Publications by authors named "Stela McLachlan"

56 Publications

Addition of hyaluronic acid to the FIB-4 liver fibrosis score improves prediction of incident cirrhosis and hepatocellular carcinoma in type 2 diabetes: The Edinburgh Type 2 Diabetes Study.

Obes Sci Pract 2021 Oct 6;7(5):497-508. Epub 2021 May 6.

Metabolic Unit Western General Hospital Edinburgh UK.

Background: Type 2 diabetes (T2D) is associated with increased risk of progression to cirrhosis and hepatocellular carcinoma (HCC) in people with chronic liver diseases, particularly non-alcoholic fatty liver disease (NAFLD). However, the absolute risk of progression is low. So, it is crucial to accurately identify patients who would benefit most from hepatology referral and intensified management. Current risk-stratification tools are suboptimal and perform worse in people with diabetes.

Aims: To determine whether the addition of complementary biomarker(s) to current NAFLD risk-stratification tools in people with T2D could improve the identification of people who are at increased risk of developing incident cirrhosis or HCC.

Methods: The Edinburgh Type 2 diabetes Study (ET2DS) is a cohort study of men and women with T2D ( = 1066, age 60-75 at baseline). Cases of cirrhosis and HCC were identified over 11 years of follow-up. Biomarkers were measured at baseline and year 1 and association with incident disease was assessed using logistic regression.

Results: Of existing risk-stratification scores tested, the Fibrosis-4 (FIB-4) index and the AST:platelet ratio index (APRI) performed best in this cohort. Addition of hyaluronic acid (cut-point ≥ 50   g/L) to FIB-4 (cut-point ≥ 1.3) maintained a false negative rate of ≤25% and reduced the number of people incorrectly identified as "high risk" for incident disease by ∼50%.

Conclusions: The addition of hyaluronic acid to FIB-4 reduced the proportion of people inappropriately identified as "high risk" for development of cirrhosis/HCC in a community population of otherwise asymptomatic people with T2D. These findings require a validation in independent cohorts.
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http://dx.doi.org/10.1002/osp4.484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488456PMC
October 2021

Genome-Wide Association Study of Peripheral Artery Disease.

Circ Genom Precis Med 2021 Oct 4:CIRCGEN119002862. Epub 2021 Oct 4.

Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, United Kingdom. (N.R.v.Z., M.A., A.M., N.R.R., N.W.R., M.I.M., A.P.M.).

Background: Peripheral artery disease (PAD) affects >200 million people worldwide and is associated with high mortality and morbidity. We sought to identify genomic variants associated with PAD overall and in the contexts of diabetes and smoking status.

Methods: We identified genetic variants associated with PAD and then meta-analyzed with published summary statistics from the Million Veterans Program and UK Biobank to replicate their findings. Next, we ran stratified genome-wide association analysis in ever smokers, never smokers, individuals with diabetes, and individuals with no history of diabetes and corresponding interaction analyses, to identify variants that modify the risk of PAD dependent on diabetic or smoking status.

Results: We identified 5 genome-wide significant ( ≤5×10) associations with PAD in 449 548 (N=12 086) individuals of European ancestry near , , , , and loci (which overlapped previously reported associations). Meta-analysis with variants previously association with PAD showed that 18 of 19 published variants remained genome-wide significant. In individuals with diabetes, rs116405693 at the locus was associated with PAD (odds ratio [95% CI], 1.51 [1.32-1.74], =2.5×10, =5.3×10). Furthermore, in smokers, rs12910984 at the locus was associated with PAD (odds ratio [95% CI], 1.15 [1.11-1.19], =9.3×10, =3.9×10).

Conclusions: Our analyses confirm the published genetic associations with PAD and identify novel variants that may influence susceptibility to PAD in the context of diabetes or smoking status.
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http://dx.doi.org/10.1161/CIRCGEN.119.002862DOI Listing
October 2021

Deaths in critical care and hospice-prevalence, trends, influences: a national decedent cohort study.

BMJ Support Palliat Care 2021 Aug 11. Epub 2021 Aug 11.

Usher Institute, The University of Edinburgh, Edinburgh, UK

Objectives: End-of-life and bereavement care support services differ in critical care and inpatient hospice settings. There are limited population-level data comparing deaths in these two locations. We aimed to compare the characteristics of people who die in critical care units and in hospices, identify factors associated with place of death and report 12-year trends in Scotland.

Methods: We undertook a cohort study of decedents aged ≥16 years in Scotland (2005-2017). Location of death was identified from linkage to the Scottish Intensive Care Society Audit Group database and National Records of Scotland Death Records. We developed a multinomial logistic regression model to identify factors independently associated with location of death.

Results: There were 710 829 deaths in Scotland, of which 36 316 (5.1%) occurred in critical care units and 42 988 (6.1%) in hospices. As a proportion of acute hospital deaths, critical care deaths increased from 8.0% to 11.2%. Approximately one in eight deaths in those aged under 40 years occurred in critical care. Factors independently associated with hospice death included living in less deprived areas, cancer as the cause of death and presence of comorbidities. In contrast, liver disease and accidents as the cause of death and absence of comorbidities were associated with death in critical care.

