Polygenic scores for cardiovascular risk factors improve estimation of clinical outcomes in CCB treatment compared to pharmacogenetic variants alone.

Pharmacogenetic variants are associated with clinical outcomes during Calcium Channel Blocker (CCB) treatment, yet whether the effects are modified by genetically predicted clinical risk factors is unknown. We analyzed 32,000 UK Biobank participants treated with dihydropiridine CCBs (mean 5.9 years), including 23 pharmacogenetic variants, and calculated polygenic scores for systolic and diastolic blood pressures, body fat mass, and other patient characteristics. Outcomes included treatment discontinuation and heart failure. Pharmacogenetic variant rs10898815-A (NUMA1) increased discontinuation rates, highest in those with high polygenic scores for fat mass. The RYR3 variant rs877087 T-allele alone modestly increased heart failure risks versus non-carriers (HR:1.13, p = 0.02); in patients with high polygenic scores for fat mass, lean mass, and lipoprotein A, risks were substantially elevated (HR:1.55, p = 4 × 10-5). Incorporating polygenic scores for adiposity and lipoprotein A may improve risk estimates of key clinical outcomes in CCB treatment such as treatment discontinuation and heart failure, compared to pharmacogenetic variants alone.

SLCO1B1 Exome Sequencing and Statin Treatment Response in 64,000 UK Biobank Patients.

The solute carrier organic anion transporter family member 1B1 (SLCO1B1) encodes the organic anion-transporting polypeptide 1B1 (OATP1B1 protein) that transports statins to liver cells. Common genetic variants in SLCO1B1, such as *5, cause altered systemic exposure to statins and therefore affect statin outcomes, with potential pharmacogenetic applications; yet, evidence is inconclusive. We studied common and rare SLCO1B1 variants in up to 64,000 patients from UK Biobank prescribed simvastatin or atorvastatin, combining whole-exome sequencing data with up to 25-year routine clinical records. We studied 51 predicted gain/loss-of-function variants affecting OATP1B1. Both SLCO1B1*5 alone and the SLCO1B1*15 haplotype increased LDL during treatment (beta*5 = 0.08 mmol/L, p = 6 × 10-8; beta*15 = 0.03 mmol/L, p = 3 × 10-4), as did the likelihood of discontinuing statin prescriptions (hazard ratio*5 = 1.12, p = 0.04; HR*15 = 1.05, p = 0.04). SLCO1B1*15 and SLCO1B1*20 increased the risk of General Practice (GP)-diagnosed muscle symptoms (HR*15 = 1.22, p = 0.003; HR*20 = 1.25, p = 0.01). We estimated that genotype-guided prescribing could potentially prevent 18% and 10% of GP-diagnosed muscle symptoms experienced by statin patients, with *15 and *20, respectively. The remaining common variants were not individually significant. Rare variants in SLCO1B1 increased LDL in statin users by up to 1.05 mmol/L, but replication is needed. We conclude that genotype-guided treatment could reduce GP-diagnosed muscle symptoms in statin patients; incorporating further SLCO1B1 variants into clinical prediction scores could improve LDL control and decrease adverse events, including discontinuation.

Calcium-channel blockers: Clinical outcome associations with reported pharmacogenetics variants in 32 000 patients.

