ABSTRACT
BACKGROUND AIMS: The HFE p.C282Y+/+ (homozygous) genotype and central adiposity both increase liver disease and diabetes risks, but combined effects are unclear. We estimated waist-to-hip ratio (WHR) associations with incident clinical outcomes in routine care in p.C282Y+/+ participants in the UK Biobank community cohort. APPROACH RESULTS: Baseline WHR in 1,297 male and 1,602 female p.C282Y+/+ with 13.3-year mean follow-up for diagnoses. Spline regressions and Cox proportional hazard models were adjusted for age and genetic principal components. Cumulative incidence was from age 40 to 80 years. In p.C282Y+/+ males, there were positive linear WHR relationships for hospital inpatient diagnosed liver fibrosis/cirrhosis (p=2.4*10-5), liver cancer (p=0.007), non-alcoholic fatty liver disease (NAFLD) (p=7.7*10-11), and type 2 diabetes (T2D) (p=5.1*10-16). The Hazard Ratio (HR) for high WHR in p.C282Y+/+ males (≥0.96; 33.9%) was HR=4.13 for liver fibrosis/cirrhosis (95%CI: 2.04-8.39, p=8.4*10-5 vs. normal WHR); cumulative age 80 incidence 15.0% (95%CI: 9.8%-22.6%) versus 3.9% (95%CI: 1.9%-7.6%); for liver cancer, cumulative incidence was 9.2% (95%CI: 5.7%-14.6%) versus 3.6% (95%CI: 1.9%-6.6%). Hemochromatosis was diagnosed in 23 (96%) of the 24 high WHR p.C282Y+/+ males with incident fibrosis/cirrhosis. High WHR (≥0.85; 30.0%) p.C282Y+/+ females had raised hazards for liver fibrosis/cirrhosis (HR=9.17, 95%CI: 2.51-33.50, p=3.8*10-7) and NAFLD (HR=5.17, 95%CI: 2.48-10.78, p=1.2*10-5). Fibrosis/cirrhosis associations were similar in the subset with additional primary care diagnoses. CONCLUSION: In p.C282Y+/+ males and females, increasing WHR is associated with substantially higher risks of liver complications. Interventions to reduce central adiposity to improve these outcomes should be tested.
ABSTRACT
The focus of aging research has shifted from increasing lifespan to enhancing healthspan to reduce the time spent living with disability. Despite significant efforts to develop biomarkers of aging, few studies have focused on biomarkers of healthspan. We developed a proteomics-based signature of healthspan (healthspan proteomic score (HPS)) using data from the UK Biobank Pharma Proteomics Project (53,018 individuals and 2920 proteins). A lower HPS was associated with higher mortality risk and several age-related conditions, such as COPD, diabetes, heart failure, cancer, myocardial infarction, dementia, and stroke. HPS showed superior predictive accuracy for these outcomes compared to chronological age and biological age measures. Proteins associated with HPS were enriched in hallmark pathways such as immune response, inflammation, cellular signaling, and metabolic regulation. Our findings demonstrate the validity of HPS, making it a valuable tool for assessing healthspan and as a potential surrogate marker in geroscience-guided studies.
