Genetic polymorphism of sterol transporters in children with future gallstones

Background & aims: Gallstone disease is related to hypersecretion of cholesterol in bile, and low serum phytosterol levels. We examined how genetic polymorphisms of sterol transporters affect childhood cholesterol metabolism trait predicting adult gallstone disease. Patients and methods: In retrospective controlled study, we determined D19H polymorphism of ABCG8 gene, genetic variation at Niemann-Pick C1-like 1 (NPC1L1) gene locus (rs41279633, rs17655652, rs2072183, rs217434 and rs2073548), and serum cholesterol, noncholesterol sterols and lipids in children affected by gallstones decades later (n = 66) and controls (n = 126). Results: In childhood, phytosterols were lower (9.7%-23.4%) in carriers of risk allele 19H compared to 19D homozygotes. Lowest campesterol/cholesterol tertile consisted of 1.9-times more future gallstone subjects, and 3.7-times more 19H carriers than highest one. Campesterol/cholesterol-ratio was highest in 19D homozygote controls, but similar to 11% lower in gallstone 19D homozygotes and similar to 25% lower among gallstone and control carriers of 19H. Gallstone subjects with alleles CC of rs41279633 and TT of rs217434 of NPC1L1 had similar to 18% lower campesterol/cholesterol-ratio compared to mutation carriers. Conclusions: Risk trait of cholesterol metabolism (low phytosterols) in childhood favouring cholesterol gallstone disease later in adulthood is influenced by risk variant 19H of ABCG8 and obviously also other factors. NPC1L1 variants have minor influence on noncholesterol sterols. (c) 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.Peer reviewe

Increased tooth brushing frequency is associated with reduced gingival pocket bacterial diversity in patients with intracranial aneurysms

Objectives The objective of this study was to investigate the association of tooth brushing frequency and bacterial communities of gingival crevicular fluid in patients subjected to preoperative dental examination prior to operative treatment for unruptured intracranial aneurysms. Methods Gingival crevicular fluid samples were taken from their deepest gingival pocket from a series of hospitalized neurosurgical patients undergoing preoperative dental screening (n = 60). The patients were asked whether they brushed their teeth two times a day, once a day, or less than every day. Total bacterial DNA was isolated and the V3–V4 region of the 16S rRNA gene was amplificated. Sequencing was performed with Illumina’s 16S metagenomic sequencing library preparation protocol and data were analyzed with QIIME (1.9.1) and R statistical software (3.3.2). Results Bacterial diversity (Chao1 index) in the crevicular fluid reduced along with reported tooth brushing frequency (p = 0.0002; R2 = 34%; p (adjusted with age and sex) = 0.09; R2 = 11%) showing that patients who reported brushing their teeth twice a day had the lowest bacterial diversity. According to the differential abundant analysis between the tooth brushing groups, tooth brushing associated with two phyla of fusobacteria [p = 0.0001; p = 0.0007], and one bacteroidetes (p = 0.004) by reducing their amounts. Conclusions Tooth brushing may reduce the gingival bacterial diversity and the abundance of periodontal bacteria maintaining oral health and preventing periodontitis, and thus it is highly recommended for neurosurgical patients

Meta-analysis of Genome-Wide Association Studies for Extraversion: Findings from the Genetics of Personality Consortium

Extraversion is a relatively stable and heritable personality trait associated with numerous psychosocial, lifestyle and health outcomes. Despite its substantial heritability, no genetic variants have been detected in previous genome-wide association (GWA) studies, which may be due to relatively small sample sizes of those studies. Here, we report on a large meta-analysis of GWA studies for extraversion in 63,030 subjects in 29 cohorts. Extraversion item data from multiple personality inventories were harmonized across inventories and cohorts. No genome-wide significant associations were found at the single nucleotide polymorphism (SNP) level but there was one significant hit at the gene level for a long non-coding RNA site (LOC101928162). Genome-wide complex trait analysis in two large cohorts showed that the additive variance explained by common SNPs was not significantly different from zero, but polygenic risk scores, weighted using linkage information, significantly predicted extraversion scores in an independent cohort. These results show that extraversion is a highly polygenic personality trait, with an architecture possibly different from other complex human traits, including other personality traits. Future studies are required to further determine which genetic variants, by what modes of gene action, constitute the heritable nature of extraversion

Genome-wide association study of nocturnal blood pressure dipping in hypertensive patients

