Application of non-HDL cholesterol for population-based cardiovascular risk stratification: results from the Multinational Cardiovascular Risk Consortium.

BACKGROUND: The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment. METHODS: In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds, adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol. FINDINGS: Of the 524 444 individuals in the 44 cohorts in the Consortium database, we identified 398 846 individuals belonging to 38 cohorts (184 055 [48·7%] women; median age 51·0 years [IQR 40·7-59·7]). 199 415 individuals were included in the derivation cohort (91 786 [48·4%] women) and 199 431 (92 269 [49·1%] women) in the validation cohort. During a maximum follow-up of 43·6 years (median 13·5 years, IQR 7·0-20·1), 54 542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year cardiovascular disease event-rates for increasing non-HDL cholesterol categories (from 7·7% for non-HDL cholesterol <2·6 mmol/L to 33·7% for ≥5·7 mmol/L in women and from 12·8% to 43·6% in men; p<0·0001). Multivariable adjusted Cox models with non-HDL cholesterol lower than 2·6 mmol/L as reference showed an increase in the association between non-HDL cholesterol concentration and cardiovascular disease for both sexes (from hazard ratio 1·1, 95% CI 1·0-1·3 for non-HDL cholesterol 2·6 to <3·7 mmol/L to 1·9, 1·6-2·2 for ≥5·7 mmol/L in women and from 1·1, 1·0-1·3 to 2·3, 2·0-2·5 in men). The derived tool allowed the estimation of cardiovascular disease event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts as reflected by smooth calibration curves analyses and a root mean square error lower than 1% for the estimated probabilities of cardiovascular disease. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of a cardiovascular disease event by the age of 75 years, and this risk reduction was greater the earlier cholesterol concentrations were reduced. INTERPRETATION: Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic cardiovascular disease. We provide a simple tool for individual long-term risk assessment and the potential benefit of early lipid-lowering intervention. These data could be useful for physician-patient communication about primary prevention strategies. FUNDING: EU Framework Programme, UK Medical Research Council, and German Centre for Cardiovascular Research

Effect of commercial rye whole-meal bread on postprandial blood glucose and gastric emptying in healthy subjects

<p>Abstract</p> <p>Background</p> <p>The intake of dietary fibre has been shown to reduce the risk of developing diabetes mellitus. The aim of this study was to compare the effects of commercial rye whole-meal bread containing whole kernels and white wheat bread on the rate of gastric emptying and postprandial glucose response in healthy subjects.</p> <p>Methods</p> <p>Ten healthy subjects took part in a blinded crossover trial. Blood glucose level and gastric emptying rate (GER) were determined after the ingestion of 150 g white wheat bread or 150 g whole-meal rye bread on two different occasions after fasting overnight. The GER was measured using real-time ultrasonography, and was calculated as the percentage change in antral cross-sectional area 15 and 90 minutes after completing the meal.</p> <p>Results</p> <p>No statistically significant difference was found between the GER values or the blood glucose levels following the two meals when evaluated with the Wilcoxon signed rank sum test.</p> <p>Conclusion</p> <p>The present study revealed no difference in postprandial blood glucose response or gastric emptying after the ingestion of rye whole-meal bread compared with white wheat bread.</p> <p>Trial registration</p> <p>NCT00779298</p

Global Biobank analyses provide lessons for developing polygenic risk scores across diverse cohorts

Polygenic risk scores (PRSs) have been widely explored in precision medicine. However, few studies have thoroughly investigated their best practices in global populations across different diseases. We here utilized data from Global Biobank Meta-analysis Initiative (GBMI) to explore methodological considerations and PRS performance in 9 different biobanks for 14 disease endpoints. Specifically, we constructed PRSs using pruning and thresholding (P + T) and PRS-continuous shrinkage (CS). For both methods, using a European-based linkage disequilibrium (LD) reference panel resulted in comparable or higher prediction accuracy compared with several other non-European-based panels. PRS-CS overall outperformed the classic P + T method, especially for endpoints with higher SNP-based heritability. Notably, prediction accuracy is heterogeneous across endpoints, biobanks, and ancestries, especially for asthma, which has known variation in disease prevalence across populations. Overall, we provide lessons for PRS construction, evaluation, and interpretation using GBMI resources and highlight the importance of best practices for PRS in the biobank-scale genomics era.</p

The botanical integrity of wheat products influences the gastric distention and satiety in healthy subjects