Conclusions: Similar proportions of deaths in Scotland occur in critical care units and hospices. Given the younger age profile and unexpected nature of deaths occurring in critical care units, there is a need for a specific focus on end-of-life and bereavement support services in critical care units.
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http://dx.doi.org/10.1136/bmjspcare-2021-003157DOI Listing
August 2021

Retinal arteriolar tortuosity and fractal dimension are associated with long-term cardiovascular outcomes in people with type 2 diabetes.

Diabetologia 2021 Oct 23;64(10):2215-2227. Epub 2021 Jun 23.

Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, UK.

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.
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http://dx.doi.org/10.1007/s00125-021-05499-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423701PMC
October 2021

Genome-wide association study of circulating interleukin 6 levels identifies novel loci.

Hum Mol Genet 2021 04;30(5):393-409

Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK.

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
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http://dx.doi.org/10.1093/hmg/ddab023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098112PMC
April 2021

Retinal venular tortuosity and fractal dimension predict incident retinopathy in adults with type 2 diabetes: the Edinburgh Type 2 Diabetes Study.

Diabetologia 2021 May 30;64(5):1103-1112. Epub 2021 Jan 30.

Usher Institute, University of Edinburgh, Edinburgh, UK.

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, 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.
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http://dx.doi.org/10.1007/s00125-021-05388-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012328PMC
May 2021

Variation in the SERPINA6/SERPINA1 locus alters morning plasma cortisol, hepatic corticosteroid binding globulin expression, gene expression in peripheral tissues, and risk of cardiovascular disease.

J Hum Genet 2021 Jun 20;66(6):625-636. Epub 2021 Jan 20.

Centre for Global Health Research, Usher Institute, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, Scotland.

The stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06-0.59) and myocardial infarction (0.21, 95% CI 0.00-0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.
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http://dx.doi.org/10.1038/s10038-020-00895-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144017PMC
June 2021

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Nat Commun 2021 01 5;12(1):24. Epub 2021 Jan 5.

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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http://dx.doi.org/10.1038/s41467-020-19366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785747PMC
January 2021

Depression as a risk factor for dementia in older people with type 2 diabetes and the mediating effect of inflammation.

Diabetologia 2021 02 16;64(2):448-457. Epub 2020 Oct 16.

Usher Institute, University of Edinburgh, Edinburgh, UK.

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.
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http://dx.doi.org/10.1007/s00125-020-05301-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801357PMC
February 2021

Non-invasive risk scores do not reliably identify future cirrhosis or hepatocellular carcinoma in Type 2 diabetes: The Edinburgh type 2 diabetes study.

Liver Int 2020 09 22;40(9):2252-2262. Epub 2020 Jul 22.

Western General Hospital, Edinburgh, UK.

Background: The incidence of cirrhosis and hepatocellular carcinoma (HCC) is increased in Type 2 diabetes, primarily secondary to non-alcoholic fatty liver disease (NAFLD). European guidelines recommend screening for NAFLD in Type 2 diabetes. American guidelines, while not advocating a screening protocol, suggest using non-invasive markers of fibrosis for risk-stratification and guiding onward referral.

Aims: To test the ability of individual fibrosis scores and the European screening algorithm to predict 11-year incident cirrhosis/HCC in an asymptomatic community cohort of older people with Type 2 diabetes.

Methods: The Edinburgh Type 2 Diabetes Study investigated men and women with Type 2 diabetes (n = 1066, aged 60-75 at baseline). Liver markers were measured at baseline and year 1; steatosis and fibrosis markers were calculated according to independently published calculations. During 11 years of follow-up, cases of cirrhosis and HCC were identified.

Results: Forty-three out of 1059 participants with no baseline cirrhosis/HCC developed incident disease. All scores were significantly associated with incident liver disease by odds ratio (P < .05). The ability of the risk-stratification tools to accurately identify those who developed incident cirrhosis/HCC was poor with low-positive predictive values (5-46%) and high false-negative and -positive rates (up to 60% and 77%) respectively. When fibrosis risk scores were used in conjunction with the European algorithm, they performed modestly better than when applied in isolation.

Conclusions: In a cohort with a moderately low incidence of cirrhosis/HCC, existing risk scores did not reliably identify participants at high risk. Better prediction models for cirrhosis/HCC in people with Type 2 diabetes are required.
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http://dx.doi.org/10.1111/liv.14590DOI Listing
September 2020

Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9.

BMC Cardiovasc Disord 2019 10 29;19(1):240. Epub 2019 Oct 29.

Department Primary Care & Population Health, University College London, London, UK.

Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9.

Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration.

Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable.

Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
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http://dx.doi.org/10.1186/s12872-019-1187-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820948PMC
October 2019

Progression of conventional cardiovascular risk factors and vascular disease risk in individuals: insights from the PROG-IMT consortium.

Eur J Prev Cardiol 2020 02 16;27(3):234-243. Epub 2019 Oct 16.

Department of Internal Medicine and Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, The Netherlands.

