SNPs identified in genome-wide association studies (GWAS) as being associated with the blood pressure phenotype explain only approximately 27% of the 30-50% estimated heritability of blood pressure, and the effect of each SNP on the blood pressure phenotype is small. A paucity of SNPs from GWAS are mapped to known genes causing monogenic blood pressure syndromes. For example, a GWAS signal mapped to the gene encoding uromodulin has been shown to affect blood pressure by influencing sodium homeostasis, and the effects of another GWAS signal were mediated by endothelin. However, the majority of blood pressure-associated SNPs show pleiotropic associations. Unravelling these associations can potentially help us to understand the underlying biological pathways. In this Review, we appraise the current knowledge of blood pressure genomics, explore the causal pathways for hypertension identified in Mendelian randomization studies and highlight the opportunities for drug repurposing and pharmacogenomics for the treatment of hypertension.

2.
Am Heart J ; 229: 70-80, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32942043

RESUMO

Microvascular angina is caused by cardiac small vessel disease, and dysregulation of the endothelin system is implicated. The minor G allele of the non-coding single nucleotide polymorphism (SNP) rs9349379 enhances expression of the endothelin 1 gene in human vascular cells, increasing circulating concentrations of ET-1. The prevalence of this allele is higher in patients with ischemic heart disease. Zibotentan is a potent, selective inhibitor of the ETA receptor. We have identified zibotentan as a potential disease-modifying therapy for patients with microvascular angina. METHODS: We will assess the efficacy and safety of adjunctive treatment with oral zibotentan (10 mg daily) in patients with microvascular angina and assess whether rs9349379 (minor G allele; population prevalence ~36%) acts as a theragnostic biomarker of the response to treatment with zibotentan. The PRIZE trial is a prospective, randomized, double-blind, placebo-controlled, sequential cross-over trial. The study population will be enriched to ensure a G-allele frequency of 50% for the rs9349379 SNP. The participants will receive a single-blind placebo run-in followed by treatment with either 10 mg of zibotentan daily for 12 weeks then placebo for 12 weeks, or vice versa, in random order. The primary outcome is treadmill exercise duration using the Bruce protocol. The primary analysis will assess the within-subject difference in exercise duration following treatment with zibotentan versus placebo. CONCLUSION: PRIZE invokes precision medicine in microvascular angina. Should our hypotheses be confirmed, this developmental trial will inform the rationale and design for undertaking a larger multicenter trial.

3.
Eur Heart J Suppl ; 22(Suppl H): H132-H134, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32884493

RESUMO

Raised blood pressure (BP) was the biggest contributor to the global burden of disease in 2017, with lack of awareness and adequate control of BP identified as the main drivers of this disease burden. In 2017, an opportunistic BP screening and awareness campaign called May Measurement Month (MMM) in the UK and Republic of Ireland (RoI) highlighted that levels of undiagnosed hypertension and uncontrolled hypertension in the community screened were approximately 23% and 40%, respectively. MMM18 was undertaken to further the campaign's efforts to increase awareness and create an evidence base of population risk associated with high BP. MMM18 BP screenings were conducted in the community at places of worship, supermarkets, GP surgeries, workplaces, community pharmacies, gyms, and various other public places. A total of 5000 volunteers, aged 47.3 (±17.2) years, 60% female were screened. Of all 5000 individuals screened, 1716 (34.3%) were hypertensive, of which only 51.3% were aware of their condition, 42.8% on antihypertensive treatment, and only 51.5% of those on medication controlled to target BP of <140/90 mmHg. Furthermore, obese, overweight, and underweight participants all had significantly higher BP values compared to individuals with a healthy body mass index (BMI). The 2018 MMM campaign in the UK and the RoI confirmed approximately one in three adults were hypertensive, with more than half having uncontrolled BP. In addition, these findings show that people with low BMI are at risk of having high BP. Finally, with only one in two people aware of their high BP, awareness remains a significant public health concern.

4.
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.

