Biology subjects

Wareham, N.

Publications and source records attributed to Wareham, N..

6 recordsLinked to original sources

bioRxiv2024

Damaging mutations in LXRα uncouple lipogenesis from hepatotoxicity and implicate hepatic cholesterol sensing in human liver health

The nuclear receptor Liver X Receptor- (LXR) activates lipogenic gene expression in hepatocytes. Its inhibition has therefore been proposed as a strategy to treat metabolic-dysfunction-associated steatotic liver disease (MASLD). In order to understand the impact of reducing LXR activity on human health we first examined the association between the carriage of rare loss of function mutations in NR1H3 (encoding LXR) and metabolic and hepatic phenotypes. We identified 63 rare predicted damaging variants in the ligand binding domain of LXR in 454,787 participants in UK Biobank. On functional characterisation, 42 of these were found to be severely impaired. Consistent with loss of the lipogenic actions of LXR, carriers of damaging mutations in LXR had reduced serum triglycerides ({beta}=-0.13 s.d. {+/-}0.03, P=2.7x10-5, N(carriers)=971). Surprisingly, these carriers also had elevated concentrations of serum liver enzymes (e.g. ALT: {beta}=0.17s.d. {+/-}0.03, P=1.1x10-8, N(carriers)=972) with a 35% increased risk of clinically significant elevations in ALT (OR=1.32, 95%CI:1.15-1.53, P=1.2x10-4, N(carriers)=972), suggestive of hepatotoxicity. We generated a knock-in mouse carrying one of the most severely damaging mutations (Nr1h3 p.W441R) which we demonstrated to have dominant negative properties. Homozygous knock-in mice rapidly developed severe hepatitis and fibrotic liver injury following exposure to western diet despite markedly reduced steatosis, liver triglycerides and lipogenic gene expression. This phenotype was completely rescued by viral over-expression of wildtype LXR specifically in hepatocytes, indicating a cell-autonomous effect of the mutant on hepatocyte health. While homozygous LXR knockout mice showed some evidence of hepatocyte injury under similar dietary conditions, the phenotype of the LXRW441R/W441R mouse was much more severe, suggesting that dominant negative mutations that actively co-repress target genes can result in pathological impacts significantly more severe than those seen with simple absence of the receptor. In summary, our results show that loss of function mutations in LXR occur in at least 1/450 people and are associated with evidence of liver dysfunction. These findings implicate LXR in the maintenance of human liver health, identify a new murine model of rapidly progressive fibrotic liver disease and caution against LXR antagonism as a therapeutic strategy for MASLD.

genetics↗

bioRxiv2019

Long-Term Exposure to Elevated Lipoprotein(a) Levels, Parental Lifespan and Risk of Mortality

BackgroundElevated Lipoprotein(a) (Lp[a]) levels are associated with a broad range of atherosclerotic cardiovascular diseases (CVD). The impact of high Lp(a) levels on human longevity is however controversial. Our objectives were to determine whether genetically-determined Lp(a) levels are associated with parental lifespan and to assess the association between measured and genetically-determined Lp(a) levels and long-term all-cause and cardiovascular mortality.\n\nMethodsWe determined the association between a genetic risk score of 26 single nucleotide polymorphisms weighted for their impact on Lp(a) levels (wGRS) and parental lifespan (at least one long-lived parent; father still alive and older than 90 or fathers age of death [≥]90 or mother still alive and older than 93 or mothers age of death [≥]93) in 139,362 participants from the UK Biobank. A total of 17,686 participants were considered as having high parental lifespan. We also investigated the association between Lp(a) levels and all-cause and cardiovascular mortality in 18,720 participants from the EPIC-Norfolk study.\n\nResultsIn the UK Biobank, increases in the wGRS (weighted for a 50 mg/dL increase in Lp(a) levels) were inversely associated with a high parental lifespan (odds ratio=0.92, 95% confidence interval [CI]=0.89-0.94, p=2.7x10-8). During the 20-year follow-up of the EPIC-Norfolk study, 5686 participants died (2412 from CVD-related causes). Compared to participants with Lp(a) levels <50 mg/dL, those with Lp(a) levels [≥]50 mg/dL had an increased hazard ratio (HR) for all-cause (HR=1.17, 95% CI=1.08-1.27) and cardiovascular (HR=1.54, 95% CI=1.37-1.72) mortality. Compared to individuals with Lp(a) levels below the 50th percentile of the Lp(a) distribution (in whom event rates were 29.8% and 11.3%, respectively for all-cause and cardiovascular mortality), those with Lp(a) levels equal or above the 95th percentile of the population distribution ([≥]70 mg/dL) had HRs of 1.22 (95% CI=1.09-1.37, event rate 37.5%) and 1.71 (95% CI=1.46-2.00, event rate 20.0%), for all-cause mortality and cardiovascular mortality, respectively.\n\nConclusionsResults of this study suggest a potentially causal effect of Lp(a) on human longevity, support the use of parental lifespan as a tool to study the genetic determinants of human longevity, and provide a rationale for a trial of Lp(a)-lowering therapy in individuals with high Lp(a) levels.