Aims: Averaged measurements, but not the progression based on multiple assessments of carotid intima-media thickness, (cIMT) are predictive of cardiovascular disease (CVD) events in individuals. Whether this is true for conventional risk factors is unclear.

Methods And Results: An individual participant meta-analysis was used to associate the annualised progression of systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with future cardiovascular disease risk in 13 prospective cohort studies of the PROG-IMT collaboration ( = 34,072). Follow-up data included information on a combined cardiovascular disease endpoint of myocardial infarction, stroke, or vascular death. In secondary analyses, annualised progression was replaced with average. Log hazard ratios per standard deviation difference were pooled across studies by a random effects meta-analysis. In primary analysis, the annualised progression of total cholesterol was marginally related to a higher cardiovascular disease risk (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.00 to 1.07). The annualised progression of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol was not associated with future cardiovascular disease risk. In secondary analysis, average systolic blood pressure (HR 1.20 95% CI 1.11 to 1.29) and low-density lipoprotein cholesterol (HR 1.09, 95% CI 1.02 to 1.16) were related to a greater, while high-density lipoprotein cholesterol (HR 0.92, 95% CI 0.88 to 0.97) was related to a lower risk of future cardiovascular disease events.

Conclusion: Averaged measurements of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol displayed significant linear relationships with the risk of future cardiovascular disease events. However, there was no clear association between the annualised progression of these conventional risk factors in individuals with the risk of future clinical endpoints.
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http://dx.doi.org/10.1177/2047487319877078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008553PMC
February 2020

GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.

Nat Commun 2018 12 3;9(1):5141. Epub 2018 Dec 3.

Department of Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA.

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.
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http://dx.doi.org/10.1038/s41467-018-07340-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277418PMC
December 2018

Ferritin, metabolic syndrome and its components: A systematic review and meta-analysis.

Atherosclerosis 2018 08 23;275:97-106. Epub 2018 May 23.

Centre for Population Health Sciences, University of Edinburgh, Edinburgh, Scotland, United Kingdom.

Background And Aims: Mechanisms for the association between iron stores and risk factors for diabetes and cardiovascular disease, such as metabolic syndrome (MetS) and its components, are still not clear. We evaluated the associations between ferritin levels, MetS and its individual components, and potential role of confounding, in a meta-analysis.

Methods: We searched articles in MEDLINE and EMBASE until February 14th, 2018. There were two approaches: meta-analysis of 1) cross-sectional and longitudinal studies and 2) only cross-sectional studies. Meta-regressions were conducted to identify sources of heterogeneity in the associations of ferritin with MetS and its individual components.

Results: Information from 26 studies (5 prospective) was systematically reviewed and 21 studies were meta-analysed. The pooled OR for MetS by increased ferritin was 1.78 (95%CI: 1.60-1.97) in the meta-analysis 1, and 1.70 (95%CI: 1.49-1.95) in the meta-analysis 2. The pooled association was weaker in studies adjusted for hepatic injury markers (meta-regression coefficient (95% CI): -0.34 (-0.60,-0.09) p = 0.008) and body mass index (BMI) (meta-regression coefficient (95% CI): -0.27 (-0.53,-0.01) p = 0.039). Among MetS components, the pooled association with increased ferritin was strongest with high triglycerides [OR (95%CI): 1.96 (1.65-2.32)] and high glucose levels [OR 95%CI: 1.60 (1.40-1.82)]. Higher cut-off points used to define high ferritin concentrations were more strongly associated with high triglycerides [meta-regression coefficient (95% CI): 0.22 (0.03, 0.041), p = 0.023].

Conclusions: High triglycerides and glucose are the components more strongly associated with ferritin. Hepatic injury and BMI appear to influence the ferritin-MetS association, and a threshold effect of high ferritin concentration on the ferritin-high triglycerides association was observed.
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http://dx.doi.org/10.1016/j.atherosclerosis.2018.05.043DOI Listing
August 2018

Predictive value for cardiovascular events of common carotid intima media thickness and its rate of change in individuals at high cardiovascular risk - Results from the PROG-IMT collaboration.

PLoS One 2018 12;13(4):e0191172. Epub 2018 Apr 12.

Radiology Department, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain.

Aims: 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.

Methods And Results: 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.

Conclusions: 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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191172PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896895PMC
July 2018

Decreased iron stores are associated with cardiovascular disease in patients with type 2 diabetes both cross-sectionally and longitudinally.

Atherosclerosis 2018 05 21;272:193-199. Epub 2018 Mar 21.

Department of Diabetes, Endocrinology and Nutrition, Institut D'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain. Electronic address:

Background And Aims: The possible contribution of iron to cardiovascular complications of type 2 diabetes (T2D) has been scarcely investigated. We aimed to study whether serum ferritin is linked to prevalent/incident cardiovascular disease (CVD) in T2D.

Methods: The prevalence of coronary heart disease (CHD), cerebrovascular disease (CEVD) and CVD was evaluated in the SIDIAP study (n = 38,617) and prevalence and 7-year incidence were analysed in the Edinburgh Type 2 Diabetes Study (ET2DS) (n = 821). Logistic and Cox regressions were used to describe associations between serum ferritin and CVD adjusting for confounding variables.