5.
Eur J Clin Pharmacol ; 76(12): 1745-1754, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32696233

RESUMO

PURPOSE: To investigate the blood pressure (BP)-lowering effects of statins by conducting a systematic review and meta-analysis of placebo-randomized controlled trials (RCTs). METHOD: We conducted a meta-analysis of placebo RCTs reporting antihypertensive effects of statins therapy. We only included RCTs that did not allow for concomitant antihypertensive therapy, or clearly stated that antihypertensive therapy was fixed throughout the study period. RESULTS: Our meta-analysis included 46 placebo RCTs, including 53 group comparisons and a total of 49,087 participants (24,589 participants in the statin groups and 24,498 participants in the placebo group). Subgroup analysis, based on use of concomitant antihypertensive, was performed. The meta-analysis showed that statin reduced systolic BP by - 1.6 mmHg (95% CI: - 2.50 to - 0.60), and diastolic BP by - 0.96 mmHg (95% CI: - 1.36 to - 0.56). Although the presence of concomitant antihypertensive therapy diluted the BP lowering effect of statins, it remained statistically significant and independent of the lipid-lowering activity. Furthermore, the BP -lowering effect of the statins was independent of the dose or type of statin (p > 0.05). CONCLUSION: Our results strengthen the evidence for pleiotropic effects of statins on BP that are independent of their lipid-lowering activity, supporting their beneficial role in hypertensive patients with dyslipidemia.

6.
Nutrients ; 12(7)2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32708992

RESUMO

Nutrition plays a key role in blood pressure (BP) regulation. Here, we examine associations between nutrient intakes and BP in a large predominantly female population-based cohort. We assessed the correlation between 45 nutrients (from food frequency questionnaires) and systolic BP/diastolic BP (SBP/DBP) in 3889 individuals from TwinsUK not on hypertensive treatments and replicated in an independent subset of monozygotic twins discordant for nutrient intake (17-242 pairs). Results from both analyses were meta-analysed. For significant nutrients, we calculated heritability using structural equation modelling. We identified and replicated 15 nutrients associated with SBP, 9 also being associated with DBP, adjusting for covariates and multiple testing. 14 of those had a heritable component (h2: 27.1-57.6%). Strong associations with SBP were observed for riboflavin (Beta(SE) = -1.49(0.38), P = 1.00 × 10-4) and tryptophan (-0.31(0.01), P = 5 × 10-4), while with DBP for alcohol (0.05(0.07), P = 1.00 × 10-4) and lactose (-0.05(0.0), P = 1.3 × 10-3). Two multivariable nutrient scores, combining independently SBP/DBP-associated nutrients, explained 22% of the variance in SBP and 13.6% of the variance in DBP. Moreover, bivariate heritability analysis suggested that nutrients and BP share some genetic influences. We confirm current understanding and extend the panel of dietary nutrients implicated in BP regulation underscoring the value of nutrient focused dietary research in preventing and managing hypertension.

7.
Am J Med Genet B Neuropsychiatr Genet ; 183(6): 309-330, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32681593

RESUMO

It is imperative to understand the specific and shared etiologies of major depression and cardio-metabolic disease, as both traits are frequently comorbid and each represents a major burden to society. This study examined whether there is a genetic association between major depression and cardio-metabolic traits and if this association is stratified by age at onset for major depression. Polygenic risk scores analysis and linkage disequilibrium score regression was performed to examine whether differences in shared genetic etiology exist between depression case control status (N cases = 40,940, N controls = 67,532), earlier (N = 15,844), and later onset depression (N = 15,800) with body mass index, coronary artery disease, stroke, and type 2 diabetes in 11 data sets from the Psychiatric Genomics Consortium, Generation Scotland, and UK Biobank. All cardio-metabolic polygenic risk scores were associated with depression status. Significant genetic correlations were found between depression and body mass index, coronary artery disease, and type 2 diabetes. Higher polygenic risk for body mass index, coronary artery disease, and type 2 diabetes was associated with both early and later onset depression, while higher polygenic risk for stroke was associated with later onset depression only. Significant genetic correlations were found between body mass index and later onset depression, and between coronary artery disease and both early and late onset depression. The phenotypic associations between major depression and cardio-metabolic traits may partly reflect their overlapping genetic etiology irrespective of the age depression first presents.

