Pharmacogenetics at scale in real-world bioresources: CYP2C19 and clopidogrel outcomes in UK Biobank.

OBJECTIVE: The impact of CYP2C19 genotype on clopidogrel outcomes is one of the most well established pharmacogenetic interactions, supported by robust evidence and recommended by the Food and Drug Administration and clinical pharmacogenetics implementation consortium. However, there is a scarcity of large-scale real-world data on the extent of this pharmacogenetic effect, and clinical testing for the CYP2C19 genotype remains infrequent. This study utilizes the UK Biobank dataset, including 10 365 patients treated with clopidogrel, to offer the largest observational analysis of these pharmacogenetic effects to date. METHODS: Incorporating time-varying drug exposure and repeated clinical outcome, we adopted semiparametric frailty models to detect and quantify exposure-based effects of CYP2C19 (*2,*17) variants and nongenetic factors on the incidence risks of composite outcomes of death or recurrent hospitalizations due to major adverse cardiovascular events (MACE) or hemorrhage in the entire cohort of clopidogrel-treated patients. RESULTS: Out of the 10 365 clopidogrel-treated patients, 40% (4115) experienced 10 625 MACE events during an average follow-up of 9.23 years. Individuals who received clopidogrel (coverage >25%) with a CYP2C19*2 loss-of-function allele had a 9.4% higher incidence of MACE [incidence rate ratios (IRR), 1.094; 1.044-1.146], but a 15% lower incidence of hemorrhage (IRR, 0.849; 0.712-0.996). These effects were stronger with high clopidogrel exposure. Conversely, the gain-of-function CYP2C19*17 variant was associated with a 5.3% lower incidence of MACE (IRR, 0.947; 0.903-0.983). Notably, there was no evidence of *2 or *17 effects when clopidogrel exposure was low, confirming the presence of a drug-gene interaction. CONCLUSION: The impact of CYP2C19 on clinical outcomes in clopidogrel-treated patients is substantial, highlighting the importance of incorporating genotype-based prescribing into clinical practice, regardless of the reason for clopidogrel use or the duration of treatment. Moreover, the methodology introduced in this study can be applied to further real-world investigations of known drug-gene and drug-drug interactions and the discovery of novel interactions.

The Relationship between AKI and CKD in Patients with Type 2 Diabetes: An Observational Cohort Study.

BACKGROUND: There are few observational studies evaluating the risk of AKI in people with type 2 diabetes, and even fewer simultaneously investigating AKI and CKD in this population. This limits understanding of the interplay between AKI and CKD in people with type 2 diabetes compared with the nondiabetic population. METHODS: In this retrospective, cohort study of participants with or without type 2 diabetes, we used electronic healthcare records to evaluate rates of AKI and various statistical methods to determine their relationship to CKD status and further renal function decline. RESULTS: We followed the cohort of 16,700 participants (9417 with type 2 diabetes and 7283 controls without diabetes) for a median of 8.2 years. Those with diabetes were more likely than controls to develop AKI (48.6% versus 17.2%, respectively) and have preexisting CKD or CKD that developed during follow-up (46.3% versus 17.2%, respectively). In the absence of CKD, the AKI rate among people with diabetes was nearly five times that of controls (121.5 versus 24.6 per 1000 person-years). Among participants with CKD, AKI rate in people with diabetes was more than twice that of controls (384.8 versus 180.0 per 1000 person-years after CKD diagnostic date, and 109.3 versus 47.4 per 1000 person-years before CKD onset in those developing CKD after recruitment). Decline in eGFR slope before AKI episodes was steeper in people with diabetes versus controls. After AKI episodes, decline in eGFR slope became steeper in people without diabetes, but not among those with diabetes and preexisting CKD. CONCLUSIONS: Patients with diabetes have significantly higher rates of AKI compared with patients without diabetes, and this remains true for individuals with preexisting CKD.

PheGWAS: a new dimension to visualize GWAS across multiple phenotypes.

