Iron and risk of dementia: Mendelian randomisation analysis in UK Biobank.

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.

MRI-derived brain iron, grey matter volume, and risk of dementia and Parkinson's disease: Observational and genetic analysis in the UK Biobank cohort.

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 âˆ¼ 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.

Genetic modifiers of penetrance to liver endpoints in HFE hemochromatosis: Associations in a large community cohort.

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.

Sarcopenic Obesity and Cardiometabolic Health and Mortality in Older Adults: a Growing Health Concern in an Ageing Population.

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.

Sarcopenic obesity in ageing: cardiovascular outcomes and mortality.

Obesity is a major public health issue with prevalence increasing worldwide. Obesity is a well-established risk factor for CVD and mortality in adult populations. However, the impact of being overweight or obese in the elderly on CVD and mortality is controversial. Some studies even suggest that overweight and obesity, measured by BMI, are apparently associated with a decreased mortality risk (known as the obesity paradox). Ageing is associated with an increase in visceral fat and a progressive loss of muscle mass. Fat mass is positively associated and lean mass is negatively associated with risk of mortality. Therefore, in older adults BMI is not a good indicator of obesity. Sarcopenia has been defined as the degenerative loss of muscle mass, quality and strength with age and is of major concern in ageing populations. Sarcopenia has previously been associated with increased risks of metabolic impairment, cardiovascular risk factors, physical disability and mortality. It is possible for sarcopenia to co-exist with obesity, and sarcopenic obesity is a new class of obesity in older adults who have high adiposity levels together with low muscle mass, quality or strength. Therefore, sarcopenia with obesity may act together to increase their effect on metabolic disorders, CVD and mortality. This review will discuss the available evidence for the health implications of sarcopenic obesity on CVD and mortality in older adults.

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.

Healthier diet quality and dietary patterns are associated with lower risk of mobility limitation in older men.

PURPOSE: To investigate associations between diet quality, dietary patterns and mobility limitation 15 years later in a population-based sample of older British men. METHODS: We used longitudinal data from 1234 men from the British Regional Heart Study, mean age 66 years at baseline. Mobility limitation was defined as difficulty going up- or downstairs or walking 400 yards as a result of a long-term health problem. Dietary intake was measured using a food frequency questionnaire data from which the Healthy Diet Indicator (HDI), the Elderly Dietary Index (EDI), and three a posteriori dietary patterns were derived. The a posteriori dietary patterns were identified using principal components analysis: (1) high fat/low fibre, (2) prudent and (3) high sugar. RESULTS: Men with greater adherence to the EDI or HDI were less likely to have mobility limitation at follow-up, top vs bottom category odds ratio for the EDI OR 0.50, 95% CI 0.34, 0.75, and for the HDI OR 0.55, 95% CI 0.35, 0.85, after adjusting for age, social class, region of residence, smoking, alcohol consumption and energy intake. Men with a higher score for the high-fat/low-fibre pattern at baseline were more likely to have mobility limitation at follow-up, top vs bottom quartile odds ratio OR 3.28 95% CI 2.05, 5.24. These associations were little changed by adjusting for BMI and physical activity. CONCLUSION: Our study provides evidence that healthier eating patterns could contribute to prevention or delay of mobility limitation in older British men.

Physical frailty in older men: prospective associations with diet quality and patterns.

BACKGROUND: increasing numbers of older adults are living with frailty and its adverse consequences. We investigated relationships between diet quality or patterns and incident physical frailty in older British men and whether any associations were influenced by inflammation. METHODS: prospective study of 945 men from the British Regional Heart Study aged 70-92 years with no prevalent frailty. Incident frailty was assessed by questionnaire after 3 years of follow-up. Frailty was defined as having at least three of: low grip strength, low physical activity, slow walking speed, unintentional weight loss and feeling of low energy, all based on self-report. The Healthy Diet Indicator (HDI) based on WHO dietary guidelines and the Elderly Dietary Index (EDI) based on a Mediterranean-style dietary intake were computed from questionnaire data and three dietary patterns were identified using principal components analysis: prudent, high fat/low fibre and high sugar. RESULTS: men in the highest EDI category and those who followed a prudent diet were less likely to become frail [top vs bottom category odds ratio (OR) (95% CI) 0.49 (0.30, 0.82) and 0.53 (0.30, 0.92) respectively] after adjustment for potential confounders including BMI and prevalent cardiovascular disease. No significant association was seen for the HDI. By contrast those who had a high fat low fibre diet pattern were more likely to become frail [OR (95% CI) 2.54 (1.46, 4.40)]. These associations were not mediated by C-reactive protein (marker of inflammation). CONCLUSIONS: the findings suggest adherence to a Mediterranean-style diet is associated with reduced risk of developing frailty in older people.