Results: Increase of 1 SD unit in log-ferritin was associated with lower CVD prevalence in fully-adjusted models (ET2DS odds ratio (OR) 95% confidence interval (CI): 0.81 (0.68-0.96), p = 0.018; SIDIAP study: 0.91 (0.88-0.94), p < 0.001). In ET2DS, ferritin in the highest (vs. the lowest) quintile was associated with lower incidence of CVD (fully adjusted HR 95% CI: 0.46 (0.26-0.83), p = 0.010). This association persisted after removing subjects with CVD at baseline (n = 536) (HR 95% CI: 0.34 (0.14-0.81), p = 0.016).

Conclusions: Low iron status was associated with CVD risk in T2D. This pattern was consistent in populations at different cardiovascular risk. Low iron status seems to be harmful for cardiovascular health in T2D and it may be a target for intervention.
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http://dx.doi.org/10.1016/j.atherosclerosis.2018.03.028DOI Listing
May 2018

mRNA and plasma hepcidin levels are influenced by sex and strain but do not predict tissue iron levels in inbred mice.

Am J Physiol Gastrointest Liver Physiol 2017 Nov 10;313(5):G511-G523. Epub 2017 Aug 10.

Department of Nutritional Science & Toxicology, University of California, Berkeley, California.

Iron homeostasis is tightly regulated, and the peptide hormone hepcidin is considered to be a principal regulator of iron metabolism. Previous studies in a limited number of mouse strains found equivocal sex- and strain-dependent differences in mRNA and serum levels of hepcidin and reported conflicting data on the relationship between hepcidin () mRNA levels and iron status. Our aim was to clarify the relationships between strain, sex, and hepcidin expression by examining multiple tissues and the effects of different dietary conditions in multiple inbred strains. Two studies were done: first, mRNA, liver iron, and plasma diferric transferrin levels were measured in 14 inbred strains on a control diet; and second, mRNA and plasma hepcidin levels in both sexes and iron levels in the heart, kidneys, liver, pancreas, and spleen in males were measured in nine inbred/recombinant inbred strains raised on an iron-sufficient or high-iron diet. Both sex and strain have a significant effect on both hepcidin mRNA (primarily a sex effect) and plasma hepcidin levels (primarily a strain effect). However, liver iron and diferric transferrin levels are not predictors of mRNA levels in mice fed iron-sufficient or high-iron diets, nor are the mRNA and plasma hepcidin levels good predictors of tissue iron levels, at least in males. We also measured plasma erythroferrone, performed RNA-sequencing analysis of liver samples from six inbred strains fed the iron-sufficient, low-iron, or high-iron diets, and explored differences in gene expression between the strains with the highest and lowest hepcidin levels. Both sex and strain have a significant effect on both hepcidin mRNA (primarily a sex effect) and plasma hepcidin levels (primarily a strain effect). Liver iron and diferric transferrin levels are not predictors of mRNA levels in mice, nor are the mRNA and plasma hepcidin levels good predictors of tissue iron levels, at least in males.
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http://dx.doi.org/10.1152/ajpgi.00307.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5792216PMC
November 2017

Comparison of non-traditional biomarkers, and combinations of biomarkers, for vascular risk prediction in people with type 2 diabetes: The Edinburgh Type 2 Diabetes Study.

Atherosclerosis 2017 Sep 12;264:67-73. Epub 2017 Jul 12.

Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland, UK. Electronic address:

Background And Aims: We aimed at comparing the impact of multiple non-traditional biomarkers (ankle brachial pressure index (ABI), N-terminal pro-brain natriuretic peptide (NT-proBNP), high sensitivity cardiac troponin (hs-cTnT), gamma-glutamyl transpeptidase (GGT) and four markers of systemic inflammation), both individually and in combination, on cardiovascular risk prediction, over and above traditional risk factors incorporated in the QRISK2 score, in older people with type 2 diabetes.

Methods: We conducted a prospective study of 1066 men and women aged 60-75 years with type 2 diabetes mellitus, living in Lothian, Scotland.

Results: After 8 years, 205 cardiovascular events occurred. Higher levels of hs-cTNT and NT-proBNP and lower ABI at baseline were associated with increased risk of CV events, independently of traditional risk factors (basic model). The C statistic of 0.722 (95% CI 0.681, 0.763) for the basic model increased on addition of individual biomarkers, most markedly for hs-cTnT (0.732; 0.690, 0.774)). Models including different combinations of biomarkers had even greater C statistics, with the highest for ABI, hs-cTnT and GGT combined (0.740; 0.699, 0.781).

Conclusions: Individually, hs-cTnT appeared to be the most promising biomarker in terms of improving vascular risk prediction in people with type 2 diabetes, over and above traditional risk factors incorporated in the QRISK2 score. Combining several non-traditional biomarkers added further predictive value, and this approach merits further investigation when developing cost effective risk prediction tools for use in clinical practice.
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http://dx.doi.org/10.1016/j.atherosclerosis.2017.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603967PMC
September 2017

Cardiovascular disease biomarkers are associated with declining renal function in type 2 diabetes.