<p>Abstract</p> <p>Background</p> <p>Maintenance of the botanical integrity of cereal kernels and the addition of acetic acid (as vinegar) in the product or meal has been shown to lower the postprandial blood glucose and insulin response and to increase satiety. However, the mechanism behind the benefits of acetic acid on blood glucose and satiety is not clear. We hypothesized that the gastric emptying rate could be involved. Thus, the aim of this study was to evaluate the possible influence of maintained botanical integrity of cereals and the presence of acetic acid (vinegar) on gastric emptying rate (GER), postprandial blood glucose and satiety.</p> <p>Methods</p> <p>Fifteen healthy subjects were included in a blinded crossover trial, and thirteen of the subjects completed the study. Equicarbohydrate amounts of the following wheat-based meals were studied: white wheat bread, whole-kernel wheat bread or wholemeal wheat bread served with white wine vinegar. The results were compared with a reference meal consisting of white wheat bread without vinegar. The GER was measured with standardized real-time ultrasonography using normal fasting blood glucose <6.1 mmol/l or plasma glucose <7.0 mmol/l as an inclusion criterion. The GER was calculated as the percentage change in the antral cross-sectional area 15 and 90 minutes after ingestion of the various meals. Satiety scores were estimated and blood glucose was measured before and 15, 30, 45, 60, 90 and 120 min after the start of the meal.</p> <p>Results</p> <p>The whole-kernel wheat bread with vinegar resulted in significantly higher (<0.05) satiety than the wholemeal wheat bread and white wheat bread with vinegar and the reference bread. Wheat fiber present in the wholemeal wheat bread, or the presence of wheat kernels per se, did not affect the postprandial blood glucose or GER significantly compared with white wheat bread, neither did the addition of vinegar to white bread affect these variables. There was no correlation found between the satiety with antral areas or GER</p> <p>Conclusion</p> <p>The present study shows higher satiety after a whole-kernel wheat bread meal with vinegar. This may be explained by increased antral distension after ingestion of intact cereal kernels but, in this study, not by a lower gastric emptying rate or higher postprandial blood glucose response.</p> <p>Trial registration</p> <p>NTR1116</p

Exome-wide association analysis reveals novel coding sequence variants associated with lipid traits in Chinese

published_or_final_versio

Circulating concentrations of vitamin D in relation to pancreatic cancer risk in European populations

Evidence from in vivo, in vitro and ecological studies are suggestive of a protective effect of vitamin D against pancreatic cancer (PC). However, this has not been confirmed by analytical epidemiological studies. We aimed to examine the association between pre-diagnostic circulating vitamin D concentrations and PC incidence in European populations. We conducted a pooled nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Nord-Trøndelag Health Study's second survey (HUNT2) cohorts. In total, 738 primary incident PC cases (EPIC n = 626; HUNT2 n = 112; median follow-up = 6.9 years) were matched to 738 controls. Vitamin D [25(OH)D2 and 25(OH)D3 combined] concentrations were determined using isotope-dilution liquid chromatography-tandem mass spectrometry. Conditional logistic regression models with adjustments for body mass index and smoking habits were used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (95%CI). Compared with a reference category of >50 to 75 nmol/L vitamin D, the IRRs (95% CIs) were 0.71 (0.42–1.20); 0.94 (0.72–1.22); 1.12 (0.82–1.53) and 1.26 (0.79–2.01) for clinically pre-defined categories of ≤25; >25 to 50; >75 to 100; and >100 nmol/L vitamin D, respectively (p for trend = 0.09). Corresponding analyses by quintiles of season-standardized vitamin D concentrations also did not reveal associations with PC risk (p for trend = 0.23). Although these findings among participants from the largest combination of European cohort studies to date show increasing effect estimates of PC risk with increasing pre-diagnostic concentrations of vitamin D, they are not statistically significant

Evaluation of four novel genetic variants affecting hemoglobin A1c levels in a population-based type 2 diabetes cohort (the HUNT2 study)

<p>Abstract</p> <p>Background</p> <p>Chronic hyperglycemia confers increased risk for long-term diabetes-associated complications and repeated hemoglobin A1c (HbA1c) measures are a widely used marker for glycemic control in diabetes treatment and follow-up. A recent genome-wide association study revealed four genetic loci, which were associated with HbA1c levels in adults with type 1 diabetes. We aimed to evaluate the effect of these loci on glycemic control in type 2 diabetes.</p> <p>Methods</p> <p>We genotyped 1,486 subjects with type 2 diabetes from a Norwegian population-based cohort (HUNT2) for single-nucleotide polymorphisms (SNPs) located near the <it>BNC2</it>, <it>SORCS1</it>, <it>GSC </it>and <it>WDR72 </it>loci. Through regression models, we examined their effects on HbA1c and non-fasting glucose levels individually and in a combined genetic score model.</p> <p>Results</p> <p>No significant associations with HbA1c or glucose levels were found for the <it>SORCS1</it>, <it>BNC2</it>, <it>GSC </it>or <it>WDR72 </it>variants (all <it>P</it>-values > 0.05). Although the observed effects were non-significant and of much smaller magnitude than previously reported in type 1 diabetes, the <it>SORCS1 </it>risk variant showed a direction consistent with increased HbA1c and glucose levels, with an observed effect of 0.11% (<it>P </it>= 0.13) and 0.13 mmol/l (<it>P </it>= 0.43) increase per risk allele for HbA1c and glucose, respectively. In contrast, the <it>WDR72 </it>risk variant showed a borderline association with reduced HbA1c levels (<it>β </it>= -0.21, <it>P </it>= 0.06), and direction consistent with decreased glucose levels (<it>β </it>= -0.29, <it>P </it>= 0.29). The allele count model gave no evidence for a relationship between increasing number of risk alleles and increasing HbA1c levels (<it>β </it>= 0.04, <it>P </it>= 0.38).</p> <p>Conclusions</p> <p>The four recently reported SNPs affecting glycemic control in type 1 diabetes had no apparent effect on HbA1c in type 2 diabetes individually or by using a combined genetic score model. However, for the <it>SORCS1 </it>SNP, our findings do not rule out a possible relationship with HbA1c levels. Hence, further studies in other populations are needed to elucidate whether these novel sequence variants, especially rs1358030 near the <it>SORCS1 </it>locus, affect glycemic control in type 2 diabetes.</p