MOTIVATION: PheGWAS was developed to enhance exploration of phenome-wide pleiotropy at the genome-wide level through the efficient generation of a dynamic visualization combining Manhattan plots from GWAS with PheWAS to create a 3D 'landscape'. Pleiotropy in sub-surface GWAS significance strata can be explored in a sectional view plotted within user defined levels. Further complexity reduction is achieved by confining to a single chromosomal section. Comprehensive genomic and phenomic coordinates can be displayed. RESULTS: PheGWAS is demonstrated using summary data from Global Lipids Genetics Consortium GWAS across multiple lipid traits. For single and multiple traits PheGWAS highlighted all 88 and 69 loci, respectively. Further, the genes and SNPs reported in Global Lipids Genetics Consortium were identified using additional functions implemented within PheGWAS. Not only is PheGWAS capable of identifying independent signals but also provides insights to local genetic correlation (verified using HESS) and in identifying the potential regions that share causal variants across phenotypes (verified using colocalization tests). AVAILABILITY AND IMPLEMENTATION: The PheGWAS software and code are freely available at (https://github.com/georgeg0/PheGWAS). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Discovery of novel heart rate-associated loci using the Exome Chip.

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

Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease.

BACKGROUND: The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. METHODS: Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes. RESULTS: We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P=4.2×10(-10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P=4.0×10(-8)), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P=0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P=0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P=2.0×10(-4)) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P=2.5×10(-7)). CONCLUSIONS: We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease. (Funded by the National Institutes of Health and others.).

Rates of glycaemic deterioration in a real-world population with type 2 diabetes.

AIMS/HYPOTHESIS: There is considerable variability in how diabetes progresses after diagnosis. Progression modelling has largely focused on 'time to failure' methods, yet determining a 'coefficient of failure' has many advantages. We derived a rate of glycaemic deterioration in type 2 diabetes, using a large real-world cohort, and aimed to investigate the clinical, biochemical, pharmacological and immunological variables associated with fast and slow rates of glycaemic deterioration. METHODS: An observational cohort study was performed using the electronic medical records from participants in the Genetics of Diabetes Audit and Research in Tayside Study (GoDARTS). A model was derived based on an individual's observed HbA1c measures from the first eligible HbA1c after the diagnosis of diabetes through to the study end (defined as insulin initiation, death, leaving the area or end of follow-up). Each HbA1c measure was time-dependently adjusted for the effects of non-insulin glucose-lowering drugs, changes in BMI and corticosteroid use. GAD antibody (GADA) positivity was defined as GAD titres above the 97.5th centile of the population distribution. RESULTS: The mean (95% CI) glycaemic deterioration for type 2 diabetes and GADA-positive individuals was 1.4 (1.3, 1.4) and 2.8 (2.4, 3.3) mmol/mol HbA1c per year, respectively. A younger age of diagnosis, lower HDL-cholesterol concentration, higher BMI and earlier calendar year of diabetes diagnosis were independently associated with higher rates of glycaemic deterioration in individuals with type 2 diabetes. The rate of deterioration in those diagnosed at over 70 years of age was very low, with 66% having a rate of deterioration of less than 1.1 mmol/mol HbA1c per year, and only 1.5% progressing more rapidly than 4.4 mmol/mol HbA1c per year. CONCLUSIONS/INTERPRETATION: We have developed a novel approach for modelling the progression of diabetes in observational data across multiple drug combinations. This approach highlights how glycaemic deterioration in those diagnosed at over 70 years of age is minimal, supporting a stratified approach to diabetes management.

A common missense variant of LILRB5 is associated with statin intolerance and myalgia.

Aims: A genetic variant in LILRB5 (leukocyte immunoglobulin-like receptor subfamily-B) (rs12975366: T > C: Asp247Gly) has been reported to be associated with lower creatine phosphokinase (CK) and lactate dehydrogenase (LDH) levels. Both biomarkers are released from injured muscle tissue, making this variant a potential candidate for susceptibility to muscle-related symptoms. We examined the association of this variant with statin intolerance ascertained from electronic medical records in the GoDARTS study. Methods and results: In the GoDARTS cohort, the LILRB5 Asp247 variant was associated with statin intolerance (SI) phenotypes; one defined as having raised CK and being non-adherent to therapy [odds ratio (OR) 1.81; 95% confidence interval (CI): 1.34-2.45] and the other as being intolerant to the lowest approved dose of a statin before being switched to two or more other statins (OR 1.36; 95% CI: 1.07-1.73). Those homozygous for Asp247 had increased odds of developing both definitions of intolerance. Importantly the second definition did not rely on CK elevations. These results were replicated in adjudicated cases of statin-induced myopathy in the PREDICTION-ADR consortium (OR1.48; 95% CI: 1.05-2.10) and for the development of myalgia in the JUPITER randomized clinical trial of rosuvastatin (OR1.35, 95% CI: 1.10-1.68). A meta-analysis across the studies showed a consistent association between Asp247Gly and outcomes associated with SI (OR1.34; 95% CI: 1.16-1.54). Conclusion: This study presents a novel immunogenetic factor associated with statin intolerance, an important risk factor for cardiovascular outcomes. The results suggest that true statin-induced myalgia and non-specific myalgia are distinct, with a potential role for the immune system in their development. We identify a genetic group that is more likely to be intolerant to their statins.