AIMS: Pharmacogenetic variants impact dihydropyridine calcium-channel blockers (dCCBs; e.g., amlodipine) treatment efficacy, yet evidence on clinical outcomes in routine primary care is limited. Reported associations in pharmacogenomics knowledge base PharmGKB have weak supporting evidence. We aimed to estimate associations between reported pharmacogenetic variants and incident adverse events in a community-based cohort prescribed dCCB. METHODS: We analysed up to 32 360 UK Biobank participants prescribed dCCB in primary care (from UK general practices, 1990-2017). We investigated 23 genetic variants. Outcomes were incident diagnosis of coronary heart disease, heart failure (HF), chronic kidney disease, oedema and switching antihypertensive medication. RESULTS: Participants were aged 40-79 years at first dCCB prescription. Carriers of rs877087 T allele in RYR3 had increased risk of hazard ratio (HF 1.13: 95% confidence interval 1.02 to 1.25, P = .02). Although nonsignificant after multiple testing correction, the association is consistent with prior evidence. We estimated that if rs877087 T allele could experience the same treatment effect as noncarriers, the incidence of HF in patients prescribed dCCB would reduce by 9.2% (95% confidence interval 3.1 to 15.4). In patients with a history of heart disease prior to dCCB (n = 2296), rs877087 homozygotes had increased risk of new coronary heart disease or HF compared to CC variant. rs10898815 in NUMA1 and rs776746 in CYP3A5 increased likelihood of switching to an alternative antihypertensive. The remaining variants were not strongly or consistently associated with studied outcomes. CONCLUSION: Patients with common genetic variants in NUMA1, CYP3A5 and RYR3 had increased adverse clinical outcomes. Work is needed to establish whether outcomes of dCCB prescribing could be improved by prior knowledge of pharmacogenetics variants supported by clinical evidence of association with adverse events.

Atrial fibrillation, transient ischaemic attack and stroke in older people. A themed collection in age and ageing journal.

With an increase in the ageing population, there is a rise in the burden of cardiovascular disease. Age and Ageing have compiled collections of their key cardiovascular themed papers. The first Age and Ageing Cardiovascular Collection focussed on blood pressure, coronary heart disease and heart failure. In this second collection, publications since 2011 were selected with emphasis on atrial fibrillation, transient ischaemic attack (TIA) and stroke. The prevalence of TIA and stroke increases as people get older. In this commentary we summarise studies published in Age and Ageing that bring to the fore the need for a multidisciplinary, person-centred approach to care, conscientious identification of risk factors and their management and prevention strategies, which will inform policy ultimately reducing the burden of cost placed by stroke care on healthcare financing. Read the latest Cardiovascular Collection here.

New horizons in the role of digital data in the healthcare of older people.

There are national and global moves to improve effective digital data design and application in healthcare. This New Horizons commentary describes the role of digital data in healthcare of the ageing population. We outline how health and social care professionals can engage in the proactive design of digital systems that appropriately serve people as they age, carers and the workforce that supports them. KEY POINTS: Healthcare improvements have resulted in increased population longevity and hence multimorbidity. Shared care records to improve communication and information continuity across care settings hold potential for older people. Data structure and coding are key considerations. A workforce with expertise in caring for older people with relevant knowledge and skills in digital healthcare is important.

Statin treatment effectiveness and the SLCO1B1*5 reduced function genotype: Long-term outcomes in women and men.

OBJECTIVE: To estimate the effect of rs4149056 (SLCO1B1*5) genotype (decreases statin transport) on cholesterol control and treatment duration in male and female primary care patients prescribed common statin medications. METHODS AND ANALYSIS: This study comprised 69 185 European-ancestry UK Biobank cohort participants prescribed simvastatin or atorvastatin (aged 40-79 years at first prescription, treatment duration 1 month to 29 years, mean 5.7 years). Principal outcomes were clinically high total cholesterol (>5 mmol/L) at baseline, plus treatment discontinuation. RESULTS: A total of 48.4% of 591 females homozygous for SLCO1B1*5 decreased function genotype had raised cholesterol vs 41.7% of those with functioning SLCO1B1 (odds ratio 1.31, 95% confidence interval [CI] 1.1-1.55, P = .001). Fewer males had high cholesterol and the genotype effect was attenuated. In primary care prescribing, females homozygous for SLCO1B1*5 were more likely to stop receiving these statins (29.5%) than women with normal SLCO1B1 (25.7%) (hazard ratio [HR] 1.19, 95% CI 1.03-1.37, P = .01), amounting to five discontinuations per 100 statin-years in the SLCO1B1*5 group vs four in the normal SLCO1B1 function group. This remained significant after the first year of treatment (HR for discontinuing >1 year after first prescription 1.3, 95% CI 1.08-1.56, P = .006). In men SLCO1B1*5 was only associated with treatment discontinuation in the first year. CONCLUSIONS: In this large community sample of patients on commonly prescribed statins, the SLCO1B1*5 decreased function variant had much larger effects on cholesterol control and treatment duration in women than in men. Efforts to improve the effectiveness of statin therapy in women may need to include SLCO1B1*5 genotype-guided statin selection.