Diabetologia 2017 08 20;60(8):1400-1408. Epub 2017 May 20.

Centre for Population Health Sciences, University of Edinburgh, Old Medical School, Teviot Place, Edinburgh, EH8 9AG, UK.

Aims/hypothesis: We investigated whether biochemical cardiovascular risk factors and/or markers of subclinical cardiovascular disease were associated with the development of reduced renal function in people with type 2 diabetes.

Methods: A cohort of 1066 Scottish men and women aged 60-74 years with type 2 diabetes from the Edinburgh Type 2 Diabetes Study were followed up for a median of 6.7 years. New-onset reduced renal function was defined as two eGFRs <60 ml min (1.73 m) at least 3 months apart with a > 25% decline from baseline eGFR. Ankle brachial pressure index (ABI), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT) were measured at baseline. Pulse wave velocity (PWV) and carotid intima media thickness were measured 1 year into follow-up. Data were analysed using Cox proportional hazards models.

Results: A total of 119 participants developed reduced renal function during follow-up. ABI, PWV, NT-proBNP and hsTnT were all associated with onset of decline in renal function following adjustment for age and sex. These associations were attenuated after adjustment for additional diabetes renal disease risk factors (systolic BP, baseline eGFR, albumin:creatinine ratio and smoking pack-years), with the exception of hsTnT which remained independently associated (HR 1.51 [95% CI 1.22, 1.87]). Inclusion of hsTnT in a predictive model improved the continuous net reclassification index by 0.165 (0.008, 0.286).

Conclusions/interpretation: Our findings demonstrate an association between hsTnT, a marker of subclinical cardiac ischaemia, and subsequent renal function decline. Further research is required to establish the predictive value of hsTnT and response to intervention.
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http://dx.doi.org/10.1007/s00125-017-4297-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491560PMC
August 2017

Causal Associations of Adiposity and Body Fat Distribution With Coronary Heart Disease, Stroke Subtypes, and Type 2 Diabetes Mellitus: A Mendelian Randomization Analysis.

Circulation 2017 Jun 12;135(24):2373-2388. Epub 2017 May 12.

From Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, United Kingdom (C.E.D., G.F., D.P.-M., A.D.H., J.P.C.); Department of Mathematics and Statistics, Lancaster University, United Kingdom (T.M.P.); UCLGenetics Institute, University College London, United Kingdom (J.W.); Applied Statistical Methods in Medical Research Group, Universidad Catolica de San Antonio de Murcia, Spain (D.P.-M.); Social Genetic & Developmental Psychiatry, King's College London, United Kingdom (D.Z.); Institute of Cardiovascular Science, University College London, United Kingdom (J.E.L.E., T.S., A.D.H., S.E.H.); MRC Unit for Lifelong Health & Ageing at UCL, London, United Kingdom (A.W., D.K.); Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (H.R.W., M.J.C., P.B.M.); NIHR Barts Cardiovascular Biomedical Research Unit, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (H.R.W., M.J.C., P.B.M.); Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, United Kingdom (S.M., J.F.P.); Department of Cardiology, Leiden University Medical Center, The Netherlands (S.T., W.J.); South Australian Health and Medical Research Institute, Adelaide (M.M., E.H.); EMBL Australia, Adelaide (M.M.); School of Social and Community Medicine, University of Bristol, United Kingdom (R.W.M., T.R.G., Y.B.-S., D.A.L., G.D.S.); Centre for Clinical Pharmacology, University College London, United Kingdom (R.S.); Institute for Social and Economic Research, University of Essex, Colchester, United Kingdom (M.K.); Centre for Population Health Research, School of Health Sciences and Sansom Institute, University of South Australia, Adelaide (E.H., A.Z.); Population, Policy & Practice, UCL Great Ormond Street Institute of Child Health, London, United Kingdom (E.H., C.P.); Department of Primary Care & Population Health, University College London, Royal Free Campus, United Kingdom (B.J.J.); MRC Integrative Epidemiology Unit, University of Bristol, United Kingdom (T.R.G., D.A.L., G.D.S.); Department of Women's Cancer, Institute for Women's Health, UCL, London, United Kingdom (A.G.-M., A.R., U.M.); Department of Clinical Epidemiology, Leiden University Medical Center, The Netherlands (R.d.M., D.O.M.-K.); Department of Internal Medicine, Section Gerontology and Geriatrics, Leiden University Medical Center, The Netherlands (R.N., S.T.); Interuniversity Cardiology Institute Netherlands, Utrecht (W.J.); Departments of Neurology and Public Health Sciences, University of Virginia, Charlottesville (B.B.W.); Department of Public Health and Primary Care, Leiden University Medical Center, The Netherlands (D.O.M.-K.); BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, United Kingdom (N.S.); Department of Epidemiology and Public Health, University College London, United Kingdom (M.K.); Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, United Kingdom (F.D.); Department of Health Sciences, University of Leicester, United Kingdom (F.D.); Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, Big Data Institute Building, University of Oxford, United Kingdom (M.V.H.); Medical Research Council Population Health Research Unit at the University of Oxford, United Kingdom (M.V.H.); and National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals, United Kingdom (M.V.H.).