Replication confirms the association of loci in FOXE1, PDE8B, CAPZB and PDE10A with thyroid traits: a Genetics of Diabetes Audit and Research Tayside study (GoDARTS).

OBJECTIVE: Replication of associations in genome-wide association studies is desirable to ensure that such signals are potentially clinically meaningful. This study aimed to replicate associations of selected single-nucleotide polymorphisms (SNPs) with hypothyroidism and serum thyroid-stimulating hormone (TSH) using electronic medical records (EMRs). PATIENTS AND METHODS: A cross-sectional study was carried out among patients of European Caucasian ethnicity from the Genetics of Diabetes Audit and Research Tayside recruited in Tayside (Scotland, UK). EMRs (biochemistry, prescribing, hospital admissions and demographics) were used to ascertain patients with hypothyroidism and their controls as well as average serum TSH concentration, and linked to genetic biobank data. Genetic tests of association were performed using logistic and linear regression models. RESULTS: We analysed 1703 cases of hypothyroidism and 9457 controls. All four SNPs located on chromosome 9 at FOXE1 were associated with hypothyroidism with similar effect estimates (odds ratio=0.75-0.76, P<5e-08). Also, loci on chromosomes 1 (PTPN22), six (HLA-E/HLA-C) and 12 (SH2B3) were replicated. For serum TSH, we confirmed 12 SNPs previously reported at PDE8B, CAPZB, PDE10A, LOC105371356, NR3C2, VEGFA, IGFBP5, INSR, PRDM11, NFIA, ITPK1 and ABO. Overall, these SNPs accounted for 6.8% of the serum TSH variation (P<1e-04). CONCLUSION: EMRs linked to genomic data in large populations enable validation of genome-wide association studies discoveries without additional genotyping costs. Our replication confirmed at genome-wide significance the association of loci at FOXE1 with hypothyroidism, and PDE8B, CAPZB and PDE10A with serum TSH. A total of 12 SNPs seemed to explain nearly 7% of the serum TSH variation.

Incremental Prognostic Value of a Coronary Heart Disease Polygenic Risk Score in Type 2 Diabetes.

OBJECTIVE: The recent availability of cardiovascular risk-reducing type 2 diabetes (T2D) therapies makes it imperative to optimally identify individuals who could derive benefit. Current clinical risk prediction may misclassify individuals as low risk and could be improved. Our aim was to determine the incremental prognostic value of a coronary heart disease (CHD) genome-wide polygenic risk score (PRS) to a clinical risk score in prediction of major adverse cardiovascular events (MACE) in patients with T2D. RESEARCH DESIGN AND METHODS: We evaluated 10,556 individuals with T2D aged 40-79 without a prior cardiovascular hospitalization. We calculated 10-year clinical cardiovascular risk at the date of recruitment using the Pooled Cohort Equation (PCE Risk) and constructed a CHD PRS. The primary outcome was time to first MACE incidence, and we assessed the additional incremental predictive value of the CHD PRS to the PCE risk. RESULTS: At 10 years, there were 1,477 MACE. After adjustment for clinical risk, the CHD PRS was significantly associated with MACE (hazard ratio [HR] 1.69 per SD increase, 95% CI 1.60-1.79). Individuals with PCE Risk <7.5% but in the top quintile of CHD PRS had a significantly increased likelihood of MACE (HR 10.69, 95% CI 5.07-22.55) compared with those in the lowest. The addition of the PRS to the clinical risk score led to significant improvements in risk prediction, particularly in those at low clinical risk. CONCLUSIONS: The addition of a CHD PRS to clinical assessment improved MACE prediction in T2D individuals without prior cardiovascular disease, particularly in those at low clinical risk.

Allopurinol and blood pressure variability following ischemic stroke and transient ischemic attack: a secondary analysis of XILO-FIST.