Age and ageing cardiovascular collection: blood pressure, coronary heart disease and heart failure.

As people age they are at increased risk of cardiovascular disease, the leading cause of mortality and morbidity worldwide. Understanding cardiovascular ageing is essential to preserving healthy ageing and preventing serious health outcomes. This collection of papers published in Age and Ageing since 2011 cover key themes in cardiovascular ageing, with a separate collection on stroke and atrial fibrillation planned. Treating high blood pressure remains important as people age and reduces strokes and heart attacks. That said, a more personalised approach to blood pressure may be even more important as people age to lower blood pressure to tight targets where appropriate but avoid overtreatment in vulnerable groups. As people age, more people experience blood pressure drops on standing (orthostatic hypotension), particularly as they become frail. This can predispose them to falls. The papers in this collection provide an insight into blood pressure and orthostatic hypotension. They highlight areas for further research to understand blood pressure changes and management in the ageing population. Inpatient clinical care of older people with heart attacks differs from younger people in UK national audit data. People aged over 80 had improved outcomes in survival after heart attack over time, but had lower rates of specialist input from cardiology compared with younger people. This may partly reflect different clinical presentations, with heart attacks occurring in the context of other health conditions, frailty and multimorbidity. The care and outcomes of acute and chronic cardiovascular disease are impacted by the frailty and health status of an individual at baseline. The research included in this collection reinforces the wide variations in the ageing population and the necessity to focus on the individual needs and priorities, and provide a person-centred multidisciplinary approach to care.

Genomics and multimorbidity.

Multimorbidity has increased in prevalence world-wide. It is anticipated to affect over 1 in 6 of the UK population by 2035 and is now recognised as a global priority for health research. Genomic medicine has rapidly advanced over the last 20 years from the first sequencing of the human genome to integration into clinical care for rarer conditions. Genetic studies help identify new disease mechanisms as they are less susceptible to the bias and confounding that affects epidemiological studies, as genetics are assigned from conception. There is also genetic variation in the efficacy of medications and the risk of side effects, pharmacogenetics. Genomic approaches offer the potential to improve our understanding of mechanisms underpinning multiple long-term conditions/multimorbidity and guide precision approaches to risk, diagnosis and optimisation of management. In this commentary as part of the Age and Ageing 50th anniversary commentary series, we summarise genomics and the potential utility of genomics in multimorbidity.

Blood pressure in frail older adults: associations with cardiovascular outcomes and all-cause mortality.

BACKGROUND: Blood pressure (BP) management in frail older people is challenging. An randomised controlled trial of largely non-frail older people found cardiovascular and mortality benefit with systolic (S) BP target <120 mmHg. However, all-cause mortality by attained BP in routine care in frail adults aged above 75 is unclear. OBJECTIVES: To estimate observational associations between baseline BP and mortality/cardiovascular outcomes in a primary-care population aged above 75, stratified by frailty. METHODS: Prospective observational analysis using electronic health records (clinical practice research datalink, n = 415,980). We tested BP associations with cardiovascular events and mortality using competing and Cox proportional-hazards models respectively (follow-up ≤10 years), stratified by baseline electronic frailty index (eFI: fit (non-frail), mild, moderate, severe frailty), with sensitivity analyses on co-morbidity, cardiovascular risk and BP trajectory. RESULTS: Risks of cardiovascular outcomes increased with SBPs >150 mmHg. Associations with mortality varied between non-frail <85 and frail 75-84-year-olds and all above 85 years. SBPs above the 130-139-mmHg reference were associated with lower mortality risk, particularly in moderate to severe frailty or above 85 years (e.g. 75-84 years: 150-159 mmHg Hazard Ratio (HR) mortality compared to 130-139: non-frail HR = 0.94, 0.92-0.97; moderate/severe frailty HR = 0.84, 0.77-0.92). SBP <130 mmHg and Diastolic(D)BP <80 mmHg were consistently associated with excess mortality, independent of BP trajectory toward the end of life. CONCLUSIONS: In representative primary-care patients aged ≥75, BP <130/80 was associated with excess mortality. Hypertension was not associated with increased mortality at ages above 85 or at ages 75-84 with moderate/severe frailty, perhaps due to complexities of co-existing morbidities. The priority given to aggressive BP reduction in frail older people requires further evaluation.

