To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization.
We ...developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10(-6)); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75).
The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.
Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with ...modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk.
In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores.
Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c (0·03%, −0·01 to 0·08), fasting insulin (0·00%, −0·06 to 0·07), and BMI (0·11 kg/m2, −0·09 to 0·30).
PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins.
British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.
Aims/hypothesis
Our aim was to determine whether a range of prespecified retinal vessel traits were associated with incident diabetic retinopathy in adults with type 2 diabetes.
Methods
In the ...prospective observational cohort Edinburgh Type 2 Diabetes Study of 1066 adults with type 2 diabetes, aged 60–75 years at recruitment, 718 were free from diabetic retinopathy at baseline. Baseline retinal traits including vessel widths, tortuosity (curvature) and fractal dimensions (network complexity), were quantified using fundus camera images and semiautomated software, and analysed using logistic regression for their association with incident diabetic retinopathy over 10 years.
Results
The incidence of diabetic retinopathy was 11.4% (
n
= 82) over 10 years. After adjustment for a range of vascular and diabetes-related risk factors, both increased venular tortuosity (OR 1.51; 95% CI 1.15, 1.98;
p
= 0.003) and decreased fractal dimension (OR 0.75; 95% CI 0.58, 0.96;
p
= 0.025) were associated with incident retinopathy. There was no evidence of an association with arterial tortuosity, and associations between measurements of vessel widths and retinopathy lost statistical significance after adjustment for diabetes-related factors and vascular disease. Adding venular tortuosity to a model including established risk factors for diabetic retinopathy (HbA
1c
, BP and kidney function) improved the discriminative ability (C statistic increased from 0.624 to 0.640,
p
= 0.013), but no such benefit was found with fractal dimension.
Conclusions/interpretation
Increased retinal venular tortuosity and decreased fractal dimension are associated with incident diabetic retinopathy, independent of classical risk factors. There is some evidence that venular tortuosity may be a useful biomarker to improve the predictive ability of models based on established retinopathy risk factors, and its inclusion in further risk prediction modelling is warranted.
Graphical abstract
Aims/hypothesis
Our aim was to determine whether quantitative retinal traits in people with type 2 diabetes are independently associated with incident major cardiovascular events including CHD and ...stroke.
Methods
A total of 1066 men and women with type 2 diabetes, aged 65–74 years, were followed up over 8 years in the population-based Edinburgh Type 2 Diabetes Study. Using retinal photographs taken at baseline and specialist software, a number of quantitative retinal traits were measured, including arteriolar and venular widths and tortuosity as well as fractal dimension (a measure of the branching pattern complexity of the retinal vasculature network). Incident CHD events occurring during follow-up included fatal and non-fatal myocardial infarction, first episodes of angina and coronary interventions for CHD. Incident cerebrovascular events included fatal and non-fatal stroke or transient ischaemic attack. Cox proportional hazard regression analyses were performed to identify the association of the retinal traits with cardiovascular events in the population with retinal data available (
n
= 1028).
Results
A total of 200 participants had an incident cardiovascular event (139 CHD and 61 cerebrovascular events). Following adjustment for age and sex, arteriolar tortuosity and fractal dimension were associated with cerebrovascular events (HR 1.27 95% CI 1.02, 1.58 and HR 0.74 95% CI 0.57, 0.95, respectively), including with stroke alone (HR 1.30 95% CI 1.01, 1.66 and HR 0.73 95% CI 0.56, 0.97, respectively). These associations persisted after further adjustment for established cardiovascular risk factors (HR 1.26 95% CI 1.01, 1.58 and HR 0.73 95% CI 0.56, 0.94, respectively). Associations generally reduced in strength after a final adjustment for the presence of diabetic retinopathy, but the association of fractal dimension with incident cerebrovascular events and stroke retained statistical significance (HR 0.73 95% CI 0.57, 0.95 and HR 0.72 95% CI 0.54, 0.97, respectively). Associations of retinal traits with CHD were generally weak and showed no evidence of statistical significance.
Conclusions/interpretation
Arteriolar tortuosity and fractal dimension were associated with incident cerebrovascular events, independent of a wide range of traditional cardiovascular risk factors including diabetic retinopathy. These findings suggest potential for measurements of early retinal vasculature change to aid in the identification of people with type 2 diabetes who are at increased risk from stroke.
Graphical abstract
Aims/hypothesis
We aimed to determine the longitudinal association of circulating markers of systemic inflammation with subsequent long-term cognitive change in older people with type 2 diabetes.