ABSTRACT
BACKGROUND: Iron overload is observed in neurodegenerative diseases, especially Alzheimer's disease (AD) and Parkinson's disease (PD). Homozygotes for the iron-overload (haemochromatosis) causing HFE p.C282Y variant have increased risk of dementia and PD. Whether brain iron deposition is causal or secondary to the neurodegenerative processes in the general population is unclear. METHODS: We analysed 39,533 UK Biobank participants of European genetic ancestry with brain MRI data. We studied brain iron estimated by R2* and quantitative susceptibility mapping (QSM) in 8 subcortical regions: accumbens, amygdala, caudate, hippocampus, pallidum, putamen, substantia nigra, and thalamus. We performed genome-wide associations studies (GWAS) and used Mendelian Randomization (MR) methods to estimate the causal effect of brain iron on grey matter volume, and risk of AD, non-AD and PD. We also used MR to test whether genetic liability to AD or PD causally increased brain iron (R2* and QSM). FINDINGS: In GWAS of R2* and QSM we replicated 83% of previously reported genetic loci and identified 174 further loci across all eight brain regions. Higher genetically predicted brain iron, using both R2* and QSM, was associated with lower grey matter volumes in the caudate, putamen and thalamus (e.g., Beta-putamenQSM: -0.37, p = 2*10-46). Higher genetically predicted thalamus R2* was associated with increased risk of non-AD dementia (OR 1.36(1.16;1.60), p = 2*10-4) but not AD (p > 0.05). In males, genetically predicted putamen R2* increased non-AD dementia risk, but not in females. Higher genetically predicted iron in the caudate, putamen, and substantia nigra was associated with an increased risk of PD (Odds Ratio QSM â¼ substantia-nigra 1.21(1.07;1.37), p = 0.003). Genetic liability to AD or PD was not associated with R2* or QSM in the dementia or PD-associated regions. INTERPRETATION: Our genetic analysis supports a causal effect of higher iron deposition in specific subcortical brain regions for Parkinson's disease, grey matter volume, and non-Alzheimer's dementia.
Subject(s)
Dementia , Gray Matter , Iron , Parkinson Disease , Aged , Female , Humans , Male , Middle Aged , Brain/pathology , Brain/diagnostic imaging , Brain/metabolism , Cohort Studies , Dementia/genetics , Dementia/pathology , Dementia/diagnostic imaging , Genome-Wide Association Study , Gray Matter/diagnostic imaging , Gray Matter/pathology , Gray Matter/metabolism , Iron/metabolism , Magnetic Resonance Imaging , Parkinson Disease/genetics , Parkinson Disease/pathology , Parkinson Disease/diagnostic imaging , UK Biobank , United Kingdom/epidemiologyABSTRACT
Beyond mere prognostication, optimal biomarkers of aging provide insights into qualitative and quantitative features of biological aging and might, therefore, offer useful information for the testing and, ultimately, clinical use of gerotherapeutics. We aimed to develop a proteomic aging clock (PAC) for all-cause mortality risk as a proxy of biological age. Data were from the UK Biobank Pharma Proteomics Project, including 53,021 participants aged between 39 and 70 years and 2923 plasma proteins assessed using the Olink Explore 3072 assay®. 10.9% of the participants died during a mean follow-up of 13.3 years, with the mean age at death of 70.1 years. The Spearman correlation between PAC proteomic age and chronological age was 0.77. PAC showed robust age-adjusted associations and predictions for all-cause mortality and the onset of various diseases in general and disease-free participants. The proteins associated with PAC proteomic age deviation were enriched in several processes related to the hallmarks of biological aging. Our results expand previous findings by showing that biological age acceleration, based on PAC, strongly predicts all-cause mortality and several incident disease outcomes. Particularly, it facilitates the evaluation of risk for multiple conditions in a disease-free population, thereby, contributing to the prevention of initial diseases, which vary among individuals and may subsequently lead to additional comorbidities.
