Abstract Background Although epidemiological studies have reported positive associations between circulating urate levels and cardiometabolic diseases, causality remains uncertain. Objectives Through ...a Mendelian randomization approach, we assessed whether serum urate levels are causally relevant in type 2 diabetes mellitus (T2DM), coronary heart disease (CHD), ischemic stroke, and heart failure (HF). Methods This study investigated 28 single nucleotide polymorphisms known to regulate serum urate levels in association with various vascular and nonvascular risk factors to assess pleiotropy. To limit genetic confounding, 14 single nucleotide polymorphisms exclusively associated with serum urate levels were used in a genetic risk score to assess associations with the following cardiometabolic diseases (cases/controls): T2DM (26,488/83,964), CHD (54,501/68,275), ischemic stroke (14,779/67,312), and HF (4,526/18,400). As a positive control, this study also investigated our genetic instrument in 3,151 gout cases and 68,350 controls. Results Serum urate levels, increased by 1 SD due to the genetic score, were not associated with T2DM, CHD, ischemic stroke, or HF. These results were in contrast with previous prospective studies that did observe increased risks of these 4 cardiometabolic diseases for an equivalent increase in circulating urate levels. However, a 1 SD increase in serum urate levels due to the genetic score was associated with increased risk of gout (odds ratio: 5.84; 95% confidence interval: 4.56 to 7.49), which was directionally consistent with previous observations. Conclusions Evidence from this study does not support a causal role of circulating serum urate levels in T2DM, CHD, ischemic stroke, or HF. Decreasing serum urate levels may not translate into risk reductions for cardiometabolic conditions.
Objectives The purpose of this study was to assess the functional significance of cardiac magnetic resonance (CMR) measures of left ventricular (LV) remodeling and myocardial perfusion reserve (MPR) ...in patients with severe aortic stenosis (AS), without obstructive coronary artery disease. Background Measures of stenosis severity do not correlate well with exercise intolerance in AS. LV remodeling in AS is associated with myocardial fibrosis and impaired MPR. The functional significance and determinants of MPR in AS are unclear. Methods Forty-six patients with isolated severe AS were prospectively studied before aortic valve replacement. The following investigations were undertaken: cardiopulmonary exercise testing to measure aerobic exercise capacity (peak VO2 ); CMR to assess left ventricular mass index (LVMI), myocardial fibrosis with late gadolinium enhancement (LGE), myocardial blood flow (MBF), and MPR; and transthoracic echocardiography to assess stenosis severity and diastolic function. Results Peak VO2 was associated with sex (β = −0.41), age (β = −0.32), MPR (β = 0.45), resting MBF (β = −0.53), and septal transmitral flow velocity to annular velocity ratio (E/E′) (β = −0.34), but not with LVMI, LGE, or echocardiographic measures of AS severity. On stepwise regression analysis, only MPR was independently associated with age- and sex-corrected peak VO2 (β = 0.46, p = 0.001). MPR was also inversely related to New York Heart Association functional class (p = 0.001). Univariate associations with MPR were sex (β = 0.38, p = 0.02), septal E/E′ (β = −0.30, p = 0.03), peak aortic valve velocity (β = −0.34, p = 0.02), LVMI (β = −0.51, p < 0.001), and LGE category (β = −0.46, p = 0.002). On multivariate analysis, LVMI and LGE were independently associated with MPR. Conclusions CMR-quantified MPR is independently associated with aerobic exercise capacity in severe AS. LV remodeling appears to be a more important determinant of impaired MPR than stenosis severity per se. Further work is required to determine how CMR assessment of MPR can aid clinical management of patients with AS.