Dietary patterns and the risk of CVD and all-cause mortality in older British men.

Dietary patterns are a major risk factor for cardiovascular morbidity and mortality; however, few studies have examined this relationship in older adults. We examined prospective associations between dietary patterns and the risk of CVD and all-cause mortality in 3226 older British men, aged 60-79 years and free from CVD at baseline, from the British Regional Heart Study. Baseline FFQ data were used to generate thirty-four food groups. Principal component analysis identified dietary patterns that were categorised into quartiles, with higher quartiles representing higher adherence to the dietary pattern. Cox proportional hazards examined associations between dietary patterns and risk of all-cause mortality and cardiovascular outcomes. We identified three interpretable dietary patterns: 'high fat/low fibre' (high in red meat, meat products, white bread, fried potato, eggs), 'prudent' (high in poultry, fish, fruits, vegetables, legumes, pasta, rice, wholemeal bread, eggs, olive oil) and 'high sugar' (high in biscuits, puddings, chocolates, sweets, sweet spreads, breakfast cereals). During 11 years of follow-up, 899 deaths, 316 CVD-related deaths, 569 CVD events and 301 CHD events occurred. The 'high-fat/low-fibre' dietary pattern was associated with an increased risk of all-cause mortality only, after adjustment for confounders (highest v. lowest quartile; hazard ratio 1·44; 95 % CI 1·13, 1·84). Adherence to a 'high-sugar' diet was associated with a borderline significant trend for an increased risk of CVD and CHD events. The 'prudent' diet did not show a significant trend with cardiovascular outcomes or mortality. Avoiding 'high-fat/low-fibre' and 'high-sugar' dietary components may reduce the risk of cardiovascular events and all-cause mortality in older adults.

Diet quality in older age: the influence of childhood and adult socio-economic circumstances.

Socio-economic gradients in diet quality are well established. However, the influence of material socio-economic conditions particularly in childhood, and the use of multiple disaggregated socio-economic measures on diet quality have been little studied in the elderly. In the present study, we examined childhood and adult socio-economic measures, and social relationships, as determinants of diet quality cross-sectionally in 4252 older British men (aged 60-79 years). A FFQ provided data on daily fruit and vegetable consumption and the Elderly Dietary Index (EDI), with higher scores indicating better diet quality. Adult and childhood socio-economic measures included occupation/father's occupation, education and household amenities, which combined to create composite scores. Social relationships included social contact, living arrangements and marital status. Both childhood and adult socio-economic factors were independently associated with diet quality. Compared with non-manual social class, men of childhood manual social class were less likely to consume fruit and vegetables daily (OR 0.80, 95% CI 0.66, 0.97), as were men of adult manual social class (OR 0.65, 95% CI 0.54, 0.79), and less likely to be in the top EDI quartile (OR 0.73, 95% CI 0.61, 0.88), similar to men of adult manual social class (OR 0.66, 95 % CI 0.55, 0.79). Diet quality decreased with increasing adverse adult socio-economic scores; however, the association with adverse childhood socio-economic scores diminished with adult social class adjustment. A combined adverse childhood and adulthood socio-economic score was associated with poor diet quality. Diet quality was most favourable in married men and those not living alone, but was not associated with social contact. Diet quality in older men is influenced by childhood and adulthood socio-economic factors, marital status and living arrangements.

High diet quality is associated with a lower risk of cardiovascular disease and all-cause mortality in older men.