Subject(s)
Aging , Proteomics , Humans , Middle Aged , Proteomics/methods , Aged , Female , Male , Adult , Biomarkers/bloodABSTRACT
OBJECTIVES: HFE haemochromatosis genetic variants have an uncertain clinical penetrance, especially to older ages and in undiagnosed groups. We estimated p.C282Y and p.H63D variant cumulative incidence of multiple clinical outcomes in a large community cohort. DESIGN: Prospective cohort study. SETTING: 22 assessment centres across England, Scotland, and Wales in the UK Biobank (2006-2010). PARTICIPANTS: 451 270 participants genetically similar to the 1000 Genomes European reference population, with a mean of 13.3-year follow-up through hospital inpatient, cancer registries and death certificate data. MAIN OUTCOME MEASURES: Cox proportional HRs of incident clinical outcomes and mortality in those with HFE p.C282Y/p.H63D mutations compared with those with no variants, stratified by sex and adjusted for age, assessment centre and genetic stratification. Cumulative incidences were estimated from age 40 years to 80 years. RESULTS: 12.1% of p.C282Y+/+ males had baseline (mean age 57 years) haemochromatosis diagnoses, with a cumulative incidence of 56.4% at age 80 years. 33.1% died vs 25.4% without HFE variants (HR 1.29, 95% CI: 1.12 to 1.48, p=4.7×10-4); 27.9% vs 17.1% had joint replacements, 20.3% vs 8.3% had liver disease, and there were excess delirium, dementia, and Parkinson's disease but not depression. Associations, including excess mortality, were similar in the group undiagnosed with haemochromatosis. 3.4% of women with p.C282Y+/+ had baseline haemochromatosis diagnoses, with a cumulative incidence of 40.5% at age 80 years. There were excess incident liver disease (8.9% vs 6.8%; HR 1.62, 95% CI: 1.27 to 2.05, p=7.8×10-5), joint replacements and delirium, with similar results in the undiagnosed. p.C282Y/p.H63D and p.H63D+/+ men or women had no statistically significant excess fatigue or depression at baseline and no excess incident outcomes. CONCLUSIONS: Male and female p.C282Y homozygotes experienced greater excess morbidity than previously documented, including those undiagnosed with haemochromatosis in the community. As haemochromatosis diagnosis rates were low at baseline despite treatment being considered effective, trials of screening to identify people with p.C282Y homozygosity early appear justified.
Subject(s)
Delirium , Hemochromatosis , Liver Diseases , Adult , Aged, 80 and over , Female , Humans , Male , Middle Aged , Biological Specimen Banks , Delirium/complications , Genotype , Hemochromatosis/diagnosis , Hemochromatosis/epidemiology , Hemochromatosis/genetics , Hemochromatosis Protein/genetics , Histocompatibility Antigens Class I/genetics , Homozygote , Liver Diseases/complications , Mutation , Prospective Studies , UK Biobank , AgedABSTRACT
BACKGROUND: Brain iron deposition is common in dementia, but whether serum iron is a causal risk factor is unknown. We aimed to determine whether genetic predisposition to higher serum iron status biomarkers increased risk of dementia and atrophy of grey matter. METHODS: We analysed UK Biobank participants clustered into European (N=451284), African (N=7477) and South Asian (N=9570) groups by genetic similarity to the 1000 genomes project. Using Mendelian randomisation methods, we estimated the association between genetically predicted serum iron (transferrin saturation [TSAT] and ferritin), grey matter volume and genetic liability to clinically defined dementia (including Alzheimer's disease [AD], non-AD dementia, and vascular dementia) from hospital and primary care records. We also performed time-to-event (competing risks) analysis of the TSAT polygenic score on risk of clinically defined non-AD dementia. RESULTS: In Europeans, higher genetically predicted TSAT increased genetic liability to dementia (Odds Ratio [OR]: 1.15, 95% Confidence Intervals [CI] 1.04 to 1.26, p=0.0051), non-AD dementia (OR: 1.27, 95% CI 1.12 to 1.45, p=0.00018) and vascular dementia (OR: 1.37, 95% CI 1.12 to 1.69, p=0.0023), but not AD (OR: 1.00, 95% CI 0.86 to 1.15, p=0.97). Higher TSAT was also associated with increased risk of non-AD dementia in participants of African, but not South Asian groups. In survival analysis using a TSAT polygenic score, the effect was independent of apolipoprotein-E ε4 genotype (with adjustment subdistribution Hazard Ratio: 1.74, 95% CI 1.33 to 2.28, p=0.00006). Genetically predicted TSAT was associated with lower grey matter volume in caudate, putamen and thalamus, and not in other areas of interest. DISCUSSION: Genetic evidence supports a causal relationship between higher TSAT and risk of clinically defined non-AD and vascular dementia, in European and African groups. This association appears to be independent of apolipoprotein-E ε4.