Objectives The study objective was to determine whether the coronary artery disease (CAD)-associated genotype at chromosome 9p21 modulates basal or induced expression of type I interferons (IFN-I). ...Background The mechanism responsible for the association between common variants in chromosome 9p21.3 and CAD remains unclear. It has been reported that the CAD risk locus is rich in enhancer-like elements and that chromosome looping can lead to its physical proximity with the IFN-I gene cluster, raising the possibility that the locus influences CAD risk by modulating expression of IFN-Is. Methods We examined whether genotype at the lead CAD-associated single nucleotide polymorphism (rs1333049) in 9p21 was associated with: 1) basal levels of IFN-I in plasma from 148 healthy male subjects; 2) induction of IFN-I by Toll-like receptor stimulants in peripheral blood mononuclear cells of 60 healthy volunteers assessed by enzyme-linked immunosorbent assay, quantitative polymerase chain reaction, Western blot, and IFN-I bioassay; and 3) enhancer activity of predicted IFN regulatory factor 3/7 binding sites within the 9p21 CAD risk region in reporter assays. Results No significant effects of 9p21 genotype were observed for plasma levels of IFN-α, IFN-α21, or CXCL10, or leukocyte induction of IFN-α, IFN-α21, IFN-β, CXCL10, or total IFN-I measured at the mRNA, protein, and biological activity levels. There was also no enhancement of reporter activity by predicted IFN regulatory factor 3/7 binding sites in the CAD risk locus of either genotype. Conclusions The mechanism underlying the association between common 9p21 variants and CAD does not involve differential regulation of IFN-I responses.
The telomere length is an indicator of biologic aging, and shorter telomeres have been associated with coronary artery calcium (CAC), a validated indicator of coronary atherosclerosis. It is unclear, ...however, whether healthy lifestyle behaviors affect the relation between telomere length and CAC. In a sample of subjects aged 40 to 64 years with no previous diagnosis of coronary heart disease, stroke, diabetes mellitus, or cancer (n = 318), healthy lifestyle behaviors of greater fruit and vegetable consumption, lower meat consumption, exercise, being at a healthy weight, and the presence of social support were examined to determine whether they attenuated the association between a shorter telomere length and the presence of CAC. Logistic regression analyses controlling for age, gender, race/ethnicity, and Framingham risk score revealed that the relation between having shorter telomeres and the presence of CAC was attenuated in the presence of high social support, low meat consumption, and high fruit and vegetable consumption. Those with shorter telomeres and these characteristics were not significantly different from those with longer telomeres. Conversely, the subjects with shorter telomeres and less healthy lifestyles had a significantly increased risk of the presence of CAC: low fruit and vegetable consumption (odds ratio 3.30, 95% confidence interval 1.61 to 6.75), high meat consumption (odds ratio 3.33, 95% confidence interval 1.54 to 7.20), and low social support (odds ratio 2.58, 95% confidence interval 1.24 to 5.37). Stratification by gender yielded similar results for men; however, among women, only fruit and vegetable consumption attenuated the shorter telomere length and CAC relation. In conclusion, the results of the present study suggest that being involved in healthy lifestyle behaviors might attenuate the association between shorter telomere length and coronary atherosclerosis, as identified using CAC.
Renal function impairment relates to poor outcome in patients with chronic heart failure (HF). Differences in biological aging could affect the susceptibility to develop renal dysfunction in chronic ...HF. In the present study, we explored the association of leukocyte telomere length with renal function in patients with chronic HF. We studied 610 patients with HF, aged 40 to 80 years, NYHA class II-IV, with left ventricular ejection fraction of 0.40 or less. Glomerular filtration rate was estimated by the Modification of Diet in Renal Diseases (MDRD) formula, and telomere length of leukocytes was determined by a validated quantitative polymerase chain reaction-based method. Age-and gender-adjusted telomere length ratio decreased steadily with decreasing quartile of the MDRD formula (mean 0.80, 95% confidence interval CI 0.73 to 0.88; mean 0.74, 95% CI 0.68 to 0.81; 0.70 mean, 95% CI 0.63 to 0.76; mean 0.67, 95% CI 0.61 to 0.73; p <0.01). Telomere length of leukocytes correlated positively with the MDRD formula (correlation coefficient 0.141; p <0.001). These findings remained significant after adjustment for baseline differences and sensitivity analysis based on propensity score one-to-one matching. In conclusion, shorter leukocyte telomere length is associated with decreased renal function as estimated by the MDRD formula in patients with HF. Further studies will be needed to determine whether shorter leukocyte telomere length is the cause or consequence in this population and whether it plays a role in the prognosis of renal dysfunction in HF.