Association of Hemochromatosis HFE p.C282Y Homozygosity With Hepatic Malignancy.

Importance: Hereditary hemochromatosis is predominantly caused by the HFE p.C282Y homozygous pathogenic variant. Liver carcinoma and mortality risks are increased in individuals with clinically diagnosed hereditary hemochromatosis, but risks are unclear in mostly undiagnosed p.C282Y homozygotes identified in community genotyping. Objective: To estimate the incidence of primary hepatic carcinoma and death by HFE variant status. Design, Setting, and Participants: Cohort study of 451 186 UK Biobank participants of European ancestry (aged 40-70 years), followed up from baseline assessment (2006-2010) until January 2018. Exposures: Men and women with HFE p.C282Y and p.H63D genotypes compared with those with neither HFE variants. Main Outcomes and Measures: Two linked co-primary outcomes (incident primary liver carcinoma and death from any cause) were ascertained from follow-up via hospital inpatient records, national cancer registry, and death certificate records, and from primary care data among a subset of participants for whom data were available. Associations between genotype and outcomes were tested using Cox regression adjusted for age, assessment center, genotyping array, and population genetics substructure. Kaplan-Meier lifetable probabilities of incident diagnoses were estimated from age 40 to 75 years by HFE genotype and sex. Results: A total of 451 186 participants (mean [SD] age, 56.8 [8.0] years; 54.3% women) were followed up for a median (interquartile range) of 8.9 (8.3-9.5) years. Among the 1294 male p.C282Y homozygotes, there were 21 incident hepatic malignancies, 10 of which were in participants without a diagnosis of hemochromatosis at baseline. p.C282Y homozygous men had a higher risk of hepatic malignancies (hazard ratio [HR], 10.5 [95% CI, 6.6-16.7]; P < .001) and all-cause mortality (n = 88; HR, 1.2 [95% CI, 1.0-1.5]; P = .046) compared with men with neither HFE variant. In lifetables projections for male p.C282Y homozygotes to age 75 years, the risk of primary hepatic malignancy was 7.2% (95% CI, 3.9%-13.1%), compared with 0.6% (95% CI, 0.4%-0.7%) for men with neither variant, and the risk of death was 19.5% (95% CI, 15.8%-24.0%), compared with 15.1% (95% CI, 14.7%-15.5%) among men with neither variant. Among female p.C282Y homozygotes (n = 1596), there were 3 incident hepatic malignancies and 60 deaths, but the associations between homozygosity and hepatic malignancy (HR, 2.1 [95% CI, 0.7-6.5]; P = .22) and death (HR, 1.2 [95% CI, 0.9-1.5]; P = .20) were not statistically significant. Conclusions and Relevance: Among men with HFE p.C282Y homozygosity, there was a significantly increased risk of incident primary hepatic malignancy and death compared with men without p.C282Y or p.H63D variants; there was not a significant association for women. Further research is needed to understand the effects of early diagnosis and treatment.

Association of blood pressure with clinical outcomes in older adults with chronic kidney disease.

BACKGROUND: in chronic kidney disease (CKD), hypertension is associated with poor outcomes at ages <70 years. At older ages, this association is unclear. We tested 10-year mortality and cardiovascular outcomes by clinical systolic blood pressure (SBP) in older CKD Stages 3 and 4 patients without diabetes or proteinuria. METHODS: retrospective cohort in population representative primary care electronic medical records linked to hospital data from the UK. CKD staged by CKD-EPI equation (≥2 creatinine measurements ≥90 days apart). SBPs were 3-year medians before baseline, with mean follow-up 5.7 years. Cox competing models accounted for mortality. RESULTS: about 158,713 subjects with CKD3 and 6,611 with CKD4 met inclusion criteria. Mortality increased with increasing CKD stage in all subjects aged >60. In the 70 plus group with SBPs 140-169 mmHg, there was no increase in mortality, versus SBP 130-139. Similarly, SBPs 140-169 mmHg were not associated with increased incident heart failure, stroke or myocardial infarctions. SBPs <120 mmHg were associated with increased mortality and cardiovascular risk. At ages 60-69, there was increased mortality at SBP <120 and SBP >150 mmHg.Results were little altered after excluding those with declining SBPs during 5 years before baseline, or for longer-term outcomes (5-10 years after baseline). CONCLUSIONS: in older primary care patients, CKD3 or 4 was the dominant outcome predictor. SBP 140-169 mmHg having little additional predictive value, <120 mmHg was associated with increased mortality. Prospective studies of representative older adults with CKD are required to establish optimum BP targets.