Subject(s)
Dementia, Vascular , Iron , Humans , Biological Specimen Banks , UK Biobank , Risk Factors , Biomarkers , Apolipoproteins , Mendelian Randomization AnalysisSubject(s)
Brain , DNA Copy Number Variations , DNA, Mitochondrial , Iron , Humans , DNA, Mitochondrial/genetics , Iron/metabolism , Brain/metabolismABSTRACT
Beyond mere prognostication, optimal biomarkers of aging provide insights into qualitative and quantitative features of biological aging and might, therefore, offer useful information for the testing and, ultimately, clinical use of gerotherapeutics. We aimed to develop a proteomic aging clock (PAC) for all-cause mortality risk as a proxy of biological age. Data were from the UK Biobank Pharma Proteomics Project, including 53,021 participants aged between 39 and 70 years and 2,923 plasma proteins assessed using the Olink Explore 3072 assay®. The Spearman correlation between PAC proteomic age and chronological age was 0.77. A total of 10.9% of the participants died during a mean follow-up of 13.3 years, with the mean age at death 70.1 years. We developed a proteomic aging clock (PAC) for all-cause mortality risk as a surrogate of BA using a combination of least absolute shrinkage and selection operator (LASSO) penalized Cox regression and Gompertz proportional hazards models. PAC showed robust age-adjusted associations and predictions for all-cause mortality and the onset of various diseases in general and disease-free participants. The proteins associated with PAC were enriched in several processes related to the hallmarks of biological aging. Our results expand previous findings by showing that age acceleration, based on PAC, strongly predicts all-cause mortality and several incident disease outcomes. Particularly, it facilitates the evaluation of risk for multiple conditions in a disease-free population, thereby, contributing to the prevention of initial diseases, which vary among individuals and may subsequently lead to additional comorbidities.
ABSTRACT
The iron overload disorder hemochromatosis is primarily caused by the homozygous HFE p.C282Y variant, but the scale of excess related musculoskeletal morbidity is uncertain. We estimated hemochromatosis-genotype associations with clinically diagnosed musculoskeletal outcomes and joint replacement surgeries in the UK Biobank community cohort. A total of 451,143 European ancestry participants (40 to 70 years at baseline) were followed in hospital records (mean 11.5-years). Cox proportional hazards models estimated HFE p.C282Y and p.H63D associations with incident outcomes. Male p.C282Y homozygotes (n = 1294) had increased incidence of osteoarthritis (n = 52, hazard ratio [HR]: 2.12 [95% confidence interval, CI: 1.61 to 2.80]; p = 8.8 × 10-8), hip replacement (n = 88, HR: 1.84 [95% CI: 1.49 to 2.27]; p = 1.6 × 10-8), knee replacement (n = 61, HR: 1.54 [95% CI: 1.20 to 1.98]; p = 8.4 × 10-4), and ankle and shoulder replacement, compared to males with no HFE mutations. Cumulative incidence analysis, using Kaplan-Meier lifetable probabilities demonstrated 10.4% of male homozygotes were projected to develop osteoarthritis and 15.5% to have hip replacements by age 75, versus 5.0% and 8.7% respectively without mutations. Male p.C282Y homozygotes also had increased incidence of femoral fractures (n = 15, HR: 1.72 [95% CI: 1.03 to 2.87]; p = 0.04) and osteoporosis (n = 21, HR: 1.71 [95% CI: 1.11 to 2.64]; p = 0.02), although the latter association was limited to those with liver fibrosis/cirrhosis diagnoses. Female p.C282Y homozygotes had increased incidence of osteoarthritis only (n = 57, HR: 1.46, [95% CI: 1.12 to 1.89]; p = 0.01). Male p.C282Y/p.H63D compound heterozygotes experienced a modest increased risk of hip replacements (n = 234, HR: 1.17 [95% CI: 1.02 to 1.33], p = 0.02), but this did not pass multiple testing corrections. In this large community cohort, the p.C282Y homozygote genotype was associated with substantial excess musculoskeletal morbidity in males. Wider HFE genotype testing may be justified, including in orthopedic clinics serving higher HFE variant prevalence populations. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