Mutations in the SCN5A gene, which encodes the cardiac sodium channel, have been implicated in the pathogenesis of Brugada syndrome (BrS). Febrile illnesses have been recognized to unmask and/or ...trigger the BrS phenotype. However, the pathophysiological mechanism has not been fully elucidated.
A novel SCN5A missense mutation, V1340I, was identified in a patient with BrS suffering from frequent episodes of polymorphic ventricular tachycardia (VT) and syncope associated with fever. The biophysical modifications of hNa(v)1.5 by V1340I were studied.
The effects of the V1340I mutation were studied in the 2 splice variants, SCN5A and SCN5A-Q1077del (delQ), using patch-clamp techniques at various temperatures between 22 degrees C and 40 degrees C.
At 22 degrees C, V1340I-SCN5A generated markedly diminished sodium currents compared to the wild-type (WT) SCN5A. On the contrary, V1340I-delQ generated almost identical current density compared to the WT-delQ. However, V1340I-delQ significantly attenuated the peak current density compared to the WT-delQ at 32 degrees C, 37 degrees C and 40 degrees C. The voltage dependency of steady-state activation was leftward shifted both in WT-delQ and V1340I-delQ at 40 degrees C. In addition, the V1340I-delQ accelerated the recovery time course from fast inactivation compared to the WT-delQ at 40 degrees C. Immunohistochemical staining showed that both V1340I-SCN5A and V1340I-dQ were expressed in the plasma membrane.
Our study supports the concept that febrile illness predisposes individuals who carry a loss of function SCN5A mutation, such as V1340I, to fever-induced ventricular arrhythmias in BrS by significantly reducing the sodium currents in the hyperthermic state.
Background Abdominal aortic aneurysms (AAA) are caused by inflammatory processes in the wall of the aorta resulting in degradation of structural proteins. This inflammatory process is mediated, in ...part, by cytokines, and interleukin-10 (IL-10) is a predominately anti-inflammatory cytokine. A single nucleotide polymorphism in the promoter region of the IL-10 gene that affects transcription has been associated with AAA in a small study. The aim of this study was to determine whether this polymorphism is associated with AAA and also examine its effect on the growth of small AAA. Methods and Results A case control study was performed. A total of 389 patients with AAA and 404 healthy controls were recruited. IL-10-1082 polymorphisms were determined by polymerase chain reaction-based methods. In the case of patients with small AAA (<5.5 cm), serial size measurements were recorded to determine mean growth rate. There was a statistically significant difference both in allele and genotype frequencies between the case and control groups with the IL-10-1082 ‘A’ allele being more common in the AAA group ( P = .006). In the AAA group, genotype frequencies were as follows: GG 84, GA 201, and AA 104. In the control group, the genotype frequencies were GG 118, GA 205, and AA 81. The odds ratio for the ‘A’ allele as a risk factor for AAA was 1.50 (95% confidence interval 1.09 to 2.07). Regression modeling revealed that the IL-10-1082 genotype was, however, not independently associated with AAA if age, tobacco use, hypertension, and history of coronary or peripheral artery disease was taken into account. There was a trend towards lower plasma IL-10 level in IL-10 AA carriers, but the IL-10 ‘A’ allele did not have any discernible effect on the growth of small AAA. Conclusions This study demonstrates that the IL-10-1082 ‘A’ allele is associated with AAA, although this association is likely to be secondary to an association between IL-10-1082 genotype and other markers of cardiovascular disease rather than AAA per se.