Much more medicine for the oldest old: trends in UK electronic clinical records.

BACKGROUND: the oldest old (85+) pose complex medical challenges. Both underdiagnosis and overdiagnosis are claimed in this group. OBJECTIVE: to estimate diagnosis, prescribing and hospital admission prevalence from 2003/4 to 2011/12, to monitor trends in medicalisation. DESIGN AND SETTING: observational study of Clinical Practice Research Datalink (CPRD) electronic medical records from general practice populations (eligible; n = 27,109) with oversampling of the oldest old. METHODS: we identified 18 common diseases and five geriatric syndromes (dizziness, incontinence, skin ulcers, falls and fractures) from Read codes. We counted medications prescribed ≥1 time in all quarters of studied years. RESULTS: there were major increases in recorded prevalence of most conditions in the 85+ group, especially chronic kidney disease (stages 3-5: prevalence <1% rising to 36.4%). The proportions of the 85+ group with ≥3 conditions rose from 32.2 to 55.1% (27.1 to 35.1% in the 65-84 year group). Geriatric syndrome trends were less marked. In the 85+ age group the proportion receiving no chronically prescribed medications fell from 29.6 to 13.6%, while the proportion on ≥3 rose from 44.6 to 66.2%. The proportion of 85+ year olds with ≥1 hospital admissions per year rose from 27.6 to 35.4%. CONCLUSIONS: there has been a dramatic increase in the medicalisation of the oldest old, evident in increased diagnosis (likely partly due to better record keeping) but also increased prescribing and hospitalisation. Diagnostic trends especially for chronic kidney disease may raise concerns about overdiagnosis. These findings provide new urgency to questions about the appropriateness of multiple diagnostic labelling.

Any versus long-term prescribing of high risk medications in older people using 2012 Beers Criteria: results from three cross-sectional samples of primary care records for 2003/4, 2007/8 and 2011/12.

BACKGROUND: High risk medications are commonly prescribed to older US patients. Currently, less is known about high risk medication prescribing in other Western Countries, including the UK. We measured trends and correlates of high risk medication prescribing in a subset of the older UK population (community/institutionalized) to inform harm minimization efforts. METHODS: Three cross-sectional samples from primary care electronic clinical records (UK Clinical Practice Research Datalink, CPRD) in fiscal years 2003/04, 2007/08 and 2011/12 were taken. This yielded a sample of 13,900 people aged 65 years or over from 504 UK general practices. High risk medications were defined by 2012 Beers Criteria adapted for the UK. Using descriptive statistical methods and regression modelling, prevalence of 'any' (drugs prescribed at least once per year) and 'long-term' (drugs prescribed all quarters of year) high risk medication prescribing and correlates were determined. RESULTS: While polypharmacy rates have risen sharply, high risk medication prevalence has remained stable across a decade. A third of older (65+) people are exposed to high risk medications, but only half of the total prevalence was long-term (any = 38.4 % [95 % CI: 36.3, 40.5]; long-term = 17.4 % [15.9, 19.9] in 2011/12). Long-term but not any high risk medication exposure was associated with older ages (85 years or over). Women and people with higher polypharmacy burden were at greater risk of exposure; lower socio-economic status was not associated. Ten drugs/drug classes accounted for most of high risk medication prescribing in 2011/12. CONCLUSIONS: High risk medication prescribing has not increased over time against a background of increasing polypharmacy in the UK. Half of patients receiving high risk medications do so for less than a year. Reducing or optimising the use of a limited number of drugs could dramatically reduce high risk medications in older people. Further research is needed to investigate why the oldest old and women are at greater risk. Interventions to reduce high risk medications may need to target shorter and long-term use separately.