ABSTRACT
PURPOSE OF REVIEW: Sarcopenic obesity (SO) is a growing public health problem in older adults. Whether SO confers higher risk of cardiometabolic disease and mortality than obesity or sarcopenia alone is still a matter of debate. We focus on recent findings on SO and cardiometabolic health and mortality in older adults. RECENT FINDINGS: SO is associated with increased mortality compared to non-sarcopenic obesity, but similar mortality risk compared to sarcopenia without obesity. SO is associated with a higher risk of cardiovascular disease (CVD), diabetes, and physical disability than obesity or sarcopenia alone. SO, in the presence of diabetes, is associated with the highest risk of CVD and chronic kidney disease. A definition and diagnostic criteria for SO has recently been proposed (ESPEN and EASO). SO is associated with more adverse outcomes overall than sarcopenia or obesity alone. Future research is required to assess the impact of the new SO definition on health outcomes.
Subject(s)
Cardiovascular Diseases , Diabetes Mellitus , Sarcopenia , Humans , Aged , Sarcopenia/complications , Sarcopenia/epidemiology , Risk Factors , Obesity/complications , Obesity/epidemiology , Cardiovascular Diseases/complications , AgingABSTRACT
BACKGROUND: In European ancestry populations, iron overload disorder hereditary hemochromatosis is predominantly caused by HFE p.C282Y and p.H63D mutations. Male p.C282Y homozygotes have markedly increased hepatic malignancy incidence, but risks for other cancers in male and female homozygotes are unclear. METHODS: 451,143 UK Biobank European ancestry participants (aged 40-70 years; 54.3% female) were followed (mean 11.6 years) via hospital admissions and national cancer registries. We estimated risks of any incident cancer (other than nonmelanoma and liver cancer) and common incident cancers [bladder, blood (with subanalyses of leukemia and lymphoma), bone, brain, breast, colorectal, kidney, lung, melanoma, esophageal, ovarian, pancreatic, prostate and stomach] in those with p.C282Y and p.H63D genotypes, compared with participants without HFE mutations. RESULTS: Male p.C282Y homozygotes (n = 2,890, 12.1% with baseline diagnosed hereditary hemochromatosis) had increased incidence of prostate cancer [6.8% vs. 5.4% without mutations; HR = 1.32; 95% confidence interval (CI), 1.07-1.63; P = 0.01; Bonferroni adjusted P = 0.17] during follow-up. In life table estimates from ages 40 to 75 years, 14.4% of male p.C282Y homozygotes are projected to develop prostate cancer (versus 10.7% without mutations, excess 3.8%; 95% CI, 1.3-6.8). No increases in risks were found for other studied cancers in male or female p.C282Y homozygotes, or in any other p.C282Y/p.H63D genotype groups of either sex. CONCLUSIONS: In a large community sample of male p.C282Y homozygotes, there is suggestive evidence of increased prostate cancer incidence, with no evidence of excess of other studied (nonliver) cancers. IMPACT: Replication of results in other large community genotyped cohorts are needed to confirm if clinical monitoring for prostate cancer is necessary in p.C282Y homozygous males.