8.
Can J Cardiol ; 36(5): 694-705, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32389342

RESUMO

The genetic architecture of blood pressure (BP) now includes more than 30 genes, with rare mutations resulting in inherited forms of hypertension or hypotension, and 1477 common single-nucleotide polymorphisms (SNPs). These signify the heterogeneity of the BP phenotype and support the mosaic theory of hypertension. The majority of monogenic syndromes involve the renin-angiotensin-aldosterone system and the adrenal glucocorticoid pathway, and a smaller fraction are due to rare neuroendocrine tumours of the adrenal glands and the sympathetic and parasympathetic paraganglia. Somatic mutations in genes coding for ion channels (KCNJ5 and CACNA1D) and adenosine triphosphatases (ATP1A1 and ATP2B3) highlight the central role of calcium signalling in autonomous aldosterone production by the adrenal gland. The per-SNP BP effect is small for SNPs according to genome-wide association studies (GWAS), and all of the GWAS-identified BP SNPs explain ∼ 27% of the 30%-50% estimated heritability of BP. Uromodulin is a novel pathway identified by GWAS, and it has now progressed to a genotype-directed clinical trial. The majority of the GWAS-identified BP SNPs show pleiotropic associations, and unravelling those signals and underpinning biological pathways offers potential opportunities for drug repurposing. The GWAS signals are predominantly from Europe-centric studies with other ancestries underrepresented, however, limiting the generalisability of the findings. In this review, we leverage the burgeoning list of polygenic and monogenic variants associated with BP regulation along with phenome-wide studies in the context of the mosaic theory of hypertension, and we explore potential translational aspects that underlie different hypertension subtypes.

9.
Nat Commun ; 11(1): 2542, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32439900

RESUMO

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.


Assuntos
Arritmias Cardíacas/genética , Eletrocardiografia , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Arritmias Cardíacas/fisiopatologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Endofenótipos , Feminino , Expressão Gênica , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Herança Multifatorial , Locos de Características Quantitativas/genética
10.
Am J Hypertens ; 33(6): 473-481, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32060494

RESUMO

Epidemiologic and genomic studies have progressively improved our understanding of the causation of hypertension and the complex relationship with diet and environment. The majority of Mendelian forms of syndromic hypotension and hypertension (HTN) have all been linked to mutations in genes whose encoded proteins regulate salt-water balance in the kidney, supporting the primacy of the kidneys in blood pressure regulation. There are more than 1,477 single nucleotide polymorphisms associated with blood pressure and hypertension and the challenge is establishing a causal role for these variants. Hypertension is a complex multifactorial phenotype and it is likely to be influenced by multiple factors including interactions between diet and lifestyle factors, microbiome, and epigenetics. Given the finite genetic variability that is possible in humans, it is likely that incremental gains from single marker analyses have now plateaued and a greater leap in our understanding of the genetic basis of disease will come from integration of other omics and the interacting environmental factors. In this review, we focus on emerging results from the microbiome and metabolomics and discuss how leveraging these findings may facilitate a deeper understanding of the interrelationships between genomics, diet, and microbial ecology in humans in the causation of essential hypertension.

11.
Psychol Med ; : 1-9, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31973782

RESUMO

BACKGROUND: Recent work suggests that antihypertensive medications may be useful as repurposed treatments for mood disorders. Using large-scale linked healthcare data we investigated whether certain classes of antihypertensive, such as angiotensin antagonists (AAs) and calcium channel blockers, were associated with reduced risk of new-onset major depressive disorder (MDD) or bipolar disorder (BD). METHOD: Two cohorts of patients treated with antihypertensives were identified from Scottish prescribing (2009-2016) and hospital admission (1981-2016) records. Eligibility for cohort membership was determined by a receipt of a minimum of four prescriptions for antihypertensives within a 12-month window. One treatment cohort (n = 538 730) included patients with no previous history of mood disorder, whereas the other (n = 262 278) included those who did. Both cohorts were matched by age, sex and area deprivation to untreated comparators. Associations between antihypertensive treatment and new-onset MDD or bipolar episodes were investigated using Cox regression. RESULTS: For patients without a history of mood disorder, antihypertensives were associated with increased risk of new-onset MDD. For AA monotherapy, the hazard ratio (HR) for new-onset MDD was 1.17 (95% CI 1.04-1.31). Beta blockers' association was stronger (HR 2.68; 95% CI 2.45-2.92), possibly indicating pre-existing anxiety. Some classes of antihypertensive were associated with protection against BD, particularly AAs (HR 0.46; 95% CI 0.30-0.70). For patients with a past history of mood disorders, all classes of antihypertensives were associated with increased risk of future episodes of MDD. CONCLUSIONS: There was no evidence that antihypertensive medications prevented new episodes of MDD but AAs may represent a novel treatment avenue for BD.