...Methods
The Edinburgh Type 2 Diabetes Study is a prospective cohort study of 1066 adults aged 60 to 75 years with type 2 diabetes. Baseline data included C-reactive protein, IL-6, TNF-α fibrinogen and neuropsychological testing on major cognitive domains. Cognitive testing was repeated after 10 years in 581 participants. A general cognitive ability score was derived from the battery of seven individual cognitive tests using principal component analysis. Linear regression was used to determine longitudinal associations between baseline inflammatory markers and cognitive outcomes at follow-up, with baseline cognitive test results included as covariables to model cognitive change over time.
Results
Following adjustment for age, sex and baseline general cognitive ability, higher baseline fibrinogen and IL-6 were associated with greater decline in general cognitive ability (standardised
β
s = −0.059,
p
=0.032 and −0.064,
p
=0.018, respectively). These associations lost statistical significance after adjustment for baseline vascular and diabetes-related covariables. When assessing associations with individual cognitive tests, higher IL-6 was associated with greater decline in tests of executive function and abstract reasoning (standardised
β
s = 0.095,
p
=0.006 and −0.127,
p
=0.001, respectively). Similarly, raised fibrinogen and C-reactive protein levels were associated with greater decline in processing speed (standardised
β
s = −0.115,
p
=0.001 and −0.111,
p
=0.001, respectively). These associations remained statistically significant after adjustment for the diabetes- and vascular-related risk factors.
Conclusions/interpretation
Higher baseline levels of inflammatory markers, including plasma IL-6, fibrinogen and C-reactive protein, were associated with subsequent cognitive decline in older people with type 2 diabetes. At least some of this association appeared to be specific to certain cognitive domains and to be independent of vascular and diabetes-related risk factors.
Graphical abstract
Aims/hypothesis
We aimed to determine the association of depression with dementia risk in people with type 2 diabetes, and to explore the possible mediating role of inflammation in this relationship.
...Methods
The Edinburgh Type 2 Diabetes Study is a prospective cohort of 1066 men and women with type 2 diabetes aged 60–75 years. Cox proportional hazards regression analysis was used to investigate the association between depression, assessed at baseline, and subsequent risk of dementia over 10 years. Depression was defined using the Hospital Anxiety and Depression Scale, while incident dementia was defined using medical records, prescription data and death certificates. The potential mediating effect of systemic inflammation was assessed by adjusting models for a generalised inflammation factor, derived from four inflammatory markers measured at baseline (C-reactive protein, IL-6, TNF-α and fibrinogen), and carrying out an exploratory mediation analysis.
Results
Dementia developed in 105 participants over a median follow-up of 10.6 years. After adjusting for age and sex, depression was associated with over a 2.5-fold increase in risk of dementia (HR 2.59 95% CI 1.62, 4.15). Additional adjustment for the generalised inflammation factor and other covariates did not attenuate the size of association between depression and incident dementia and mediation analysis showed that it was not a mediator. Adjusted logistic regression models showed cross-sectional associations of C-reactive protein and IL-6 with depression.
Conclusions/interpretation
Depression is an important risk factor for dementia in people with type 2 diabetes. Some inflammatory markers were associated with depression, but systemic inflammation does not appear to mediate the relationship between depression and dementia.
Graphical abstract
We conducted a systematic review and meta-analysis of studies reporting circulating IL-6 in AAA, and new investigations of the association between a common non-synonymous functional variant ...(Asp358Ala) in the IL-6R gene (IL6R) and AAA, followed the analysis of the variant both in vitro and in vivo. Inflammation may play a role in the development of abdominal aortic aneurysms (AAA). Interleukin-6 (IL-6) signalling through its receptor (IL-6R) is one pathway that could be exploited pharmacologically. We investigated this using a Mendelian randomization approach.
Up to October 2011, we identified seven studies (869 cases, 851 controls). Meta-analysis demonstrated that AAA cases had higher levels of IL-6 than controls standardized mean difference (SMD) = 0.46 SD, 95% CI = 0.25-0.66, I(2) = 70%, P = 1.1 × 10-5 random effects. Meta-analysis of five studies (4524 cases/15 710 controls) demonstrated that rs7529229 (which tags the non-synonymous variant Asp358Ala, rs2228145) was associated with a lower risk of AAA, per Ala358 allele odds ratio 0.84, 95% CI: 0.80-0.89, I(2) = 0%, P = 2.7 × 10-11). In vitro analyses in lymphoblastoid cell lines demonstrated a reduction in the expression of downstream targets (STAT3, MYC and ICAM1) in response to IL-6 stimulation in Ala358 carriers.
A Mendelian randomization approach provides robust evidence that signalling via the IL-6R is likely to be a causal pathway in AAA. Drugs that inhibit IL-6R may play a role in AAA management.
Carotid intima media thickness (CIMT) predicts cardiovascular (CVD) events, but the predictive value of CIMT change is debated. We assessed the relation between CIMT change and events in individuals ...at high cardiovascular risk.
