Common conditions associated with hereditary haemochromatosis genetic variants: cohort study in UK Biobank

This is the final published version. Available from BMJ publishing group via the DOI in this record.Data are available on application to the UK Biobank (www.ukbiobank.ac.uk/register-apply).Objective To compare prevalent and incident morbidity and mortality between those with the HFE p.C282Y genetic variant (responsible for most hereditary haemochromatosis type 1) and those with no p.C282Y mutations, in a large UK community sample of European descent. Design Cohort study. Setting 22 centres across England, Scotland, and Wales in UK Biobank (2006-10). Participants 451 243 volunteers of European descent aged 40 to 70 years, with a mean follow-up of seven years (maximum 9.4 years) through hospital inpatient diagnoses and death certification. Main outcome measure Odds ratios and Cox hazard ratios of disease rates between participants with and without the haemochromatosis mutations, adjusted for age, genotyping array type, and genetic principal components. The sexes were analysed separately as morbidity due to iron excess occurs later in women. Results Of 2890 participants homozygous for p.C282Y (0.6%, or 1 in 156), haemochromatosis was diagnosed in 21.7% (95% confidence interval 19.5% to 24.1%, 281/1294) of men and 9.8% (8.4% to 11.2%, 156/1596) of women by end of follow-up. p.C282Y homozygous men aged 40 to 70 had a higher prevalence of diagnosed haemochromatosis (odds ratio 411.1, 95% confidence interval 299.0 to 565.3, P<0.001), liver disease (4.30, 2.97 to 6.18, P<0.001), rheumatoid arthritis (2.23, 1.51 to 3.31, P<0.001), osteoarthritis (2.01, 1.71 to 2.36, P<0.001), and diabetes mellitus (1.53, 1.16 to 1.98, P=0.002), versus no p.C282Y mutations (n=175 539). During the seven year follow-up, 15.7% of homozygous men developed at least one incident associated condition versus 5.0% (P<0.001) with no p.C282Y mutations (women 10.1% v 3.4%, P<0.001). Haemochromatosis diagnoses were more common in p.C282Y/p.H63D heterozygotes, but excess morbidity was modest. Conclusions In a large community sample, HFE p.C282Y homozygosity was associated with substantial prevalent and incident clinically diagnosed morbidity in both men and women. As p.C282Y associated iron overload is preventable and treatable if intervention starts early, these findings justify re-examination of options for expanded early case ascertainment and screening.Medical Research Council (MRC)University of Exeter Medical SchoolUniversity of Conneticut Health CentreNational Centre for AgeingPublic Health Englan

Outcomes of Treated Hypertension at Age 80 and Older: Cohort Analysis of 79,376 Individuals

This is the final version of the article. Available from Wiley via the DOI in this record.OBJECTIVES: To estimate outcomes according to attained blood pressure (BP) in the oldest adults treated for hypertension in routine family practice. DESIGN: Cohort analysis of primary care inpatient and death certificate data for individuals with hypertension. SETTING: Primary care practices in England (Clinical Practice Research Datalink). PARTICIPANTS: Individuals aged 80 and older taking antihypertensive medication and free of dementia, cancer, coronary heart disease, stroke, heart failure, and end-stage renal failure at baseline. MEASUREMENTS: Outcomes were mortality, cardiovascular events, and fragility fractures. Systolic BP (SBP) was grouped in 10-mmHg increments from less than 125 to 185 mmHg or more (reference 145–154 mmHg). RESULTS: Myocardial infarction hazards increased linearly with increasing SBP, and stroke hazards increased for SBP of 145 mmHg or greater, although lowest mortality was in individuals with SBP of 135 to 154 mmHg. Mortality of the 13.1% of patients with SBP less than 135 mmHg was higher than that of the reference group (Cox hazard ratio=1.25, 95% confidence interval=1.19–1.31; equating to one extra death per 12.6 participants). This difference in mortality was consistent over short- and long-term follow-up; adjusting for diastolic BP did not change the risk. Incident heart failure rates were higher in those with SBP less than 125 mmHg than in the reference group. CONCLUSION: In routine primary care, SBP less than 135 mmHg was associated with greater mortality in the oldest adults with hypertension and free of selected potentially confounding comorbidities. Although important confounders were accounted for, observational studies cannot exclude residual confounding. More work is needed to establish whether unplanned SBPs less than 135 mmHg in older adults with hypertension may be a useful clinical sign of poor prognosis, perhaps requiring clinical review of overall care.This work was supported in part by the National Institute for Health Research (NIHR) School for Public Health Research Ageing Well programme

Synaptic Innervation Density Is Regulated by Neuron-Derived BDNF

AbstractIn this report, we have examined the role of neuron-derived BDNF at an accessible synapse, that of preganglionic neurons onto their sympathetic neuron targets. Developing and mature sympathetic neurons synthesize BDNF, and preganglionic neurons express the full-length BDNF/TrkB receptor. When sympathetic neuron-derived BDNF is increased 2- to 4-fold in transgenic mice, preganglionic cell bodies and axons hypertrophy, and the synaptic innervation to sympathetic neurons is increased. Conversely, when BDNF synthesis is eliminated in BDNF −/− mice, preganglionic synaptic innervation to sympathetic neurons is decreased. Together these results indicate that variations in neuronal neurotrophin synthesis directly regulate neuronal circuitry by selectively modulating synaptic innervation density