Blood Pressure Variability (BPV) is associated with cardiovascular risk and serum uric acid level. We investigated whether BPV was lowered by allopurinol and whether it was related to neuroimaging markers of cerebral small vessel disease (CSVD) and cognition. We used data from a randomised, double-blind, placebo-controlled trial of two years allopurinol treatment after recent ischemic stroke or transient ischemic attack. Visit-to-visit BPV was assessed using brachial blood pressure (BP) recordings. Short-term BPV was assessed using ambulatory BP monitoring (ABPM) performed at 4 weeks and 2 years. Brain MRI was performed at baseline and 2 years. BPV measures were compared between the allopurinol and placebo groups, and with CSVD and cognition. 409 participants (205 allopurinol; 204 placebo) were included in the visit-to-visit BPV analyses. There were no significant differences found between placebo and allopurinol groups for any measure of visit-to-visit BPV. 196 participants were included in analyses of short-term BPV at week 4. Two measures were reduced by allopurinol: the standard deviation (SD) of systolic BP (by 1.30 mmHg (95% confidence interval (CI) 0.18-2.42, p = 0.023)); and the average real variability (ARV) of systolic BP (by 1.31 mmHg (95% CI 0.31-2.32, p = 0.011)). There were no differences in other measures at week 4 or in any measure at 2 years, and BPV was not associated with CSVD or cognition. Allopurinol treatment did not affect visit-to-visit BPV in people with recent ischemic stroke or TIA. Two BPV measures were reduced at week 4 by allopurinol but not at 2 years.

The Scottish Medical Imaging Archive: 57.3 Million Radiology Studies Linked to Their Medical Records.

Keywords: MRI, Imaging Sequences, Ultrasound, Mammography, CT, Angiography, Conventional Radiography Published under a CC BY 4.0 license. See also the commentary by Whitman and Vining in this issue.

Robust association of the LPA locus with low-density lipoprotein cholesterol lowering response to statin treatment in a meta-analysis of 30 467 individuals from both randomized control trials and observational studies and association with coronary artery disease outcome during statin treatment.

OBJECTIVES: The LPA single-nucleotide polymorphism rs10455872 has been associated with low-density lipoprotein cholesterol (LDLc) lowering response to statins in several randomized control trials (RCTs) and is a known coronary artery disease (CAD) marker. However, it is unclear what residual risk of CAD this marker may have during statin treatment. METHODS: Using electronic medical records linked to the GoDARTS genotyped population, we identified over 8000 patients on statins in Tayside, Scotland. RESULTS: We replicated the findings of the RCTs, with the G allele of rs10455872 being associated with a 0.10 mmol/l per allele poorer reduction in LDLc in response to statin treatment, and conducted a meta-analysis with previously published RCTs (P = 1.46 × 10, n = 30 467). We showed an association between rs10455872 and CAD in statin-treated individuals and have replicated this finding in the Utrecht Cardiovascular Pharmacogenetics study (combined odds ratio 1.41, 95% confidence interval 1.17-1.68, P = 4.5 × 10, n = 8822) suggesting that statin treatment does not abrogate this well-established genetic risk for CAD. Furthermore, in a Cox proportional hazards model with LDLc measured time dependently, we demonstrated that the relationship between CAD and rs10455872 was independent of LDLc during statin treatment. CONCLUSION: Individuals with the G allele of rs10455872, which represents approximately one in seven patients, have a higher risk of CAD than the majority of the population even after treatment with statins; and therefore represent a vulnerable group requiring an alternative medication in addition to statin treatment.

Integrating oculomics with genomics reveals imaging biomarkers for preventive and personalized prediction of arterial aneurysms.