genetics↗

bioRxiv2019

Diurnal profiles of physical activity and postures derived from wrist-worn accelerometry in UK adults

BackgroundWrist-worn accelerometry is the commonest objective method for measuring physical activity in large-scale epidemiological studies. Research-grade devices capture raw triaxial acceleration which, in addition to quantifying movement, facilitates assessment of orientation relative to gravity. No population-based study has yet described the interrelationship and variation of these features by time and personal characteristics. Methods2043 UK adults (35-65years) wore an accelerometer on the non-dominant wrist and a chest-mounted combined heart-rate-and-movement sensor for 7days free-living. From raw (60Hz) wrist acceleration, we derived movement (non-gravity acceleration) and pitch and roll (arm) angles relative to gravity. We inferred physical activity energy expenditure (PAEE) from combined sensing and sedentary time from approximate horizontal arm-angle coupled with low movement. ResultsMovement differences by time-of-day and day-of-week were associated with arm-angles; more movement in downward arm-positions. Mean(SD) movement was similar between sexes [~]31(42)mg, despite higher PAEE in men, 53(22) vs 48(19)J{middle dot}min-1{middle dot}kg-1. Women spent longer with the arm pitched >0{degrees} (53% vs 36%) and less time at <0{degrees} (37% vs 53%). Diurnal pitch was 2.5-5{degrees} above and 0-7.5{degrees} below horizontal during night and daytime, respectively; corresponding roll angles were [~]0{degrees} and [~]20{degrees} (thumb-up). Differences were more pronounced in younger participants. All diurnal profiles indicated later wake-times on weekends. Daytime pitch was closer to horizontal on weekdays; roll was similar. Sedentary time was higher (17 vs 15hours/day) in obese vs normal-weight individuals. ConclusionsMore movement occurred in arm positions below horizontal, commensurate with activities including walking. Findings suggest time-specific population differences in behaviours by age, sex, and BMI.

epidemiology↗

bioRxiv2019

Descriptive epidemiology of energy expenditure in the UK: Findings from the National Diet and Nutrition Survey 2008 to 2015

BackgroundLittle is known about population levels of energy expenditure as national surveillance systems typically employ only crude measures. The National Diet and Nutrition Survey (NDNS) in the UK measures energy expenditure in a 10% subsample by gold-standard doubly-labelled water (DLW). MethodsDLW-subsample participants from the NDNS (383 males, 387 females) aged 4-91yrs were recruited between 2008 and 2015. Height and weight were measured, and bodyfat percentage was estimated by deuterium dilution. ResultsAbsolute Total Energy Expenditure (TEE) increases steadily throughout childhood, ranging from 6.3 and 7.2 MJ/day in 4-7yr-old to 9.9 and 11.8 MJ/day for 14-16yr-old girls and boys, respectively. TEE peaked in 17-27yr-old women (10.9 MJ/day) and 28-43yr-old men (14.4 MJ/day), before decreasing gradually in old age. Physical Acitivty Energy Expenditure (PAEE) declines steadily with age from childhood (87.7 kJ/day/kg in 4-7yr olds) through to old age (38.9 kJ/day/kg in 71-91yr olds). Bodyfat percentage was strongly inversely associated with PAEE throughout life, irrespective of expressing PAEE relative to bodymass or fat-free mass. Compared to females with <30% bodyfat, females >40% recorded 28 kJ/day/kg and 17 kJ/day/kg fat-free mass less PAEE in analyses adjusted for age, geographical region, and time of assessment. Similarly, compared to males with <25% bodyfat, males >35% recorded 26 kJ/day/kg and 10 kJ/day/kg fat-free mass less PAEE. ConclusionsThis first nationally representative study reports levels of human energy expenditure as measured by gold-standard methodology; values may serve as reference for other population studies. Age, sex and body composition are main biological determinants of energy expenditure. Key messagesO_LIFirst nationally representative study of human energy expenditure, covering the UK in the period 2008-2015 C_LIO_LITotal Energy Expenditure (MJ/day) increases steadily with age thoughout childhood and adolescence, peaks in the 3rd decade of life in women and 4th decade of life in men, before decreasing gradually in old age C_LIO_LIPhysical Acitivty Energy Expenditure (kJ/day/kg or kJ/day/kg fat-free mass) declines steadily with age from childhood to old age, more steeply so in males C_LIO_LIBodyfat percentage is strongly inversely associated with physical activity energy expenditure C_LI