Abstract Background Reduced nocturnal fall (non-dipping) of blood pressure (BP) is a predictor of cardiovascular target organ damage. No genome-wide association studies (GWAS) on BP dipping have been previously reported. Methods To study genetic variation affecting BP dipping, we conducted a GWAS in Genetics of Drug Responsiveness in Essential Hypertension (GENRES) cohort (n = 204) using the mean night-to-day BP ratio from up to four ambulatory BP recordings conducted on placebo. Associations with P < 1 × 10− 5 were further tested in two independent cohorts: Haemodynamics in Primary and Secondary Hypertension (DYNAMIC) (n = 183) and Dietary, Lifestyle and Genetic determinants of Obesity and Metabolic Syndrome (DILGOM) (n = 180). We also tested the genome-wide significant single nucleotide polymorphism (SNP) for association with left ventricular hypertrophy in GENRES. Results In GENRES GWAS, rs4905794 near BCL11B achieved genome-wide significance (β = − 4.8%, P = 9.6 × 10− 9 for systolic and β = − 4.3%, P = 2.2 × 10− 6 for diastolic night-to-day BP ratio). Seven additional SNPs in five loci had P values < 1 × 10− 5. The association of rs4905794 did not significantly replicate, even though in DYNAMIC the effect was in the same direction (β = − 0.8%, P = 0.4 for systolic and β = − 1.6%, P = 0.13 for diastolic night-to-day BP ratio). In GENRES, the associations remained significant even during administration of four different antihypertensive drugs. In separate analysis in GENRES, rs4905794 was associated with echocardiographic left ventricular mass (β = − 7.6 g/m2, P = 0.02). Conclusions rs4905794 near BCL11B showed evidence for association with nocturnal BP dipping. It also associated with left ventricular mass in GENRES. Combined with earlier data, our results provide support to the idea that BCL11B could play a role in cardiovascular pathophysiology

Pro-opiomelanocortin and its Processing Enzymes Associate with Plaque Stability in Human Atherosclerosis -Tampere Vascular Study

alpha-melanocyte-stimulating hormone (alpha-MSH) is processed from pro-opiomelanocortin (POMC) and mediates anti-inflammatory actions in leukocytes. alpha-MSH also promotes macrophage reverse cholesterol transport by inducing ATP-binding cassette transporters ABCA1 and ABCG1. Here we investigated the regulation of POMC and alpha-MSH expression in atherosclerosis. First, transcript levels of POMC and its processing enzymes were analyzed in human arterial plaques (n = 68) and non-atherosclerotic controls (n = 24) as well as in whole blood samples from coronary artery disease patients (n = 55) and controls (n = 45) by microarray. POMC expression was increased in femoral plaques compared to control samples as well as in unstable advanced plaques. alpha-MSH-producing enzyme, carboxypeptidase E, was down-regulated, whereas prolylcarboxypeptidase, an enzyme inactivating alpha-MSH, was up-regulated in unstable plaques compared to stable plaques, suggesting a possible reduction in intraplaque alpha-MSH levels. Second, immunohistochemical analyses revealed the presence of alpha-MSH in atherosclerotic plaques and its localization in macrophages and other cell types. Lastly, supporting the role of alpha-MSH in reverse cholesterol transport, POMC expression correlated with ABCA1 and ABCG1 in human plaque and whole blood samples. In conclusion, alpha-MSH is expressed in atherosclerotic plaques and its processing enzymes associate with plaque stability, suggesting that measures to enhance the local bioavailability of alpha-MSH might protect against atherosclerosis

EpiMetal:an open-source graphical web browser tool for easy statistical analyses in epidemiology and metabolomics

MOTIVATION: An intuitive graphical interface that allows statistical analyses and visualizations of extensive data without any knowledge of dedicated statistical software or programming. IMPLEMENTATION: EpiMetal is a single-page web application written in JavaScript, to be used via a modern desktop web browser. GENERAL FEATURES: Standard epidemiological analyses and self-organizing maps for data-driven metabolic profiling are included. Multiple extensive datasets with an arbitrary number of continuous and category variables can be integrated with the software. Any snapshot of the analyses can be saved and shared with others via a www-link. We demonstrate the usage of EpiMetal using pilot data with over 500 quantitative molecular measures for each sample as well as in two large-scale epidemiological cohorts (N >10 000). AVAILABILITY: The software usage exemplar and the pilot data are open access online at [http://EpiMetal.computationalmedicine.fi]. MIT licensed source code is available at the Github repository at [https://github.com/amergin/epimetal]