Sarcopenia and Variation in the Human Leukocyte Antigen Complex

Background: Aging is characterized by chronic inflammation plus loss of muscle mass and strength, termed sarcopenia. Human leukocyte antigen (HLA) types are drivers of autoimmune disease, although with limited penetrance. We tested whether autoimmune diagnoses are associated with sarcopenia, and whether HLA types and related genetic variants are associated with sarcopenia in autoimmune disease-free older people. Methods: Data were collected from 181,301 UK Biobank European descent volunteers aged 60-70 with measured hand grip strength and impedance. Logistic regression analysis estimated HLA type and sarcopenia associations, adjusted for confounders and multiple testing. Results: Having any autoimmune diagnosis was associated with sarcopenia (odds ratio [OR] 1.83, 95% confidence interval (CI) 1.74-1.92, p = 4.0*10-125). After excluding autoimmune diagnoses, 6 of 100 HLA types (allele frequency >1%) were associated with sarcopenia (low grip strength and muscle mass). Having two HLA-DQA1*03:01 alleles increased odds of sarcopenia by 19.3% (OR 1.19, CI 1.09-1.29, p = 2.84*10-5), compared to no alleles. Having ≥6 of the 12 HLA alleles increased sarcopenia odds by 23% (OR 1.23, CI 1.12-1.35, p = 7.28*10-6). Of 658 HLA region non-coding genetic variants previously implicated in disease, 4 were associated with sarcopenia, including rs41268896 and rs29268645 (OR 1.08, CI 1.05-1.11, p = 1.06*10-8 and 1.07, CI 1.04-1.09, p = 1.5*10-6, respectively). Some HLA associations with sarcopenia were greater in female participants. Conclusion: Autoimmune diagnoses are strongly associated with sarcopenia in 60- to 70-year olds. Variation in specific HLA types and non-coding single nucleotide polymorphisms is also associated with sarcopenia in older carriers free of diagnosed autoimmune diseases. Patients with sarcopenia might benefit from targeted treatment of autoimmune processes.This article is freely available via NHS OpenAthens. Click on the Publisher URL to access it via the publisher's site.This work was generously funded by an award to D.M. by the Medical Research Council (http://dx.doi.org/10.13039/501100000265) MR/M023095/1. D.M. and L.C.P. were supported by the University of Exeter Medical School. (http://dx.doi.org/10.13039/501100000737) Input from C.-L.K. and G.K. was supported by the University of Connecticut Health Center http://dx.doi.org/10.13039/100007710). L.F. was supported by the Intramural Research Program of the National Institute on Aging, U.S. National Institutes of Health (http://dx.doi.org/10.13039/100000002). This work was supported by an IPA Assignment Agreement with Dr. Luigi Ferrucci at the National Institute on Aging (http://dx.doi.org/10.13039/100000002) (#20170526

High-throughput field imaging and basic image analysis in a wheat breeding programme

Visual assessment of colour-based traits plays a key role within field-crop breeding programmes, though the process is subjective and time-consuming. Digital image analysis has previously been investigated as an objective alternative to visual assessment for a limited number of traits, showing suitability and slight improvement to throughput over visual assessment. However, easily adoptable, field-based high-throughput methods are still lacking. The aim of the current study was to produce a high-throughput digital imaging and analysis pipeline for the assessment of colour-based traits within a wheat breeding programme. This was achieved through the steps of (i) a proof-of-concept study demonstrating basic image analysis methods in a greenhouse, (ii) application of these methods to field trials using hand-held imaging, and (iii) developing a field-based high-throughput imaging infrastructure for data collection. The proof of concept study showed a strong correlation (r = 0.95) between visual and digital assessments of wheat physiological yellowing (PY) in a greenhouse environment, with both scores having similar heritability (H2 = 0.85 and 0.76, respectively). Digital assessment of hand-held field images showed strong correlations to visual scores for PY (r = 0.61 and 0.78), senescence (r = 0.74 and 0.75) and Septoria tritici blotch (STB; r = 0.76), with greater heritability of digital scores, excluding STB. Development of the high-throughput imaging infrastructure allowed for images of field plots to be collected at a rate of 7,400 plots per hour. Images of an advanced breeding trial collected with this system were analysed for canopy cover at two time-points, with digital scores correlating strongly to visual scores (r = 0.88 and 0.86) and having similar or greater heritability. This study details how high-throughput digital phenotyping can be applied to colour-based traits within field trials of a wheat breeding programme. It discusses the logistics of implementing such systems with minimal disruption to the programme, provides a detailed methodology for the basic image analysis methods utilized, and has potential for application to other field-crop breeding or research programmes.James Walter, James Edwards, Jinhai Cai, Glenn McDonald, Stanley J. Miklavcic, and Haydn Kuche

HYPER-RESPONSIVENESS OF ALDOSTERONE TO METOCLOPRAMIDE IN ALDOSTERONISM

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73101/1/j.1365-2265.1982.tb02761.x.pd