12.
Eur Heart J ; 41(34): 3239-3252, 2020 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31972008

RESUMO

AIMS: Endothelin-1 (ET-1) is a potent vasoconstrictor peptide linked to vascular diseases through a common intronic gene enhancer [(rs9349379-G allele), chromosome 6 (PHACTR1/EDN1)]. We performed a multimodality investigation into the role of ET-1 and this gene variant in the pathogenesis of coronary microvascular dysfunction (CMD) in patients with symptoms and/or signs of ischaemia but no obstructive coronary artery disease (CAD). METHODS AND RESULTS: Three hundred and ninety-one patients with angina were enrolled. Of these, 206 (53%) with obstructive CAD were excluded leaving 185 (47%) eligible. One hundred and nine (72%) of 151 subjects who underwent invasive testing had objective evidence of CMD (COVADIS criteria). rs9349379-G allele frequency was greater than in contemporary reference genome bank control subjects [allele frequency 46% (129/280 alleles) vs. 39% (5551/14380); P = 0.013]. The G allele was associated with higher plasma serum ET-1 [least squares mean 1.59 pg/mL vs. 1.28 pg/mL; 95% confidence interval (CI) 0.10-0.53; P = 0.005]. Patients with rs9349379-G allele had over double the odds of CMD [odds ratio (OR) 2.33, 95% CI 1.10-4.96; P = 0.027]. Multimodality non-invasive testing confirmed the G allele was associated with linked impairments in myocardial perfusion on stress cardiac magnetic resonance imaging at 1.5 T (N = 107; GG 56%, AG 43%, AA 31%, P = 0.042) and exercise testing (N = 87; -3.0 units in Duke Exercise Treadmill Score; -5.8 to -0.1; P = 0.045). Endothelin-1 related vascular mechanisms were assessed ex vivo using wire myography with endothelin A receptor (ETA) antagonists including zibotentan. Subjects with rs9349379-G allele had preserved peripheral small vessel reactivity to ET-1 with high affinity of ETA antagonists. Zibotentan reversed ET-1-induced vasoconstriction independently of G allele status. CONCLUSION: We identify a novel genetic risk locus for CMD. These findings implicate ET-1 dysregulation and support the possibility of precision medicine using genetics to target oral ETA antagonist therapy in patients with microvascular angina. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03193294.

13.
JAMA Cardiol ; 5(4): 432-441, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31995119

RESUMO

Importance: Accurate prediction of risk of death or hospitalizations in patients with heart failure (HF) may allow physicians to explore how more accurate decisions regarding appropriateness and timing of disease-modifying treatments, advanced therapies, or the need for end-of-life care can be made. Objective: To develop and validate a prognostic model for patients with HF. Design, Setting, and Participants: Multivariable analyses were performed in a stepwise fashion. Harrell C statistic was used to assess the discriminative ability. The derivation cohort was Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF) participants. The models were validated using the Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure Trial (ATMOSPHERE) study and in the Swedish Heart Failure Registry (SwedeHF). A total of 8399 participants enrolled in PARADIGM-HF. Data were analyzed between June 2016 and June 2018. Main Outcomes and Measures: Cardiovascular death, all-cause mortality, and the composite of cardiovascular death or HF hospitalization at both 1 and 2 years. Results: Complete baseline clinical data were available for 8011 patients in PARADIGM-HF. The mean (SD) age of participants was 64 (11.4) years, 78.2% were men (n = 6567 of 8399), and 70.6% were New York Heart Association class II (n = 5919 of 8399). During a mean follow-up of 27 months, 1546 patients died, and 2031 had a cardiovascular death or HF hospitalization. The common variables were: male sex, race/ethnicity (black or Asian), region (Central Europe or Latin America), HF duration of more than 5 years, New York Heart Association class III/ IV, left ventricular ejection fraction, diabetes mellitus, ß-blocker use at baseline, and allocation to sacubitril/valsartan. Ranked by χ2, N-terminal pro brain natriuretic peptide was the single most powerful independent predictor of each outcome. The C statistic at 1 and 2 years was 0.74 (95% CI, 0.71-0.76) and 0.71 (95% CI, 0.70-0.73) for the primary composite end point, 0.73 (95% CI, 0.71-0.75) and 0.71 (95% CI, 0.69-0.73) for cardiovascular death, and 0.71 (95% CI, 0.69-0.74) and 0.70 (95% CI, 0.67-0.74) for all-cause death, respectively. When validated in ATMOSPHERE, the C statistic at 1 and 2 years was 0.71 (95% CI, 0.69-0.72) and 0.70 (95% CI, 0.68-0.71) for the primary composite end point, 0.71 (95% CI, 0.69-0.74) and 0.70 (95% CI, 0.69-0.72) for cardiovascular death, and 0.71 (95% CI, 0.69-0.74) and 0.70 (95% CI, 0.68-0.72) for all-cause death, respectively. An online calculator was created to allow calculation of an individual's risk (http://www.predict-hf.com). Conclusions and Relevance: Predictive models performed well and were developed and externally validated in large cohorts of geographically representative patients, comprehensively characterized with clinical and laboratory data including natriuretic peptides, who were receiving contemporary evidence-based treatment.