Influenza vaccination reduced myocardial infarctions in United Kingdom older adults: a prior event rate ratio study.

OBJECTIVES: We aimed to estimate the real-world effectiveness of the influenza vaccine against myocardial infarction (MI) and influenza in the decade since adults aged ≥ 65 years were first recommended the vaccine. STUDY DESIGN AND SETTING: We identified annual cohorts, 1997 to 2011, of adults aged ≥ 65 years, without previous influenza vaccination, from UK general practices, registered with the Clinical Practice Research Datalink. Using a quasi-experimental study design to control for confounding bias, we estimated influenza vaccine effectiveness on hospitalization for MI, influenza, and antibiotic prescriptions for lower respiratory tract infections. RESULTS: Vaccination was moderately effective against influenza, the prior event rate ratio-adjusted hazard ratios ranging from 0.70 in 1999 to 0.99 in 2001. Prior event rate ratio-adjusted hazard ratios demonstrated a protective effect against MIs, varying between 0.40 in 2010 and 0.89 in 2001. Aggregated across the cohorts, influenza vaccination reduced the risk of MIs by 39% (95% confidence interval: 34%, 44%). CONCLUSION: Effectiveness of the flu vaccine in preventing MIs in older UK adults is consistent with the limited evidence from clinical trials. Similar trends in effectiveness against influenza and against MIs suggest the risk of influenza mediates the effectiveness against MIs, although divergence in some years implies the mechanism may be complex.

Blood pressure, frailty and dementia.

High blood pressure (BP) affects 75% of people aged over 70. Ageing alters BP homeostasis, resulting in postural hypotension and increased BP variability. Co-morbidity and frailty add complexity to understanding BP changes in later life. Longitudinal BP declines are likely driven by accumulating co-morbidity and are accelerated in both frailty and dementia. This narrative review summarises what is known about the association between BP and frailty, the clinical management of BP in frailty and the association between BP, cognitive decline and dementia.

A report from the NIHR UK working group on remote trial delivery for the COVID-19 pandemic and beyond.

BACKGROUND: Prior to the COVID-19 pandemic, the majority of clinical trial activity took place face to face within clinical or research units. The COVID-19 pandemic resulted in a significant shift towards trial delivery without in-person face-to-face contact or "Remote Trial Delivery". The National Institute of Health Research (NIHR) assembled a Remote Trial Delivery Working Group to consider challenges and enablers to this major change in clinical trial delivery and to provide a toolkit for researchers to support the transition to remote delivery. METHODS: The NIHR Remote Trial Delivery Working Group evaluated five key domains of the trial delivery pathway: participant factors, recruitment, intervention delivery, outcome measurement and quality assurance. Independent surveys were disseminated to research professionals, and patients and carers, to ascertain benefits, challenges, pitfalls, enablers and examples of good practice in Remote Trial Delivery. A toolkit was constructed to support researchers, funders and governance structures in moving towards Remote Trial Delivery. The toolkit comprises a website encompassing the key principles of Remote Trial Delivery, and a repository of best practice examples and questions to guide research teams. RESULTS: The patient and carer survey received 47 respondents, 34 of whom were patients and 13 of whom were carers. The professional survey had 115 examples of remote trial delivery practice entered from across England. Key potential benefits included broader reach and inclusivity, the ability for standardisation and centralisation, and increased efficiency and patient/carer convenience. Challenges included the potential exclusion of participants lacking connectivity or digital skills, the lack of digitally skilled workforce and appropriate infrastructure, and validation requirements. Five key principles of Remote Trial Delivery were proposed: national research standards, inclusivity, validity, cost-effectiveness and evaluation of new methodologies. CONCLUSIONS: The rapid changes towards Remote Trial Delivery catalysed by the COVID-19 pandemic could lead to sustained change in clinical trial delivery. The NIHR Remote Trial Delivery Working Group provide a toolkit for researchers recommending five key principles of Remote Trial Delivery and providing examples of enablers.