Smooth muscle cells in human atherosclerosis: proteomic profiling reveals differences in expression of Annexin A1 and mitochondrial proteins in carotid disease.

n/

Expression of sterol regulatory element-binding transcription factor (SREBF) 2 and SREBF cleavage-activating protein (SCAP) in human atheroma and the association of their allelic variants with sudden cardiac death

<p>Abstract</p> <p>Background</p> <p>Disturbed cellular cholesterol homeostasis may lead to accumulation of cholesterol in human atheroma plaques. Cellular cholesterol homeostasis is controlled by the sterol regulatory element-binding transcription factor 2 (SREBF-2) and the SREBF cleavage-activating protein (SCAP). We investigated whole genome expression in a series of human atherosclerotic samples from different vascular territories and studied whether the non-synonymous coding variants in the interacting domains of two genes, <it>SREBF-2 </it>1784G>C (rs2228314) and <it>SCAP </it>2386A>G, are related to the progression of coronary atherosclerosis and the risk of pre-hospital sudden cardiac death (SCD).</p> <p>Methods</p> <p>Whole genome expression profiling was completed in twenty vascular samples from carotid, aortic and femoral atherosclerotic plaques and six control samples from internal mammary arteries. Three hundred sudden pre-hospital deaths of middle-aged (33–69 years) Caucasian Finnish men were subjected to detailed autopsy in the Helsinki Sudden Death Study. Coronary narrowing and areas of coronary wall covered with fatty streaks or fibrotic, calcified or complicated lesions were measured and related to the <it>SREBF-2 </it>and <it>SCAP </it>genotypes.</p> <p>Results</p> <p>Whole genome expression profiling showed a significant (p = 0.02) down-regulation of <it>SREBF-2 </it>in atherosclerotic carotid plaques (types IV-V), but not in the aorta or femoral arteries (p = NS for both), as compared with the histologically confirmed non-atherosclerotic tissues. In logistic regression analysis, a significant interaction between the <it>SREBF-2 </it>1784G>C and the <it>SCAP </it>2386A>G genotype was observed on the risk of SCD (p = 0.046). Men with the <it>SREBF-2 </it>C allele and the <it>SCAP </it>G allele had a significantly increased risk of SCD (OR 2.68, 95% CI 1.07–6.71), compared to <it>SCAP </it>AA homologous subjects carrying the <it>SREBF-2 </it>C allele. Furthermore, similar trends for having complicated lesions and for the occurrence of thrombosis were found, although the results were not statistically significant.</p> <p>Conclusion</p> <p>The results suggest that the allelic variants (<it>SREBF-2 </it>1784G>C and <it>SCAP </it>2386A>G) in the cholesterol homeostasis regulating SREBF-SCAP pathway may contribute to SCD in early middle-aged men.</p

Association of circulating metabolites with healthy diet and risk of cardiovascular disease : analysis of two cohort studies

Diet may modify metabolomic profiles towards higher or lower cardiovascular disease (CVD) risk. We aimed to identify metabolite profiles associated with high adherence to dietary recommendations-the Alternative Healthy Eating Index (AHEI) - and the extent to which metabolites associated with AHEI also predict incident CVD. Relations between AHEI score and 80 circulating lipids and metabolites, quantified by nuclear magnetic resonance metabolomics, were examined using linear regression models in the Whitehall II study (n = 4824, 55.9 +/- 6.1 years, 28.0% women) and were replicated in the Cardiovascular Risk in Young Finns Study (n = 1716, 37.7 +/- 5.0 years, 56.3% women). We used Cox models to study associations between metabolites and incident CVD over the 15.8-year follow-up in the Whitehall II study. After adjustment for confounders, higher AHEI score (indicating healthier diet) was associated with higher degree of unsaturation of fatty acids (FA) and higher ratios of polyunsaturated FA, omega-3 and docosahexaenoic acid relative to total FA in both Whitehall II and Young Finns studies. A concordance of associations of metabolites with higher AHEI score and lower CVD risk was observed in Whitehall II. Adherence to healthy diet seems to be associated with specific FA that reduce risk of CVD.Peer reviewe