14.
Pharmacogenomics J ; 20(2): 329-341, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-30700811

RESUMO

Antidepressants demonstrate modest response rates in the treatment of major depressive disorder (MDD). Despite previous genome-wide association studies (GWAS) of antidepressant treatment response, the underlying genetic factors are unknown. Using prescription data in a population and family-based cohort (Generation Scotland: Scottish Family Health Study; GS:SFHS), we sought to define a measure of (a) antidepressant treatment resistance and (b) stages of antidepressant resistance by inferring antidepressant switching as non-response to treatment. GWAS were conducted separately for antidepressant treatment resistance in GS:SFHS and the Genome-based Therapeutic Drugs for Depression (GENDEP) study and then meta-analysed (meta-analysis n = 4213, cases = 358). For stages of antidepressant resistance, a GWAS on GS:SFHS only was performed (n = 3452). Additionally, we conducted gene-set enrichment, polygenic risk scoring (PRS) and genetic correlation analysis. We did not identify any significant loci, genes or gene sets associated with antidepressant treatment resistance or stages of resistance. Significant positive genetic correlations of antidepressant treatment resistance and stages of resistance with neuroticism, psychological distress, schizotypy and mood disorder traits were identified. These findings suggest that larger sample sizes are needed to identify the genetic architecture of antidepressant treatment response, and that population-based observational studies may provide a tractable approach to achieving the necessary statistical power.

15.
Mol Psychiatry ; 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31767999

RESUMO

Alcohol use and smoking are leading causes of death and disability worldwide. Both genetic and environmental factors have been shown to influence individual differences in the use of these substances. In the present study we tested whether genetic factors, modelled alongside common family environment, explained phenotypic variance in alcohol use and smoking behaviour in the Generation Scotland (GS) family sample of up to 19,377 individuals. SNP and pedigree-associated effects combined explained between 18 and 41% of the variance in substance use. Shared couple effects explained a significant amount of variance across all substance use traits, particularly alcohol intake, for which 38% of the phenotypic variance was explained. We tested whether the within-couple substance use associations were due to assortative mating by testing the association between partner polygenic risk scores in 34,987 couple pairs from the UK Biobank (UKB). No significant association between partner polygenic risk scores were observed. Associations between an individual's alcohol PRS (b = 0.05, S.E. = 0.006, p < 2 × 10-16) and smoking status PRS (b = 0.05, S.E. = 0.005, p < 2 × 10-16) were found with their partner's phenotype. In support of this, G carriers of a functional ADH1B polymorphism (rs1229984), known to be associated with greater alcohol intake, were found to consume less alcohol if they had a partner who carried an A allele at this SNP. Together these results show that the shared couple environment contributes significantly to patterns of substance use. It is unclear whether this is due to shared environmental factors, assortative mating, or indirect genetic effects. Future studies would benefit from longitudinal data and larger sample sizes to assess this further.