Objective: Arterial aneurysms are life-threatening but usually asymptomatic before requiring hospitalization. Oculomics of retinal vascular features (RVFs) extracted from retinal fundus images can reflect systemic vascular properties and therefore were hypothesized to provide valuable information on detecting the risk of aneurysms. By integrating oculomics with genomics, this study aimed to (i) identify predictive RVFs as imaging biomarkers for aneurysms and (ii) evaluate the value of these RVFs in supporting early detection of aneurysms in the context of predictive, preventive and personalized medicine (PPPM). Methods: This study involved 51,597 UK Biobank participants who had retinal images available to extract oculomics of RVFs. Phenome-wide association analyses (PheWASs) were conducted to identify RVFs associated with the genetic risks of the main types of aneurysms, including abdominal aortic aneurysm (AAA), thoracic aneurysm (TAA), intracranial aneurysm (ICA) and Marfan syndrome (MFS). An aneurysm-RVF model was then developed to predict future aneurysms. The performance of the model was assessed in both derivation and validation cohorts and was compared with other models employing clinical risk factors. An RVF risk score was derived from our aneurysm-RVF model to identify patients with an increased risk of aneurysms. Results: PheWAS identified a total of 32 RVFs that were significantly associated with the genetic risks of aneurysms. Of these, the number of vessels in the optic disc ('ntreeA') was associated with both AAA (ß = -0.36, P = 6.75e-10) and ICA (ß = -0.11, P = 5.51e-06). In addition, the mean angles between each artery branch ('curveangle_mean_a') were commonly associated with 4 MFS genes (FBN1: ß = -0.10, P = 1.63e-12; COL16A1: ß = -0.07, P = 3.14e-09; LOC105373592: ß = -0.06, P = 1.89e-05; C8orf81/LOC441376: ß = 0.07, P = 1.02e-05). The developed aneurysm-RVF model showed good discrimination ability in predicting the risks of aneurysms. In the derivation cohort, the C-index of the aneurysm-RVF model was 0.809 [95% CI: 0.780-0.838], which was similar to the clinical risk model (0.806 [0.778-0.834]) but higher than the baseline model (0.739 [0.733-0.746]). Similar performance was observed in the validation cohort, with a C-index of 0.798 (0.727-0.869) for the aneurysm-RVF model, 0.795 (0.718-0.871) for the clinical risk model and 0.719 (0.620-0.816) for the baseline model. An aneurysm risk score was derived from the aneurysm-RVF model for each study participant. The individuals in the upper tertile of the aneurysm risk score had a significantly higher risk of aneurysm compared to those in the lower tertile (hazard ratio = 17.8 [6.5-48.8], P = 1.02e-05). Conclusion: We identified a significant association between certain RVFs and the risk of aneurysms and revealed the impressive capability of using RVFs to predict the future risk of aneurysms by a PPPM approach. Our finds have great potential to support not only the predictive diagnosis of aneurysms but also a preventive and more personalized screening plan which may benefit both patients and the healthcare system. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-023-00315-7.

Fine-mapping of retinal vascular complexity loci identifies Notch regulation as a shared mechanism with myocardial infarction outcomes.

There is increasing evidence that the complexity of the retinal vasculature measured as fractal dimension, Df, might offer earlier insights into the progression of coronary artery disease (CAD) before traditional biomarkers can be detected. This association could be partly explained by a common genetic basis; however, the genetic component of Df is poorly understood. We present a genome-wide association study (GWAS) of 38,000 individuals with white British ancestry from the UK Biobank aimed to comprehensively study the genetic component of Df and analyse its relationship with CAD. We replicated 5 Df loci and found 4 additional loci with suggestive significance (P < 1e-05) to contribute to Df variation, which previously were reported in retinal tortuosity and complexity, hypertension, and CAD studies. Significant negative genetic correlation estimates support the inverse relationship between Df and CAD, and between Df and myocardial infarction (MI), one of CAD's fatal outcomes. Fine-mapping of Df loci revealed Notch signalling regulatory variants supporting a shared mechanism with MI outcomes. We developed a predictive model for MI incident cases, recorded over a 10-year period following clinical and ophthalmic evaluation, combining clinical information, Df, and a CAD polygenic risk score. Internal cross-validation demonstrated a considerable improvement in the area under the curve (AUC) of our predictive model (AUC = 0.770 ± 0.001) when comparing with an established risk model, SCORE, (AUC = 0.741 ± 0.002) and extensions thereof leveraging the PRS (AUC = 0.728 ± 0.001). This evidences that Df provides risk information beyond demographic, lifestyle, and genetic risk factors. Our findings shed new light on the genetic basis of Df, unveiling a common control with MI, and highlighting the benefits of its application in individualised MI risk prediction.

Xanthine oxidase inhibition and white matter hyperintensity progression following ischaemic stroke and transient ischaemic attack (XILO-FIST): a multicentre, double-blinded, randomised, placebo-controlled trial.