Subject(s)
Hemochromatosis , Prostatic Neoplasms , Biological Specimen Banks , Follow-Up Studies , Genotype , Hemochromatosis/complications , Hemochromatosis/epidemiology , Hemochromatosis/genetics , Hemochromatosis Protein/genetics , Histocompatibility Antigens Class I/genetics , Homozygote , Humans , Male , Mutation , Prostatic Neoplasms/epidemiology , Prostatic Neoplasms/genetics , United Kingdom/epidemiologyABSTRACT
BACKGROUND: The iron overload condition hereditary hemochromatosis (HH) can cause liver cirrhosis and cancer, diabetes, and arthritis. Males homozygous for the p.C282Y missense mutation in the Homeostatin Iron Regulator (HFE) gene have greatest risk; yet, only a minority develop these conditions. We aimed to determine whether common genetic variants influencing iron levels or liver disease risk in the general population also modify clinical penetrance in HFE p.C282Y and p.H63D carriers. METHODS: We studied 1294 male and 1596 female UK Biobank HFE p.C282Y homozygous participants of European ancestry with medical records up to 14 years after baseline assessment. Polygenic scores quantified genetic effects of blood iron biomarkers and relevant diseases (identified in the general population). Analyses were also performed in other HFE p.C282Y/p.H63D genotype groups. RESULTS: In male p.C282Y homozygotes, a higher iron polygenic score increased the risk of liver fibrosis or cirrhosis diagnoses (odds ratio for the top 20% of iron polygenic score vs. the bottom 20% = 4.90: 95% confidence intervals, 1.63-14.73; p = 0.005), liver cancer, and osteoarthritis but not diabetes. A liver cirrhosis polygenic score was associated with liver cancer diagnoses. In female p.C282Y homozygotes, the osteoarthritis polygenic score was associated with increased osteoarthritis diagnoses and type-2 diabetes polygenic score with diabetes. However, the iron polygenic score was not robustly associated with diagnoses in p.C282Y female homozygotes or in other p.C282Y/p.H63D genotypes. CONCLUSIONS: HFE p.C282Y homozygote penetrance to clinical disease in a large community cohort was partly explained by common genetic variants that influence iron and risks of related diagnoses in the general population, including polygenic scores in HH screening and diagnosis, may help in estimating prognosis and treatment planning.
Subject(s)
Hemochromatosis , Liver Neoplasms , Osteoarthritis , Humans , Male , Female , Hemochromatosis/complications , Hemochromatosis/genetics , Hemochromatosis/diagnosis , Hemochromatosis Protein/genetics , Penetrance , Histocompatibility Antigens Class I/genetics , Membrane Proteins/genetics , Homozygote , Genotype , Iron , Liver Cirrhosis/genetics , Liver Cirrhosis/complications , Liver Neoplasms/complications , Osteoarthritis/complications , MutationABSTRACT
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.
Subject(s)
Brain Ischemia , Stroke , Adult , Aged , Brain Ischemia/epidemiology , Brain Ischemia/genetics , Clopidogrel/therapeutic use , Cytochrome P-450 CYP2C19/genetics , Genotype , Humans , Middle Aged , Platelet Aggregation Inhibitors/adverse effects , Primary Health Care , Retrospective Studies , Stroke/drug therapy , Stroke/epidemiology , Stroke/genetics , Treatment Outcome , United Kingdom/epidemiologyABSTRACT
Frailty is a syndrome of growing importance given the global ageing population. While frailty is a multifactorial process, poor nutritional status is considered a key contributor to its pathophysiology. As nutrition is a modifiable risk factor for frailty, strategies to prevent and treat frailty should consider dietary change. Observational evidence linking nutrition with frailty appears most robust for dietary quality: for example, dietary patterns such as the Mediterranean diet appear to be protective. In addition, research on specific foods, such as a higher consumption of fruit and vegetables and lower consumption of ultra-processed foods are consistent, with healthier profiles linked to lower frailty risk. Few dietary intervention studies have been conducted to date, although a growing number of trials that combine supplementation with exercise training suggest a multi-domain approach may be more effective. This review is based on an interdisciplinary workshop, held in November 2020, and synthesises current understanding of dietary influences on frailty, focusing on opportunities for prevention and treatment. Longer term prospective studies and well-designed trials are needed to determine the causal effects of nutrition on frailty risk and progression and how dietary change can be used to prevent and/or treat frailty in the future.