16.
Sci Rep ; 9(1): 15088, 2019 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-31636301

RESUMO

Electrolytes have a crucial role in maintaining health and their serum levels are homeostatically maintained within a narrow range by multiple pathways involving the kidneys. Here we use metabolomics profiling (592 fasting serum metabolites) to identify molecular markers and pathways associated with serum electrolyte levels in two independent population-based cohorts. We included 1523 adults from TwinsUK not on blood pressure-lowering therapy and without renal impairment to look for metabolites associated with chloride, sodium, potassium and bicarbonate by running linear mixed models adjusting for covariates and multiple comparisons. For each electrolyte, we further performed pathway enrichment analysis (PAGE algorithm). Results were replicated in an independent cohort. Chloride, potassium, bicarbonate and sodium associated with 10, 58, 36 and 17 metabolites respectively (each P < 2.1 × 10-5), mainly lipids. Of all the electrolytes, serum potassium showed the most significant associations with individual fatty acid metabolites and specific enrichment of fatty acid pathways. In contrast, serum sodium and bicarbonate showed associations predominantly with amino-acid related species. In the first study to examine systematically associations between serum electrolytes and small circulating molecules, we identified novel metabolites and metabolic pathways associated with serum electrolyte levels. The role of these metabolic pathways on electrolyte homeostasis merits further studies.


Assuntos
Equilíbrio Ácido-Base , Eletrólitos/metabolismo , Homeostase , Metabolômica , Adulto , Idoso , Feminino , Humanos , Masculino , Redes e Vias Metabólicas , Metaboloma , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Gêmeos , Reino Unido
17.
BMJ Open ; 9(9): e024433, 2019 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-31575565

RESUMO

OBJECTIVES: To assess whether a history of major depressive disorder (MDD) in middle-aged individuals with hypertension influences first-onset cardiovascular disease outcomes. DESIGN: Prospective cohort survival analysis using Cox proportional hazards regression with a median follow-up of 63 months (702 902 person-years). Four mutually exclusive groups were compared: hypertension only (n=56 035), MDD only (n=15 098), comorbid hypertension plus MDD (n=12 929) and an unaffected (no hypertension, no MDD) comparison group (n=50 798). SETTING: UK Biobank. PARTICIPANTS: UK Biobank participants without cardiovascular disease aged 39-70 who completed psychiatric questions relating International Classification of Diseases-10 Revision (ICD-10) diagnostic criteria on a touchscreen questionnaire at baseline interview in 2006-2010 (n=134 860). PRIMARY AND SECONDARY OUTCOME MEASURES: First-onset adverse cardiovascular outcomes leading to hospital admission or death (ICD-10 codes I20-I259, I60-69 and G45-G46), adjusted in a stepwise manner for sociodemographic, health and lifestyle features. Secondary analyses were performed looking specifically at stroke outcomes (ICD-10 codes I60-69 and G45-G46) and in gender-separated models. RESULTS: Relative to controls, adjusted HRs for adverse cardiovascular outcomes were increased for the hypertension only group (HR 1.36, 95% CI 1.22 to 1.52) and were higher still for the comorbid hypertension plus MDD group (HR 1.66, 95% CI 1.45 to 1.9). HRs for the comorbid hypertension plus MDD group were significantly raised compared with hypertension alone (HR 1.22, 95% CI 1.1 to 1.35). Interaction measured using relative excess risk due to interaction (RERI) and likelihood ratios (LRs) were identified at baseline (RERI 0.563, 95% CI 0.189 to 0.938; LR p=0.0116) but not maintained during the follow-up. LIMITATIONS: Possible selection bias in UK Biobank and inability to assess for levels of medication adherence. CONCLUSIONS: Comorbid hypertension and MDD conferred greater hazard than hypertension alone for adverse cardiovascular outcomes, although evidence of interaction between hypertension and MDD was inconsistent over time. Future cardiovascular risk prediction tools may benefit from the inclusion of questions about prior history of depressive disorders.