Background: People who experience an ischaemic stroke are at risk of recurrent vascular events, progression of cerebrovascular disease, and cognitive decline. We assessed whether allopurinol, a xanthine oxidase inhibitor, reduced white matter hyperintensity (WMH) progression and blood pressure (BP) following ischaemic stroke or transient ischaemic attack (TIA). Methods: In this multicentre, prospective, randomised, double-blinded, placebo-controlled trial conducted in 22 stroke units in the United Kingdom, we randomly assigned participants within 30-days of ischaemic stroke or TIA to receive oral allopurinol 300 mg twice daily or placebo for 104 weeks. All participants had brain MRI performed at baseline and week 104 and ambulatory blood pressure monitoring at baseline, week 4 and week 104. The primary outcome was the WMH Rotterdam Progression Score (RPS) at week 104. Analyses were by intention to treat. Participants who received at least one dose of allopurinol or placebo were included in the safety analysis. This trial is registered with ClinicalTrials.gov, NCT02122718. Findings: Between 25th May 2015 and the 29th November 2018, 464 participants were enrolled (232 per group). A total of 372 (189 with placebo and 183 with allopurinol) attended for week 104 MRI and were included in analysis of the primary outcome. The RPS at week 104 was 1.3 (SD 1.8) with allopurinol and 1.5 (SD 1.9) with placebo (between group difference -0.17, 95% CI -0.52 to 0.17, p = 0.33). Serious adverse events were reported in 73 (32%) participants with allopurinol and in 64 (28%) with placebo. There was one potentially treatment related death in the allopurinol group. Interpretation: Allopurinol use did not reduce WMH progression in people with recent ischaemic stroke or TIA and is unlikely to reduce the risk of stroke in unselected people. Funding: The British Heart Foundation and the UK Stroke Association.

Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution.

To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9x10(-11)) and MSRA (WC, P = 8.9x10(-9)). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6x10(-8)). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.

Adverse events and overall health and well-being after COVID-19 vaccination: interim results from the VAC4COVID cohort safety study.

OBJECTIVES: To describe the incidence of adverse events (AEs), reactogenicity symptoms, menstrual changes and overall self-rated improvement in health and well-being after COVID-19 vaccination. DESIGN: VAC4COVID is an ongoing prospective, active observational, post-authorisation cohort safety study (PASS) of UK-approved vaccines for COVID-19 disease. SETTING: The study is conducted through a secure website (www.vac4covid.com) by MEMO Research, University of Dundee, UK. PARTICIPANTS: 16 265 adult (18 years or older) UK residents with a valid email address and internet access. INTERVENTIONS: Any UK-authorised COVID-19 vaccination. MAIN OUTCOME MEASURES: The outcomes reported in this interim analysis include AEs, reactogenicity-type AEs (headache, fatigue, muscle or joint pain, fever, nausea, dizziness or local vaccine reaction), menstrual changes and reported improvement in overall health and well-being. RESULTS: 11 475 consented participants (mean age 54.8 years) provided follow-up data between 2 February and 5 October 2021 (mean follow-up duration 184 days), by which date 89.2% of participants had received two vaccine doses. 89.8% of 5222 participants who completed a follow-up questionnaire in the 7 days after any COVID-19 vaccination reported no AEs. The risk of experiencing any event (not necessarily vaccine-related) requiring hospitalisation was less than 0.2%. 43.7% of post-vaccination follow-up records reported improvement in health and well-being. Reactogenicity-type reactions were more common in the week after the first dose of ChAdOx1 than BNT162b2 (7.8% vs 1.6%), but this relationship was reversed after the second dose (1.3% vs 3.1%). 0.3% of women reported menstrual symptoms after vaccination; no differences between vaccine type or dose order were detected. CONCLUSIONS: The study provides reassuring data on low rates of AEs after COVID-19 vaccination. Differences in reactogenicity-type AE profiles between ChAdOx1 and BNT162b2 and between first and second doses of these vaccines were observed. TRIAL REGISTRATION NUMBER: ISRCTN95881792; Pre-results.

Metabolic dysfunction-related liver disease as a risk factor for cancer.