Background: The implications of different adiposity measures on cardiovascular disease etiology remain unclear. In this article, we quantify and contrast causal associations of central adiposity (waist-to-hip ratio adjusted for body mass index [WHRadjBMI]) and general adiposity (body mass index [BMI]) with cardiometabolic disease.

Methods: Ninety-seven independent single-nucleotide polymorphisms for BMI and 49 single-nucleotide polymorphisms for WHRadjBMI were used to conduct Mendelian randomization analyses in 14 prospective studies supplemented with coronary heart disease (CHD) data from CARDIoGRAMplusC4D (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics; combined total 66 842 cases), stroke from METASTROKE (12 389 ischemic stroke cases), type 2 diabetes mellitus from DIAGRAM (Diabetes Genetics Replication and Meta-analysis; 34 840 cases), and lipids from GLGC (Global Lipids Genetic Consortium; 213 500 participants) consortia. Primary outcomes were CHD, type 2 diabetes mellitus, and major stroke subtypes; secondary analyses included 18 cardiometabolic traits.

Results: Each one standard deviation (SD) higher WHRadjBMI (1 SD≈0.08 U) associated with a 48% excess risk of CHD (odds ratio [OR] for CHD, 1.48; 95% confidence interval [CI], 1.28-1.71), similar to findings for BMI (1 SD≈4.6 kg/m; OR for CHD, 1.36; 95% CI, 1.22-1.52). Only WHRadjBMI increased risk of ischemic stroke (OR, 1.32; 95% CI, 1.03-1.70). For type 2 diabetes mellitus, both measures had large effects: OR, 1.82 (95% CI, 1.38-2.42) and OR, 1.98 (95% CI, 1.41-2.78) per 1 SD higher WHRadjBMI and BMI, respectively. Both WHRadjBMI and BMI were associated with higher left ventricular hypertrophy, glycemic traits, interleukin 6, and circulating lipids. WHRadjBMI was also associated with higher carotid intima-media thickness (39%; 95% CI, 9%-77% per 1 SD).

Conclusions: Both general and central adiposity have causal effects on CHD and type 2 diabetes mellitus. Central adiposity may have a stronger effect on stroke risk. Future estimates of the burden of adiposity on health should include measures of central and general adiposity.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.116.026560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515354PMC
June 2017

Identifying low density lipoprotein cholesterol associated variants in the Annexin A2 (ANXA2) gene.

Atherosclerosis 2017 06 13;261:60-68. Epub 2017 Apr 13.

Cardiovascular Genetics, BHF Laboratories, Institute of Cardiovascular Science, University College London, London, United Kingdom.

Background And Aims: Annexin-A2 (AnxA2) is an endogenous inhibitor of proprotein convertase subtilisin/kexin type-9 (PCSK9). The repeat-one (R1) domain of AnxA2 binds to PCSK9, blocking its ability to promote degradation of low-density lipoprotein cholesterol-receptors (LDL-R) and thereby regulate low-density lipoprotein cholesterol (LDL-C) levels. Here we identify variants in ANXA2 influencing LDL-C levels and we determine the molecular mechanisms of their effects.

Results: The ANXA2 single nucleotide polymorphism (SNP) genotype-phenotype association was examined using the Second-Northwick-Park Heart Study (NPHSII) (n∼2700) and the UCL-LSHTM-Edinburgh-Bristol (UCLEB) consortium (n∼14,600). The ANXA2-R1 domain coding-SNP rs17845226 (V98L) associated with LDL-C, homozygotes for the minor allele having ≈18.8% higher levels of LDL-C (p = 0.004), and higher risk of coronary heart disease (CHD) (p = 0.04). The SNP is in modest linkage disequilibrium (r > 0.5) with two intergenic SNPs, rs17191344 and rs11633032. Both SNPs showed allele-specific protein binding, and the minor alleles caused significant reduction in reporter gene expression (≈18%, p < 0.001). In the expression quantitative trait loci (eQTL) study, minor allele homozygotes have significantly lower levels of ANXA2-mRNA expression (p = 1.36 × 10).

Conclusions: Both rs11633032 and rs17191344 SNPs are functional variants, where the minor alleles create repressor-binding protein sites for transcription factors that contribute to reduced ANXA2 gene expression. Lower AnxA2 levels could increase plasma levels of PCSK9 and thus increase LDL-C levels and risk of CHD. This supports, for the first time in humans, previous observations in mouse models that changes in the levels of AnxA2 directly influence plasma LDL-C levels, and thus implicate this protein as a potential therapeutic target for LDL-C lowering.
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http://dx.doi.org/10.1016/j.atherosclerosis.2017.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446264PMC
June 2017

PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study.

Lancet Diabetes Endocrinol 2017 02 29;5(2):97-105. Epub 2016 Nov 29.

Centre for Population Health Sciences, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.

Background: 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.

Methods: 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, HbA, 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.

