Nicholas Wareham

IntroductionBlood pressure (BP) is a highly heritable trait with over 2000 underlying genomic loci identified to date. Although the kidney plays a key role, little is known about specific cell types involved in the genetic regulation of BP.MethodsHere, we applied stratified linkage disequilibrium score (LDSC) regression to connect BP genome-wide association studies (GWAS) results to specific cell types of the mature human kidney. We used the largest single-stage BP genome-wide analysis to date, including up to 1,028,980 adults of European ancestry, and single-cell transcriptomic data from 14 mature human kidneys, with mean age of 41 years.ResultsOur analyses prioritized myofibroblasts and endothelial cells, among the total of 33 annotated cell type, as specifically involved in BP regulation (P < 0.05/33, i.e., 0.001515). Enrichment of heritability for systolic BP (SBP) was observed in myofibroblast cells in mature …

To better understand sex differences in human health and disease, we conducted a systematic, large-scale investigation of sex differences in the genetic regulation of the plasma proteome (>5,000 targets), including their disease relevance. Plasma levels of two-thirds of protein targets differed significantly by sex. In contrast, genetic effects on protein targets were remarkably similar, with very few protein quantitative loci (pQTLs, n=74) showing significant sex-differential effects (for 3.9% and 0.3% of protein targets from antibody- and aptamer-based platforms, respectively). Most of these 74 pQTLs represented directionally concordant effects significant in both sexes, with only 21 pQTLs showing evidence of sexual dimorphism, i.e. effects restricted to one sex (n=20) or with opposite directions between sexes (n=1 for CDH15). None of the sex-differential pQTLs translated into sex-differential disease risk. Our results demonstrate strong similarity in the genetic regulation of the plasma proteome between sexes with important implications for genetically guided drug target discovery and validation.

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses …

The ERFC co-ordinating centre was underpinned by programme grants from the British Heart Foundation (SP/09/002; RG/13/13/30194; RG/18/13/33946), BHF Centre of Research Excellence (RE/18/1/34212), the UK Medical Research Council (MR/L003120/1), and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC-1215-20014), with project-specific support received from the UK NIHR [*], British United Provident Association UK Foundation and an unrestricted educational grant from GlaxoSmithKline. A variety of funding sources have supported recruitment, follow-up, and laboratory measurements in the studies contributing data to the ERFC, which are listed on the ERFC website (www. phpc. cam. ac. uk/ceu/erfc/list-of-studies). National Science Centre, Poland (grant 2018/29/B/NZ7/02118 (for A. Pająk). This study was funded by EU H2020 grant 692145, Estonian Research Council Grant IUT20-60, IUT24-6, PUT (PRG687) and European Union through the European Regional Development Fund Project No. 2014-2020.4. 01.15-0012 GENTRANSMED and 2014-2020.4. 01.16-0125; Data analysis was carried out in part in the High-Performance Computing Center of University of Tartu. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 101016775 (INTERVENE).

Background Post-COVID complications are emerging as a global public health crisis. Effective prevention strategies are needed to inform patients, clinicians and policy makers, and to reduce their cumulative burden. We aimed to investigate whether a habitual healthy lifestyle predated pandemic is associated with lower risks of multisystem sequelae and other adverse outcomes of COVID-19, and whether the potential protective effects are independent of pre-existing comorbidities. Methods The prospective population-based cohort study enrolled participants with SARS-CoV-2 infection confirmed by a positive polymerase chain reaction test result between March 1, 2020, and March 1, 2022. Participants with no history of the related outcome one year before infection were included and followed up for 210 days. Exposures included ten modifiable healthy lifestyle factors including past or never smoking, moderate alcohol intake (≤4 times week), body mass index <30 kg/m2, at least 150 minutes of moderate or 75 minutes of vigorous physical activity per week, less sedentary time (<4 hours per day), healthy sleep duration (7-9 hours per day), adequate intake of fruit and vegetables (≥400 g/day), adequate oily fish intake (≥1 portion/week), moderate intake of red meat (≤4 portions week) and processed meat (≤4 portions week). Outcomes included multisystem COVID-19 sequelae (consisting of 75 diseases/symptoms in 10 organ systems), death, and hospital admission following SARS-CoV-2 infection, confirmed by hospital inpatient and death records. Risk was reported in relative scale (hazard ratio [HR]) and absolute scale (absolute risk reduction …

BACKGROUND It is unknown whether dietary intake of polyunsaturated fatty acids (PUFA) modifies the cardiovascular disease (CVD) risk associated with a family history of CVD. We assessed interactions between biomarkers of low PUFA intake and a family history in relation to long-term CVD risk in a large consortium. METHODS Blood and tissue PUFA data from 40 885 CVD-free adults were assessed. PUFA levels ≤25th percentile were considered to reflect low intake of linoleic, alpha-linolenic, and eicosapentaenoic/docosahexaenoic acids (EPA/DHA). Family history was defined as having ≥1 first-degree relative who experienced a CVD event. Relative risks with 95% CI of CVD were estimated using Cox regression and meta-analyzed. Interactions were assessed by analyzing product terms and calculating relative excess risk due to interaction. RESULTS After multivariable adjustments, a significant …

Aims Better understanding of sex differences in cardiovascular disease (CVD) is essential in tailoring appropriate preventative strategies. Using a large population-based study with follow-up >25 years, we aimed to determine sex-specific lifetime risks of incident CVD and cardiovascular (CV) mortality amongst populations with and without prevalent CVD. Methods and results Participants were drawn from the European Prospective Investigation into Cancer-Norfolk and followed up for a median of 26.2 years. Sex-specific lifetime risks were ascertained accounting for the competing risk of death. Models were adjusted for ethnicity and time-updated covariates: material deprivation, CV risk factors, lifestyle factors, comorbidities, and medication. A total of 23 859 participants [54.5% women; mean age (standard deviation) 59.2 (9.3) years at baseline] were included. Adjusted lifetime …

BackgroundEpidemiological evidence suggests that a potential association between dietary protein intake and cardiovascular disease (CVD) may depend on the protein source, that is, plant- or animal-derived, but past research was limited and inconclusive.ObjectivesTo evaluate the association of dietary plant- or animal-derived protein consumption with risk of CVD, and its components ischemic heart disease (IHD) and stroke.MethodsThis analysis in the European Prospective Investigation into Cancer and Nutrition (EPIC)-CVD case–cohort study included 16,244 incident CVD cases (10,784 IHD and 6423 stroke cases) and 15,141 subcohort members from 7 European countries. We investigated the association of estimated dietary protein intake with CVD, IHD, and stroke (total, fatal, and nonfatal) using multivariable-adjusted Prentice-weighted Cox regression. We estimated isocaloric substitutions of replacing fats …