Carmel Moore

Adherence to cardiovascular therapy: a meta-analysis of prevalence and clinical consequences

AIMS The aim of this study was to determine the extent to which adherence to individual vascular medications, assessed by different methods, influences the absolute and relative risks (RRs) of cardiovascular disease (CVD) and all-cause mortality. METHODS AND RESULTS We performed a systematic review and meta-analysis of prospective epidemiological studies (cohort, nested case-control, or clinical trial) identified through electronic searches using MEDLINE, Web of Science, EMBASE, and Cochrane databases, involving adult populations (≥ 18 years old) and reporting risk estimates of cardiovascular medication adherence with any CVD (defined as any fatal or non-fatal coronary heart disease, stroke or sudden cardiac death) and/or all-cause mortality (defined as mortality from any cause) outcomes. Relative risks were combined using random-effects models. Forty-four unique prospective studies comprising 1 978 919 non-overlapping participants, with 135 627 CVD events and 94 126 cases of all-cause mortality. Overall, 60% (95% CI: 52-68%) of included participants had good adherence (adherence ≥ 80%) to cardiovascular medications. The RRs (95% CI) of development of CVD in those with good vs. poor (<80%) adherence were 0.85 (0.81-0.89) and 0.81 (0.76-0.86) for statins and antihypertensive medications, respectively. Corresponding RRs of all-cause mortality were 0.55 (0.46-0.67) and 0.71 (0.64-0.78) for good adherence to statins and antihypertensive agents. These associations remained consistent across subgroups representing different study characteristics. Estimated absolute risk differences for any CVD associated with poor medication adherence were 13 cases for any vascular medication, 9 cases for statins and 13 cases for antihypertensive agents, per 100 000 individuals per year. CONCLUSION A substantial proportion of people do not adhere adequately to cardiovascular medications, and the prevalence of suboptimal adherence is similar across all individual CVD medications. Absolute and relative risk assessments demonstrate that a considerable proportion of all CVD events (~9% in Europe) could be attributed to poor adherence to vascular medications alone, and that the level of optimal adherence confers a significant inverse association with subsequent adverse outcomes. Measures to enhance adherence to help maximize the potentials of effective cardiac therapies in the clinical setting are urgently required.

Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders

By analyzing the whole-exome sequences of 4,264 schizophrenia cases, 9,343 controls and 1,077 trios, we identified a genome-wide significant association between rare loss-of-function (LoF) variants in SETD1A and risk for schizophrenia (P = 3.3 × 10−9). We found only two heterozygous LoF variants in 45,376 exomes from individuals without a neuropsychiatric diagnosis, indicating that SETD1A is substantially depleted of LoF variants in the general population. Seven of the ten individuals with schizophrenia carrying SETD1A LoF variants also had learning difficulties. We further identified four SETD1A LoF carriers among 4,281 children with severe developmental disorders and two more carriers in an independent sample of 5,720 Finnish exomes, both with notable neuropsychiatric phenotypes. Together, our observations indicate that LoF variants in SETD1A cause a range of neurodevelopmental disorders, including schizophrenia. Combining these data with previous common variant evidence, we suggest that epigenetic dysregulation, specifically in the histone H3K4 methylation pathway, is an important mechanism in the pathogenesis of schizophrenia.

The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease

Summary Many common variants have been associated with hematological traits, but identification of causal genes and pathways has proven challenging. We performed a genome-wide association analysis in the UK Biobank and INTERVAL studies, testing 29.5 million genetic variants for association with 36 red cell, white cell, and platelet properties in 173,480 European-ancestry participants. This effort yielded hundreds of low frequency (<5%) and rare (<1%) variants with a strong impact on blood cell phenotypes. Our data highlight general properties of the allelic architecture of complex traits, including the proportion of the heritable component of each blood trait explained by the polygenic signal across different genome regulatory domains. Finally, through Mendelian randomization, we provide evidence of shared genetic pathways linking blood cell indices with complex pathologies, including autoimmune diseases, schizophrenia, and coronary heart disease and evidence suggesting previously reported population associations between blood cell indices and cardiovascular disease may be non-causal.

Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease

Primary sclerosing cholangitis (PSC) is a rare progressive disorder leading to bile duct destruction; ∼75% of patients have comorbid inflammatory bowel disease (IBD). We undertook the largest genome-wide association study of PSC (4,796 cases and 19,955 population controls) and identified four new genome-wide significant loci. The most associated SNP at one locus affects splicing and expression of UBASH3A, with the protective allele (C) predicted to cause nonstop-mediated mRNA decay and lower expression of UBASH3A. Further analyses based on common variants suggested that the genome-wide genetic correlation (rG) between PSC and ulcerative colitis (UC) (rG = 0.29) was significantly greater than that between PSC and Crohns disease (CD) (rG = 0.04) (P = 2.55 × 10−15). UC and CD were genetically more similar to each other (rG = 0.56) than either was to PSC (P < 1.0 × 10−15). Our study represents a substantial advance in understanding of the genetics of PSC.

Comparative validity of vitamin C and carotenoids as indicators of fruit and vegetable intake: a systematic review and meta-analysis of randomised controlled trials.

Circulating vitamin C and carotenoids are used as biomarkers of fruit and vegetable intake in research, but their comparative validity has never been meta-analysed. PubMed, EMBASE, CENTRAL, CINAHL and Web of Science were systematically searched up to December 2013 for randomised trials of different amounts of fruit and vegetable provision on changes in blood concentrations of carotenoids or vitamin C. Reporting followed PRISMA guidelines. Evidence quality was assessed using the GRADE system. Random effects meta-analysis combined estimates and meta-regression tested for sub-group differences. In all, nineteen fruit and vegetable trials (n 1382) measured at least one biomarker, of which nine (n 667) included five common carotenoids and vitamin C. Evidence quality was low and between-trial heterogeneity (I 2) ranged from 74% for vitamin C to 94 % for α-carotene. Groups provided with more fruit and vegetables had increased blood concentrations of vitamin C, α-carotene, β-carotene, β-cryptoxanthin and lutein but not lycopene. However, no clear dose-response effect was observed. Vitamin C showed the largest between-group difference in standardised mean change from the pre-intervention to the post-intervention period (smd 0·94; 95% CI 0·66, 1·22), followed by lutein (smd 0·70; 95% CI 0·37, 1·03) and α-carotene (smd 0·63; 95% CI 0·25, 1·01), but all CI were overlapping, suggesting that none of the biomarkers responded more than the others. Therefore, until further evidence identifies a particular biomarker to be superior, group-level compliance to fruit and vegetable interventions can be indicated equally well by vitamin C or a range of carotenoids. High heterogeneity and a lack of dose-response suggest that individual-level biomarker responses to fruit and vegetables are highly variable.

Efficiency and safety of varying the frequency of whole blood donation: randomised trial of 45,000 donors

EDA received research funding from the UK Medical Research Council, British Heart Foundation, National Institute for Health Research, and NHSBT during the conduct of the study. SGT received grants from the UK Medical Research Council, British Heart Foundation, National Institute for Health Research, and NHSBT during the conduct of the study. SK received grants from the UK Medical Research Council, British Heart Foundation, National Institute for Health Research, and NHSBT during the conduct of the study. JD has received research funding from the UK Medical Research Council, British Heart Foundation, National Institute for Health Research, NHSBT, European Commission, European Research Council, Merck Sharpe & Dohme UK, Biogen, Novartis, Pfizer, Merck, and Wellcome Trust during the conduct of the study. All other members of the writing committee declare no competing interests. The trial was funded by NHSBT and the NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024). The trial’s coordinating centre at the Department of Public Health and Primary Care at the University of Cambridge, Cambridge, UK, has received core support from the UK Medical Research Council (G0800270), British Heart Foundation (SP/09/002), and the NIHR Cambridge Biomedical Research Centre. Investigators at the University of Oxford, Oxford, UK, have been supported by the Research and Development Programme of NHSBT, the NHSBT Howard Ostin Trust Fund, and the NIHR Oxford Biomedical Research Centre through the programme grant NIHR-RP-PG-0310-1004.