epidemiology↗

bioRxiv2019

Genetic predisposition to mosaic Y chromosome loss in blood is associated with genomic instability in other tissues and susceptibility to non-haematological cancers

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism, yet our knowledge of the causes and consequences of this is limited. Using a newly developed approach, we estimate that 20% of the UK Biobank male population (N=205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes involved in cell-cycle regulation, cancer susceptibility, somatic drivers of tumour growth and cancer therapy targets. Genetic susceptibility to LOY is associated with non-haematological health outcomes in both men and women, supporting the hypothesis that clonal haematopoiesis is a biomarker of genome instability in other tissues. Single-cell RNA sequencing identifies dysregulated autosomal gene expression in leukocytes with LOY, providing insights into how LOY may confer cellular growth advantage. Collectively, these data highlight the utility of studying clonal mosaicism to uncover fundamental mechanisms underlying cancer and other ageing-related diseases.

genetics↗

bioRxiv2018

Estimating energy expenditure from wrist and thigh accelerometry in free-living adults: a doubly labelled water study

BackgroundMany large studies have implemented wrist or thigh accelerometry to capture physical activity, but the accuracy of these measurements to infer Activity Energy Expenditure (AEE) and consequently Total Energy Expenditure (TEE) has not been demonstrated. The purpose of this study was to assess the validity of acceleration intensity at wrist and thigh sites as estimates of AEE and TEE under free-living conditions using a gold-standard criterion.\n\nMethodsMeasurements for 193 UK adults (105 men, 88 women, aged 40-66 years, BMI 20.4-36.6 kg{middle dot}m-2) were collected with triaxial accelerometers worn on the dominant wrist, non-dominant wrist and thigh in free-living conditions for 9-14 days. In a subsample (50 men, 50 women) TEE was simultaneously assessed with doubly labelled water (DLW). AEE was estimated from non-dominant wrist using an established estimation model, and novel models were derived for dominant wrist and thigh in the non-DLW subsample. Agreement with both AEE and TEE from DLW was evaluated by mean bias, Root Mean Squared Error (RMSE) and Pearson correlation.\n\nResultsMean TEE and AEE derived from DLW was 11.6 (2.3) MJ{middle dot}day-1 and 49.8 (16.3) kJ{middle dot}day-1{middle dot}kg-1. Dominant and non-dominant wrist acceleration were highly correlated in free-living (r=0.93), but less so with thigh (r=0.73 and 0.66, respectively). Estimates of AEE were 48.6 (11.8) kJ{middle dot}day-1{middle dot}kg-1 from dominant wrist, 48.6 (12.3) from non-dominant wrist, and 46.0 (10.1) from thigh; these agreed strongly with AEE (RMSE ~12.2 kJ{middle dot}day-1{middle dot}kg-1, r ~0.71) with small mean biases at the population level (~6%). Only the thigh estimate bias was statistically significantly different from the criterion. When combining these AEE estimates with estimated REE, agreement was stronger with the criterion (RMSE ~1.0 MJ{middle dot}day-1, r ~0.90). Conclusions: In UK adults, acceleration measured at either wrist or thigh can be used to estimate population levels of AEE and TEE in free-living conditions with high precision.

epidemiology↗