Findings: 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 HbA (0·03%, -0·01 to 0·08), fasting insulin (0·00%, -0·06 to 0·07), and BMI (0·11 kg/m, -0·09 to 0·30).

Interpretation: 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.

Funding: British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.
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http://dx.doi.org/10.1016/S2213-8587(16)30396-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5266795PMC
February 2017

Soluble transferrin receptor levels are positively associated with insulin resistance but not with the metabolic syndrome or its individual components.

Br J Nutr 2016 Oct 8;116(7):1165-1174. Epub 2016 Sep 8.

5Department of Public Health,School of Medicine,University of Split,21000 Split,Croatia.

The metabolic syndrome (MetS) is known to be associated with elevated serum ferritin levels. The possible association with other Fe markers has been less well studied. We aimed to investigate the cross-sectional association of soluble transferrin receptor (sTfR) and ferritin levels with the MetS components, insulin resistance and glycosylated Hb (HbA1C). The sample consisted of 725 adults, aged 19-93 years (284 men, 151 premenopausal and 290 postmenopausal women), from the Croatian island of Vis. Serum sTfR and ferritin levels were measured by immunoturbidimetry and electrochemiluminescence assays, respectively. The MetS was defined using modified international consensus criteria. Logistic and linear regression analyses were conducted to investigate the associations adjusting for age, fibrinogen, smoking status, alcohol consumption and BMI. Prevalence of the MetS was 48·7 %. Standardised values of ferritin were positively associated with all of the MetS components (except high blood pressure and waist circumference) in men (P0·05). sTfR levels could be spuriously elevated in subjects with insulin resistance and without association with the MetS or its components. We conclude that different markers of Fe metabolism are not consistently associated with cardiometabolic risk.
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http://dx.doi.org/10.1017/S0007114516002968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860738PMC
October 2016

Variant rs10911021 that associates with coronary heart disease in type 2 diabetes, is associated with lower concentrations of circulating HDL cholesterol and large HDL particles but not with amino acids.

Cardiovasc Diabetol 2016 08 22;15(1):115. Epub 2016 Aug 22.

Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Science, University College London, University Street, London, UK.

Aims: An intergenic locus on chromosome 1 (lead SNP rs10911021) was previously associated with coronary heart disease (CHD) in type 2 diabetes (T2D). Using data from the UCLEB consortium we investigated the relationship between rs10911021 and CHD in T2D, whether rs10911021 was associated with levels of amino acids involved in the γ-glutamyl cycle or any conventional risk factors (CRFs) for CHD in the T2D participants.

Methods: Four UCLEB studies (n = 6531) had rs10911021 imputation, CHD in T2D, CRF and metabolomics data determined using a nuclear magnetic resonance based platform.

Results: The expected direction of effect between rs10911021 and CHD in T2D was observed (1377 no CHD/160 CHD; minor allele OR 0.80, 95 % CI 0.60-1.06) although this was not statistically significant (p = 0.13). No association between rs10911021 and CHD was seen in non-T2D participants (11218 no CHD/1274 CHD; minor allele OR 1.00 95 % CIs 0.92-1.10). In T2D participants, while no associations were observed between rs10911021 and the nine amino acids measured, rs10911021 was associated with HDL-cholesterol (p = 0.0005) but the minor "protective" allele was associated with lower levels (-0.034 mmol/l per allele). Focusing more closely on the HDL-cholesterol subclasses measured, we observed that rs10911021 was associated with six large HDL particle measures in T2D (all p < 0.001). No significant associations were seen in non-T2D subjects.

Conclusions: Our findings are consistent with a true association between rs10911021 and CHD in T2D. The protective minor allele was associated with lower HDL-cholesterol and reductions in HDL particle traits. Our results indicate a complex relationship between rs10911021 and CHD in T2D.
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http://dx.doi.org/10.1186/s12933-016-0435-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4994200PMC
August 2016

Marginal role for 53 common genetic variants in cardiovascular disease prediction.

Heart 2016 10 30;102(20):1640-7. Epub 2016 Jun 30.

Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK.

Objective: We investigated discrimination and calibration of cardiovascular disease (CVD) risk scores when genotypic was added to phenotypic information. The potential of genetic information for those at intermediate risk by a phenotype-based risk score was assessed.

Methods: Data were from seven prospective studies including 11 851 individuals initially free of CVD or diabetes, with 1444 incident CVD events over 10 years' follow-up. We calculated a score from 53 CVD-related single nucleotide polymorphisms and an established CVD risk equation 'QRISK-2' comprising phenotypic measures. The area under the receiver operating characteristic curve (AUROC), detection rate for given false-positive rate (FPR) and net reclassification improvement (NRI) index were estimated for gene scores alone and in addition to the QRISK-2 CVD risk score. We also evaluated use of genetic information only for those at intermediate risk according to QRISK-2.

Results: The AUROC was 0.635 for QRISK-2 alone and 0.623 with addition of the gene score. The detection rate for 5% FPR improved from 11.9% to 12.0% when the gene score was added. For a 10-year CVD risk cut-off point of 10%, the NRI was 0.25% when the gene score was added to QRISK-2. Applying the genetic risk score only to those with QRISK-2 risk of 10%-<20% and prescribing statins where risk exceeded 20% suggested that genetic information could prevent one additional event for every 462 people screened.