Abstract Background Familial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3 major lipid fractions, is caused by mutations that inactivate the gene ...angiopoietin-like 3 ( ANGPTL3 ). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown. Objectives The study goal was to leverage 3 distinct lines of evidence—a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in patients with myocardial infarction (MI)—to test whether ANGPTL3 deficiency is associated with lower risk for CAD. Methods We assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3 wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. LOF mutations were defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in <25% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 people who presented with MI and 3,232 control subjects. Results The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 people was a heterozygous carrier for an LOF mutation. Compared with those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17% reduction in circulating triglycerides and a 12% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34% reduction in odds of CAD (odds ratio: 0.66; 95% confidence interval: 0.44 to 0.98; p = 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95% confidence interval: 0.55 to 0.77; p < 0.001). Conclusions ANGPTL3 deficiency is associated with protection from CAD.
Abstract Background Genomic analyses have suggested that the LPA gene and its associated plasma biomarker, lipoprotein(a) (Lpa), represent a causal risk factor for coronary heart disease (CHD). As ...such, lowering Lp(a) levels has emerged as a therapeutic strategy. Beyond target identification, human genetics may contribute to the development of new therapies by defining the full spectrum of beneficial and adverse consequences and by developing a dose–response curve of target perturbation. Objectives The goal of this study was to establish the full phenotypic impact of LPA gene variation and to estimate a dose–response curve between genetically altered plasma Lp(a) and risk for CHD. Methods We leveraged genetic variants at the LPA gene from 3 data sources: individual-level data from 112,338 participants in the U.K. Biobank; summary association results from large-scale genome-wide association studies; and LPA gene sequencing results from case subjects with CHD and control subjects free of CHD. Results One SD genetically lowered Lp(a) level was associated with a 29% lower risk of CHD (odds ratio OR: 0.71; 95% confidence interval CI: 0.69 to 0.73), a 31% lower risk of peripheral vascular disease (OR: 0.69; 95% CI: 0.59 to 0.80), a 13% lower risk of stroke (OR: 0.87; 95% CI: 0.79 to 0.96), a 17% lower risk of heart failure (OR: 0.83; 95% CI: 0.73 to 0.94), and a 37% lower risk of aortic stenosis (OR: 0.63; 95% CI: 0.47 to 0.83). We observed no association with 31 other disorders, including type 2 diabetes and cancer. Variants that led to gain of LPA gene function increased the risk for CHD, whereas those that led to loss of gene function reduced the CHD risk. Conclusions Beyond CHD, genetically lowered Lp(a) levels are associated with a lower risk of peripheral vascular disease, stroke, heart failure, and aortic stenosis. As such, pharmacological lowering of plasma Lp(a) may influence a range of atherosclerosis-related diseases.
Summary Background We tested whether genetic factors distinctly contribute to either development of coronary atherosclerosis or, specifically, to myocardial infarction in existing coronary ...atherosclerosis. Methods We did two genome-wide association studies (GWAS) with coronary angiographic phenotyping in participants of European ancestry. To identify loci that predispose to angiographic coronary artery disease (CAD), we compared individuals who had this disorder (n=12 393) with those who did not (controls, n=7383). To identify loci that predispose to myocardial infarction, we compared patients who had angiographic CAD and myocardial infarction (n=5783) with those who had angiographic CAD but no myocardial infarction (n=3644). Findings In the comparison of patients with angiographic CAD versus controls, we identified a novel locus, ADAMTS7 (p=4·98×10−13 ). In the comparison of patients with angiographic CAD who had myocardial infarction versus those with angiographic CAD but no myocardial infarction, we identified a novel association at the ABO locus (p=7·62×10−9 ). The ABO association was attributable to the glycotransferase-deficient enzyme that encodes the ABO blood group O phenotype previously proposed to protect against myocardial infarction. Interpretation Our findings indicate that specific genetic predispositions promote the development of coronary atherosclerosis whereas others lead to myocardial infarction in the presence of coronary atherosclerosis. The relation to specific CAD phenotypes might modify how novel loci are applied in personalised risk assessment and used in the development of novel therapies for CAD. Funding The PennCath and MedStar studies were supported by the Cardiovascular Institute of the University of Pennsylvania, by the MedStar Health Research Institute at Washington Hospital Center and by a research grant from GlaxoSmithKline. The funding and support for the other cohorts contributing to the paper are described in the webappendix.
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