Plasma Proteomics of Renal Function: A Transethnic Meta-Analysis and Mendelian Randomization Study.

BACKGROUND: Studies on the relationship between renal function and the human plasma proteome have identified several potential biomarkers. However, investigations have been conducted largely in European populations, and causality of the associations between plasma proteins and kidney function has never been addressed. METHODS: A cross-sectional study of 993 plasma proteins among 2882 participants in four studies of European and admixed ancestries (KORA, INTERVAL, HUNT, QMDiab) identified transethnic associations between eGFR/CKD and proteomic biomarkers. For the replicated associations, two-sample bidirectional Mendelian randomization (MR) was used to investigate potential causal relationships. Publicly available datasets and transcriptomic data from independent studies were used to examine the association between gene expression in kidney tissue and eGFR. RESULTS: In total, 57 plasma proteins were associated with eGFR, including one novel protein. Of these, 23 were additionally associated with CKD. The strongest inferred causal effect was the positive effect of eGFR on testican-2, in line with the known biological role of this protein and the expression of its protein-coding gene (SPOCK2) in renal tissue. We also observed suggestive evidence of an effect of melanoma inhibitory activity (MIA), carbonic anhydrase III, and cystatin-M on eGFR. CONCLUSIONS: In a discovery-replication setting, we identified 57 proteins transethnically associated with eGFR. The revealed causal relationships are an important stepping stone in establishing testican-2 as a clinically relevant physiological marker of kidney disease progression, and point to additional proteins warranting further investigation.The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. This work was also supported by the Biomedical Research Program at Weill Cornell Medicine in Qatar, a program funded by the Qatar Foundation. K.S. is supported by Qatar National Research Fund (QNRF) grant no. NPRPC11-0115-180010. The Nord-Trøndelag Health Study (The HUNT Study) is a collaboration between HUNT Research Centre (Faculty of Medicine, Norwegian University of Science and Technology NTNU), Nord-Trøndelag County Council, Central Norway Health Authority, and the Norwegian Institute of Public Health. The HUNT part of the project re-used protein data that was originally analysed and paid for by Somalogic Inc, CO, USA. Somalogic had no role in the design and conduct of the study; collection of phenotypic data, statistical analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Professor John Danesh is funded by the National Institute for Health Research [Senior Investigator Award]. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. RNA-sequencing experiments and kidney gene expression studies were supported by British Heart Foundation project grants [PG/17/35/33001 and PG/19/16/34270] and Kidney Research UK grants [ RP_017_20180302 and RP_013_20190305] to M.T. The German Diabetes Center is funded by the German Federal Ministry of Health (Berlin, Germany), the Ministry of Culture and Science of the state North Rhine-Westphalia (Düsseldorf, Germany), and grants from the German Federal Ministry of Education and Research (Berlin, Germany) to the German Center for Diabetes Research e.V. (DZD)

Genome-wide association analysis of self-reported daytime sleepiness identifies 42 loci that suggest biological subtypes

This is the final version. Available from the publisher via the DOI in this record.UK Biobank Sleep Traits GWAS summary statistics are available at the Sleep Disorder Knowledge Portal (SDKP) website (http://www.sleepdisordergenetics.org). All other data are contained within the article and its supplementary information or available upon request.Excessive daytime sleepiness (EDS) affects 10–20% of the population and is associated with substantial functional deficits. Here, we identify 42 loci for self-reported daytime sleepiness in GWAS of 452,071 individuals from the UK Biobank, with enrichment for genes expressed in brain tissues and in neuronal transmission pathways. We confirm the aggregate effect of a genetic risk score of 42 SNPs on daytime sleepiness in independent Scandinavian cohorts and on other sleep disorders (restless legs syndrome, insomnia) and sleep traits (duration, chronotype, accelerometer-derived sleep efficiency and daytime naps or inactivity). However, individual daytime sleepiness signals vary in their associations with objective short vs long sleep, and with markers of sleep continuity. The 42 sleepiness variants primarily cluster into two predominant composite biological subtypes - sleep propensity and sleep fragmentation. Shared genetic links are also seen with obesity, coronary heart disease, psychiatric diseases, cognitive traits and reproductive ageing.Medical Research Council (MRC