Conclusion: The gene score produced minimal incremental population-wide utility over phenotypic risk prediction of CVD. Tailored prediction using genetic information for those at intermediate risk may have clinical utility.
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http://dx.doi.org/10.1136/heartjnl-2016-309298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5099215PMC
October 2016

Mendelian Randomisation study of the influence of eGFR on coronary heart disease.

Sci Rep 2016 06 24;6:28514. Epub 2016 Jun 24.

Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, UK.

Impaired kidney function, as measured by reduced estimated glomerular filtration rate (eGFR), has been associated with increased risk of coronary heart disease (CHD) in observational studies, but it is unclear whether this association is causal or the result of confounding or reverse causation. In this study we applied Mendelian randomisation analysis using 17 genetic variants previously associated with eGFR to investigate the causal role of kidney function on CHD. We used 13,145 participants from the UCL-LSHTM-Edinburgh-Bristol (UCLEB) Consortium and 194,427 participants from the Coronary ARtery DIsease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease (CARDIoGRAMplusC4D) consortium. We observed significant association of an unweighted gene score with CHD risk (odds ratio = 0.983 per additional eGFR-increasing allele, 95% CI = 0.970-0.996, p = 0.008). However, using weights calculated from UCLEB, the gene score was not associated with disease risk (p = 0.11). These conflicting results could be explained by a single SNP, rs653178, which was not associated with eGFR in the UCLEB sample, but has known pleiotropic effects that prevent us from drawing a causal conclusion. The observational association between low eGFR and increased CHD risk was not explained by potential confounders, and there was no evidence of reverse causation, therefore leaving the remaining unexplained association as an open question.
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http://dx.doi.org/10.1038/srep28514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919785PMC
June 2016

Imputing Phenotypes for Genome-wide Association Studies.

Am J Hum Genet 2016 Jul 9;99(1):89-103. Epub 2016 Jun 9.

Department of Computer Science, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address:

Genome-wide association studies (GWASs) have been successful in detecting variants correlated with phenotypes of clinical interest. However, the power to detect these variants depends on the number of individuals whose phenotypes are collected, and for phenotypes that are difficult to collect, the sample size might be insufficient to achieve the desired statistical power. The phenotype of interest is often difficult to collect, whereas surrogate phenotypes or related phenotypes are easier to collect and have already been collected in very large samples. This paper demonstrates how we take advantage of these additional related phenotypes to impute the phenotype of interest or target phenotype and then perform association analysis. Our approach leverages the correlation structure between phenotypes to perform the imputation. The correlation structure can be estimated from a smaller complete dataset for which both the target and related phenotypes have been collected. Under some assumptions, the statistical power can be computed analytically given the correlation structure of the phenotypes used in imputation. In addition, our method can impute the summary statistic of the target phenotype as a weighted linear combination of the summary statistics of related phenotypes. Thus, our method is applicable to datasets for which we have access only to summary statistics and not to the raw genotypes. We illustrate our approach by analyzing associated loci to triglycerides (TGs), body mass index (BMI), and systolic blood pressure (SBP) in the Northern Finland Birth Cohort dataset.
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http://dx.doi.org/10.1016/j.ajhg.2016.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5005435PMC
July 2016

Replication and Characterization of Association between ABO SNPs and Red Blood Cell Traits by Meta-Analysis in Europeans.

PLoS One 2016 9;11(6):e0156914. Epub 2016 Jun 9.

Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, United Kingdom.

Red blood cell (RBC) traits are routinely measured in clinical practice as important markers of health. Deviations from the physiological ranges are usually a sign of disease, although variation between healthy individuals also occurs, at least partly due to genetic factors. Recent large scale genetic studies identified loci associated with one or more of these traits; further characterization of known loci and identification of new loci is necessary to better understand their role in health and disease and to identify potential molecular mechanisms. We performed meta-analysis of Metabochip association results for six RBC traits-hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV) and red blood cell count (RCC)-in 11 093 Europeans from seven studies of the UCL-LSHTM-Edinburgh-Bristol (UCLEB) Consortium. We identified 394 non-overlapping SNPs in five loci at genome-wide significance: 6p22.1-6p21.33 (with HFE among others), 6q23.2 (with HBS1L among others), 6q23.3 (contains no genes), 9q34.3 (only ABO gene) and 22q13.1 (with TMPRSS6 among others), replicating previous findings of association with RBC traits at these loci and extending them by imputation to 1000 Genomes. We further characterized associations between ABO SNPs and three traits: hemoglobin, hematocrit and red blood cell count, replicating them in an independent cohort. Conditional analyses indicated the independent association of each of these traits with ABO SNPs and a role for blood group O in mediating the association. The 15 most significant RBC-associated ABO SNPs were also associated with five cardiometabolic traits, with discordance in the direction of effect between groups of traits, suggesting that ABO may act through more than one mechanism to influence cardiometabolic risk.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0156914PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900668PMC
July 2017
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