Assuntos
Transtorno Depressivo Maior/epidemiologia , Nível de Saúde , Hipertensão/epidemiologia , Estilo de Vida , Adulto , Idoso , Sistema Cardiovascular , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Estudos Prospectivos , Análise de Regressão , Análise de Sobrevida , Reino Unido
18.
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
19.
Hypertension ; 74(4): 767-775, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31422693

RESUMO

Concerns exist regarding the potential increased cardiovascular risk from lowering diastolic blood pressure (DBP) in hypertensive patients. We analyzed 30-year follow-up data of 10 355 hypertensive patients attending the Glasgow Blood Pressure Clinic. The association between blood pressure during the first 5 years of treatment and cause-specific hospital admissions or mortality was analyzed using multivariable adjusted Cox proportional hazard models. The primary outcome was a composite of cardiovascular admissions and deaths. DBP showed a U-shaped association (nadir, 92 mm Hg) for the primary cardiovascular outcome hazard and a reverse J-shaped association with all-cause mortality (nadir, 86 mm Hg) and noncardiovascular mortality (nadir, 92 mm Hg). The hazard ratio for the primary cardiovascular outcome after adjustment for systolic blood pressure was 1.38 (95% CI, 1.18-1.62) for DBP <80 compared with DBP of 80 to 89.9 mm Hg (referrant), and the subdistribution hazard ratio after accounting for competing risk was 1.33 (1.17-1.51) compared with DBP ≥80 mm Hg. Cause-specific nonfatal outcome analyses showed a reverse J-shaped relationship for myocardial infarction, ischemic heart disease, and heart failure admissions but a U-shaped relationship for stroke admissions. Age-stratified analyses showed DBP had no independent effect on stroke admissions among the older patient subgroup (≥60 years of age), but the younger subgroup showed a clear U-shaped relationship. Intensive blood pressure reduction may lead to unintended consequences of higher healthcare utilization because of increased cardiovascular morbidity, and this merits future prospective studies. Low on-treatment DBP is associated with increased risk of noncardiovascular mortality, the reasons for which are unclear.


Assuntos
Pressão Sanguínea/fisiologia , Diástole/fisiologia , Hipertensão/fisiopatologia , Infarto do Miocárdio/fisiopatologia , Adulto , Idoso , Anti-Hipertensivos/uso terapêutico , Determinação da Pressão Arterial , Feminino , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/mortalidade , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Fatores de Risco , Taxa de Sobrevida , Atenção Terciária à Saúde
20.
Hypertension ; 74(3): 614-622, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31327267

RESUMO

Selection of antihypertensive treatment according to self-defined ethnicity is recommended by some guidelines but might be better guided by individual genotype rather than ethnicity or race. We compared the extent to which variation in blood pressure response across different ethnicities may be explained by genetic factors: genetically defined ancestry and gene variants at loci known to be associated with blood pressure. We analyzed data from 5 trials in which genotyping had been performed (n=4696) and in which treatment responses to ß-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blocker, thiazide or thiazide-like diuretic and calcium channel blocker were available. Genetically defined ancestry for proportion of African ancestry was computed using the 1000 genomes population database as a reference. Differences in response to the thiazide diuretic hydrochlorothiazide, the ß-blockers atenolol and metoprolol, the angiotensin-converting enzyme inhibitor lisinopril, and the angiotensin receptor blocker candesartan were more closely associated to genetically defined ancestry than self-defined ethnicity in admixed subjects. A relatively small number of gene variants related to loci associated with drug-signaling pathways (KCNK3, SULT1C3, AMH, PDE3A, PLCE1, PRKAG2) with large effect size (-3.5 to +3.5 mm Hg difference in response per allele) and differing allele frequencies in black versus white individuals explained a large proportion of the difference in response to candesartan and hydrochlorothiazide between these groups. These findings suggest that a genomic precision medicine approach can be used to individualize antihypertensive treatment within and across populations without recourse to surrogates of genetic structure such as self-defined ethnicity.


Assuntos
Afro-Americanos/genética , Anti-Hipertensivos/uso terapêutico , Grupo com Ancestrais do Continente Europeu/genética , Loci Gênicos/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipertensão/genética , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Idoso , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Ensaios Clínicos como Assunto , Feminino , Variação Genética/efeitos dos fármacos , Humanos , Hidroclorotiazida/uso terapêutico , Hipertensão/etnologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Resultado do Tratamento , Estados Unidos
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