Subject(s)
Diet, Healthy/methods , Diet/adverse effects , Frailty/prevention & control , Malnutrition/diet therapy , Nutritional Status , Aged , Aged, 80 and over , Aging/physiology , Causality , Feeding Behavior/physiology , Female , Frail Elderly , Frailty/etiology , Humans , Male , Malnutrition/complications , Malnutrition/physiopathologyABSTRACT
Frailty is a common geriatric syndrome and strongly associated with disability, mortality and hospitalization. Frailty is commonly measured using the frailty index (FI), based on the accumulation of a number of health deficits during the life course. The mechanisms underlying FI are multifactorial and not well understood, but a genetic basis has been suggested with heritability estimates between 30 and 45%. Understanding the genetic determinants and biological mechanisms underpinning FI may help to delay or even prevent frailty. We performed a genome-wide association study (GWAS) meta-analysis of a frailty index in European descent UK Biobank participants (n = 164,610, 60-70 years) and Swedish TwinGene participants (n = 10,616, 41-87 years). FI calculation was based on 49 or 44 self-reported items on symptoms, disabilities and diagnosed diseases for UK Biobank and TwinGene, respectively. 14 loci were associated with the FI (p < 5*10-8 ). Many FI-associated loci have established associations with traits such as body mass index, cardiovascular disease, smoking, HLA proteins, depression and neuroticism; however, one appears to be novel. The estimated single nucleotide polymorphism (SNP) heritability of the FI was 11% (0.11, SE 0.005). In enrichment analysis, genes expressed in the frontal cortex and hippocampus were significantly downregulated (adjusted p < 0.05). We also used Mendelian randomization to identify modifiable traits and exposures that may affect frailty risk, with a higher educational attainment genetic risk score being associated with a lower degree of frailty. Risk of frailty is influenced by many genetic factors, including well-known disease risk factors and mental health, with particular emphasis on pathways in the brain.
Subject(s)
Aging/genetics , Brain/metabolism , Frailty/genetics , Adult , Aged , Aging/metabolism , Frailty/metabolism , Genome-Wide Association Study , Humans , Middle Aged , Twins/geneticsABSTRACT
Biological age measures outperform chronological age in predicting various aging outcomes, yet little is known regarding genetic predisposition. We performed genome-wide association scans of two age-adjusted biological age measures (PhenoAgeAcceleration and BioAgeAcceleration), estimated from clinical biochemistry markers (Levine et al., 2018; Levine, 2013) in European-descent participants from UK Biobank. The strongest signals were found in the APOE gene, tagged by the two major protein-coding SNPs, PhenoAgeAccel-rs429358 (APOE e4 determinant) (p = 1.50 × 10-72 ); BioAgeAccel-rs7412 (APOE e2 determinant) (p = 3.16 × 10-60 ). Interestingly, we observed inverse APOE e2 and e4 associations and unique pathway enrichments when comparing the two biological age measures. Genes associated with BioAgeAccel were enriched in lipid related pathways, while genes associated with PhenoAgeAccel showed enrichment for immune system, cell function, and carbohydrate homeostasis pathways, suggesting the two measures capture different aging domains. Our study reaffirms that aging patterns are heterogeneous across individuals, and the manner in which a person ages may be partly attributed to genetic predisposition.
Subject(s)
Aging/genetics , Genome-Wide Association Study/methods , Phenotype , HumansABSTRACT
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.
Subject(s)
Aging/physiology , Biological Specimen Banks , COVID-19 Testing/statistics & numerical data , COVID-19/epidemiology , Mortality/trends , Severity of Illness Index , Aged , Biomarkers , Chronic Disease , Humans , Middle Aged , Models, Statistical , Preexisting Condition Coverage/statistics & numerical data , SARS-CoV-2/isolation & purification , Time Factors , United Kingdom/epidemiologyABSTRACT
Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10-17), arthritis (GDF5 p = 4 × 10-13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.