OBJECTIVE: The aim of this study was to investigate the association between obesity, diabetes and metabolic related liver dysfunction and the incidence of cancer. DESIGN: This study was conducted with health record data available from the National Health Service in Tayside and Fife. Genetics of Diabetes Audit and Research Tayside, Scotland (GoDARTS), Scottish Health Research Register (SHARE) and Tayside and Fife diabetics, three Scottish cohorts of 13 695, 62 438 and 16 312 patients, respectively, were analysed in this study. Participants in GoDARTS were a volunteer sample, with half having type 2 diabetes mellitus(T2DM). SHARE was a volunteer sample. Tayside and Fife diabetics was a population-level cohort. Metabolic dysfunction-related liver disease (MDLD) was defined using alanine transaminase measurements, and individuals with alternative causes of liver disease (alcohol abuse, viruses, etc) were excluded from the analysis. RESULTS: MDLD associated with increased cancer incidence with a HR of 1.31 in a Cox proportional hazards model adjusted for sex, type 2 diabetes, body mass index(BMI), and smoking status (95% CI 1.27 to 1.35, p<0.0001). This was replicated in two further cohorts, and similar associations with cancer incidence were found for Fatty Liver Index (FLI), Fibrosis-4 Index (FIB-4) and non-alcoholic steatohepatitis (NASH). Homozygous carriers of the common non-alcoholic fatty liver disease (NAFLD) risk-variant PNPLA3 rs738409 had increased risk of cancer. (HR=1.27 (1.02 to 1.58), p=3.1×10 -2). BMI was not independently associated with cancer incidence when MDLD was included as a covariate. CONCLUSION: MDLD, FLI, FIB-4 and NASH associated with increased risk of cancer incidence and death. NAFLD may be a major component of the relationship between obesity and cancer incidence.

Prediction of Major Adverse Cardiovascular Events From Retinal, Clinical, and Genomic Data in Individuals With Type 2 Diabetes: A Population Cohort Study.

OBJECTIVE: Improved identification of individuals with type 2 diabetes at high cardiovascular (CV) risk could help in selection of newer CV risk-reducing therapies. The aim of this study was to determine whether retinal vascular parameters, derived from retinal screening photographs, alone and in combination with a genome-wide polygenic risk score for coronary heart disease (CHD PRS) would have independent prognostic value over traditional CV risk assessment in patients without prior CV disease. RESEARCH DESIGN AND METHODS: Patients in the Genetics of Diabetes Audit and Research Tayside Scotland (GoDARTS) study were linked to retinal photographs, prescriptions, and outcomes. Retinal photographs were analyzed using VAMPIRE (Vascular Assessment and Measurement Platform for Images of the Retina) software, a semiautomated artificial intelligence platform, to compute arterial and venous fractal dimension, tortuosity, and diameter. CHD PRS was derived from previously published data. Multivariable Cox regression was used to evaluate the association between retinal vascular parameters and major adverse CV events (MACE) at 10 years compared with the pooled cohort equations (PCE) risk score. RESULTS: Among 5,152 individuals included in the study, a MACE occurred in 1,017 individuals. Reduced arterial fractal dimension and diameter and increased venous tortuosity each independently predicted MACE. A risk score combining these parameters significantly predicted MACE after adjustment for age, sex, PCE, and the CHD PRS (hazard ratio 1.11 per SD increase, 95% CI 1.04-1.18, P = 0.002) with similar accuracy to PCE (area under the curve [AUC] 0.663 vs. 0.658, P = 0.33). A model incorporating retinal parameters and PRS improved MACE prediction compared with PCE (AUC 0.686 vs. 0.658, P < 0.001). CONCLUSIONS: Retinal parameters alone and in combination with genome-wide CHD PRS have independent and incremental prognostic value compared with traditional CV risk assessment in type 2 diabetes.

Heterogeneity in phenotype, disease progression and drug response in type 2 diabetes.

Type 2 diabetes (T2D) is a complex chronic disease characterized by considerable phenotypic heterogeneity. In this study, we applied a reverse graph embedding method to routinely collected data from 23,137 Scottish patients with newly diagnosed diabetes to visualize this heterogeneity and used partitioned diabetes polygenic risk scores to gain insight into the underlying biological processes. Overlaying risk of progression to outcomes of insulin requirement, chronic kidney disease, referable diabetic retinopathy and major adverse cardiovascular events, we show how these risks differ by patient phenotype. For example, patients at risk of retinopathy are phenotypically different from those at risk of cardiovascular events. We replicated our findings in the UK Biobank and the ADOPT clinical trial, also showing that the pattern of diabetes drug monotherapy response differs for different drugs. Overall, our analysis highlights how, in a European population, underlying phenotypic variation drives T2D onset and affects subsequent diabetes outcomes and drug response, demonstrating the need to incorporate these factors into personalized treatment approaches for the management of T2D.