Although diet quality is implicated in cardiovascular disease (CVD) risk, few studies have investigated the relation between diet quality and the risks of CVD and mortality in older adults. This study examined the prospective associations between dietary scores and risk of CVD and all-cause mortality in older British men. A total of 3328 men (aged 60-79 y) from the British Regional Heart Study, free from CVD at baseline, were followed up for 11.3 y for CVD and mortality. Baseline food-frequency questionnaire data were used to generate 2 dietary scores: the Healthy Diet Indicator (HDI), based on WHO dietary guidelines, and the Elderly Dietary Index (EDI), based on a Mediterranean-style dietary intake, with higher scores indicating greater compliance with dietary recommendations. Cox proportional hazards regression analyses assessed associations between quartiles of HDI and EDI and risk of all-cause mortality, CVD mortality, CVD events, and coronary heart disease (CHD) events. During follow-up, 933 deaths, 327 CVD deaths, 582 CVD events, and 307 CHD events occurred. Men in the highest compared with the lowest EDI quartile had significantly lower risks of all-cause mortality (HR: 0.75; 95% CI: 0.60, 0.94; P-trend = 0.03), CVD mortality (HR: 0.63; 95% CI: 0.42, 0.94; P-trend = 0.03), and CHD events (HR: 0.66; 95% CI: 0.45, 0.97; P-trend = 0.05) but not CVD events (HR: 0.79; 95% CI: 0.60, 1.05; P-trend = 0.16) after adjustment for sociodemographic, behavioral, and cardiovascular risk factors. The HDI was not significantly associated with any of the outcomes. The EDI appears to be more useful than the HDI for assessing diet quality in relation to CVD and morality risk in older men. Encouraging older adults to adhere to the guidelines inherent in the EDI criteria may have public health benefits.

HFE genotypes, haemochromatosis diagnosis and clinical outcomes at age 80 years: a prospective cohort study in the UK Biobank.

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.

Proteomic aging clock (PAC) predicts age-related outcomes in middle-aged and older adults.

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.

Proteomic aging clock (PAC) predicts age-related outcomes in middle-aged and older adults.

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.

A proteomic signature of healthspan.

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.

Repeat genital Chlamydia trachomatis testing rates in young adults in England, 2010.

OBJECTIVES: To explore patterns of repeat chlamydia testing among young people in England and factors associated with testing positive at repeat test. METHODS: We analysed chlamydia testing among 15 to 24-year-olds in England in a single calendar year (2010) using data from the genitourinary medicine clinic activity dataset (GUMCAD) and tests reported through the National Chlamydia Screening Programme (NCSP). Case records were linked using patient clinic numbers (GUMCAD), or by matching date of birth, gender and postcode (NCSP). Individuals could not be linked between datasets. The incidence of repeat testing was estimated using survival analysis. Risk factors for testing positive at repeat test were explored using multivariable logistic regression. RESULTS: 1 235 058 tests in the NCSP dataset and 502 095 in GUMCAD were included. The incidence of repeat testing was 18.4 and 26.1 per 100 person years in the NCSP dataset and GUMCAD respectively. Among NCSP repeat tests, the proportion testing positive was higher in those reporting recent change of sexual partner (adjusted OR males 1.44; females 1.52), and among those with a positive compared to a negative baseline test (adjusted OR males 2.57; females 1.95). CONCLUSIONS: We observed moderate levels of repeat testing within a year. Considering the frequency of partner change among young people, more could be done to encourage re-testing upon change of sexual partner. Increasing re-testing following a positive test could probably identify unresolved or repeat infections that may otherwise go untreated. Work to establish the optimum approach to repeat testing in England is now warranted.

Hemochromatosis Genetic Variants and Musculoskeletal Outcomes: 11.5-Year Follow-Up in the UK Biobank Cohort Study.

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.

Hereditary Hemochromatosis Variant Associations with Incident Nonliver Malignancies: 11-Year Follow-up in UK Biobank.

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.

Genetic associations for two biological age measures point to distinct aging phenotypes.

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.

Hemochromatosis Mutations, Brain Iron Imaging, and Dementia in the UK Biobank Cohort.

BACKGROUND: Brain iron deposition occurs in dementia. In European ancestry populations, the HFE p.C282Y variant can cause iron overload and hemochromatosis, mostly in homozygous males. OBJECTIVE: To estimate p.C282Y associations with brain MRI features plus incident dementia diagnoses during follow-up in a large community cohort. METHODS: UK Biobank participants with follow-up hospitalization records (mean 10.5 years). MRI in 206 p.C282Y homozygotes versus 23,349 without variants, including T2* measures (lower values indicating more iron). RESULTS: European ancestry participants included 2,890 p.C282Y homozygotes. Male p.C282Y homozygotes had lower T2* measures in areas including the putamen, thalamus, and hippocampus, compared to no HFE mutations. Incident dementia was more common in p.C282Y homozygous men (Hazard Ratio HR = 1.83; 95% CI 1.23 to 2.72, p = 0.003), as was delirium. There were no associations in homozygote women or in heterozygotes. CONCLUSION: Studies are needed of whether early iron reduction prevents or slows related brain pathologies in male HFE p.C282Y homozygotes.