Biological Aging Predicts Vulnerability to COVID-19 Severity in UK Biobank Participants.

BACKGROUND: Age and disease prevalence are the 2 biggest risk factors for Coronavirus disease 2019 (COVID-19) symptom severity and death. We therefore hypothesized that increased biological age, beyond chronological age, may be driving disease-related trends in COVID-19 severity. METHODS: Using the UK Biobank England data, we tested whether a biological age estimate (PhenoAge) measured more than a decade prior to the COVID-19 pandemic was predictive of 2 COVID-19 severity outcomes (inpatient test positivity and COVID-19-related mortality with inpatient test-confirmed COVID-19). Logistic regression models were used with adjustment for age at the pandemic, sex, ethnicity, baseline assessment centers, and preexisting diseases/conditions. RESULTS: Six hundred and thirteen participants tested positive at inpatient settings between March 16 and April 27, 2020, 154 of whom succumbed to COVID-19. PhenoAge was associated with increased risks of inpatient test positivity and COVID-19-related mortality (ORMortality = 1.63 per 5 years, 95% CI: 1.43-1.86, p = 4.7 × 10-13) adjusting for demographics including age at the pandemic. Further adjustment for preexisting diseases/conditions at baseline (ORM = 1.50, 95% CI: 1.30-1.73 per 5 years, p = 3.1 × 10-8) and at the early pandemic (ORM = 1.21, 95% CI: 1.04-1.40 per 5 years, p = .011) decreased the association. CONCLUSIONS: PhenoAge measured in 2006-2010 was associated with COVID-19 severity outcomes more than 10 years later. These associations were partly accounted for by prevalent chronic diseases proximate to COVID-19 infection. Overall, our results suggest that aging biomarkers, like PhenoAge may capture long-term vulnerability to diseases like COVID-19, even before the accumulation of age-related comorbid conditions.

Analysis of CYP2C19 genetic variants with ischaemic events in UK patients prescribed clopidogrel in primary care: a retrospective cohort study.

OBJECTIVE: To determine whether CYP2C19 loss-of-function (LoF) alleles increase risk of ischaemic stroke and myocardial infarction (MI) in UK primary care patients prescribed clopidogrel. DESIGN: Retrospective cohort analysis. SETTING: Primary care practices in the UK from January 1999 to September 2017. PARTICIPANTS: 7483 European-ancestry adults from the UK Biobank study with genetic and linked primary care data, aged 36-79 years at time of first clopidogrel prescription. INTERVENTIONS: Clopidogrel prescription in primary care, mean duration 2.6 years (range 2 months to 18 years). MAIN OUTCOME MEASURE: Hospital inpatient-diagnosed ischaemic stroke, MI or angina while treated with clopidogrel. RESULTS: 28.7% of participants carried at least one CYP2C19 LoF variant. LoF carriers had higher rates of incident ischaemic stroke while treated with clopidogrel compared with those without the variants (8 per 1000 person-years vs 5.2 per 1000 person-years; HR 1.53, 95% CIs 1.04 to 2.26, p=0.031). LoF carriers also had increased risk of MI (HR 1.14, 95% CI 1.04 to 1.26, p=0.008). In combined analysis LoF carriers had increased risk of any ischaemic event (stroke or MI) (HR 1.17, 95% CI 1.06 to 1.29, p=0.002). Adjustment for aspirin coprescription produced similar estimates. In lifetables using observed incidence rates, 22.5% (95% CI 14.4% to 34.0%) of CYP2C19 LoF carriers on clopidogrel were projected to develop an ischaemic stroke by age 79 (oldest age in the study), compared with 15.4% (95% CI 11.4% to 20.5%) in non-carriers, that is, 7.1% excess stroke incidence in LoF carriers by age 79. CONCLUSIONS: A substantial proportion of the UK population carry genetic variants that reduce metabolism of clopidogrel to its active form. In family practice patients on clopidogrel, CYP2C19 LoF variants are associated with substantially higher incidence of ischaemic events. Genotype-guided selection of antiplatelet medications may improve outcomes in patients carrying CYP2C19 genetic variants.