From 31 cohorts with two CIMT scans (total n = 89070) on average 3.6 years apart and clinical follow-up, subcohorts were drawn: (A) individuals with at least 3 cardiovascular risk factors without previous CVD events, (B) individuals with carotid plaques without previous CVD events, and (C) individuals with previous CVD events. Cox regression models were fit to estimate the hazard ratio (HR) of the combined endpoint (myocardial infarction, stroke or vascular death) per standard deviation (SD) of CIMT change, adjusted for CVD risk factors. These HRs were pooled across studies. In groups A, B and C we observed 3483, 2845 and 1165 endpoint events, respectively. Average common CIMT was 0.79mm (SD 0.16mm), and annual common CIMT change was 0.01mm (SD 0.07mm), both in group A. The pooled HR per SD of annual common CIMT change (0.02 to 0.43mm) was 0.99 (95% confidence interval: 0.95-1.02) in group A, 0.98 (0.93-1.04) in group B, and 0.95 (0.89-1.04) in group C. The HR per SD of common CIMT (average of the first and the second CIMT scan, 0.09 to 0.75mm) was 1.15 (1.07-1.23) in group A, 1.13 (1.05-1.22) in group B, and 1.12 (1.05-1.20) in group C.
We confirm that common CIMT is associated with future CVD events in individuals at high risk. CIMT change does not relate to future event risk in high-risk individuals.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We investigated causal effect of completed growth, measured by adult height, on coronary heart disease (CHD), stroke and cardiovascular traits, using instrumental variable (IV) Mendelian ...randomization meta-analysis.
We developed an allele score based on 69 single nucleotide polymorphisms (SNPs) associated with adult height, identified by the IBCCardioChip, and used it for IV analysis against cardiovascular risk factors and events in 21 studies and 60 028 participants. IV analysis on CHD was supplemented by summary data from 180 height-SNPs from the GIANT consortium and their corresponding CHD estimates derived from CARDIoGRAMplusC4D.
IV estimates from IBCCardioChip and GIANT-CARDIoGRAMplusC4D showed that a 6.5-cm increase in height reduced the odds of CHD by 10% odds ratios 0.90; 95% confidence intervals (CIs): 0.78 to 1.03 and 0.85 to 0.95, respectively,which agrees with the estimate from the Emerging Risk Factors Collaboration (hazard ratio 0.93; 95% CI: 0.91 to 0.94). IV analysis revealed no association with stroke (odds ratio 0.97; 95% CI: 0.79 to 1.19). IV analysis showed that a 6.5-cm increase in height resulted in lower levels of body mass index ( P < 0.001), triglycerides ( P < 0.001), non high-density (non-HDL) cholesterol ( P < 0.001), C-reactive protein ( P = 0.042), and systolic blood pressure ( P = 0.064) and higher levels of forced expiratory volume in 1 s and forced vital capacity ( P < 0.001 for both).
Taller individuals have a lower risk of CHD with potential explanations being that taller people have a better lung function and lower levels of body mass index, cholesterol and blood pressure.
Iron stores, estimated as ferritin levels, and type 2 diabetes (T2D) have been associated previously, while findings regarding coronary heart disease (CHD) and cerebrovascular disease (CEVD) are ...still inconclusive. No study has focused on simultaneous evaluation of associations between iron stores and the above cardiometabolic diseases (CMD) in the same population. We aim to evaluate the association between serum ferritin and risk of T2D, CHD and CEVD in Scottish population over a wide range of ferritin levels.
Longitudinal study in 6,497 participants of the 1995 and 1998 Scottish health surveys, who were followed-up until 2011. Cox regression models were conducted adjusting for age, sex/menopausal status, fibrinogen, GGT levels, smoking, alcohol consumption, total cholesterol, HDL-cholesterol, blood pressure, and BMI. Ferritin was used as continuous (sex/menopausal status-specific Z score) and categorical variable (sex/menopausal status-specific quartiles, quintiles and sextiles).
During follow-up, 4.9% of the participants developed T2D, 5.3% CHD, and 2.3% CEVD. By using ferritin quartiles, serum ferritin was positively associated with T2D, CHD and CEVD but only the association with T2D remained after adjustment for covariates Quartile 4 v. 1: adjusted HR 95% CI 1.59 (1.10-2.34); P = 0.006. When ferritin sextiles were used (6 v. 1), the ferritin-CEVD association became slightly stronger and significant adjusted HR 95% CI 2.08 (1.09-3.94); P = 0.024.
Iron stores relate differently to each CMD. Serum ferritin levels were positively and independently associated with incident T2D, and with incident CEVD if higher cut-off points for high ferritin levels were considered.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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