RTN4B interacting protein FAM134C promotes ER membrane curvature and has a functional role in autophagy

The endoplasmic reticulum (ER) is composed of a controlled ratio of sheets and tubules, which are maintained by several proteins with multiple functions. Reticulons (RTNs), especially RTN4, and DP1Nop1p family members are known to induce ER membrane curvature. RTN4B is the main RTN4 isoform expressed in nonneuronal cells. In this study, we identified FAM134C as a RTN4B interacting protein in mammalian, nonneuronal cells. FAM134C localized specifically to the ER tubules and sheet edges. Ultrastructural analysis revealed that overexpression of FAM134C induced the formation of unbranched, long tubules or dense globular structures composed of heavily branched narrow tubules. In both cases, tubules were nonmotile. ER tubulation was dependent on the reticulon homology domain (RHD) close to the N-terminus. FAM134C plays a role in the autophagy pathway as its level elevated significantly upon amino acid starvation but not during ER stress. Moreover, FAM134C depletion reduced the number and size of autophagic structures and the amount of ER as a cargo within autophagic structures under starvation conditions. Dominant-negative expression of FAM134C forms with mutated RHD or LC3 interacting region also led to a reduced number of autophagic structures. Our results suggest that FAM134C provides a link between regulation of ER architecture and ER turnover by promoting ER tubulation required for subsequent ER fragmentation and engulfment into autophagosomes.Peer reviewe

Comprehensive biomarker profiling of hypertension in 36 985 Finnish individuals

Objective: Previous studies on the association between metabolic biomarkers and hypertension have been limited by small sample sizes, low number of studied biomarkers, and cross-sectional study design. In the largest study to date, we assess the cross-sectional and longitudinal associations between high-abundance serum biomarkers and blood pressure (BP). Methods: We studied cross-sectional (N = 36 985; age 50.5 +/- 14.2; 53.1% women) and longitudinal (N = 4197; age 49.4 +/- 11.8, 55.3% women) population samples of Finnish individuals. We included 53 serum biomarkers and other detailed lipoprotein subclass measures in our analyses. We studied the associations between serum biomarkers and BP using both conventional statistical methods and a machine learning algorithm (gradient boosting) while adjusting for clinical risk factors. Results: Fifty-one of 53 serum biomarkers were cross-sectionally related to BP (adjusted P < 0.05 for all). Conventional linear regression modeling demonstrated that LDL cholesterol, remnant cholesterol, apolipoprotein B, and acetate were positively, and HDL particle size was negatively, associated with SBP change over time (adjusted P < 0.05 for all). Adding serum biomarkers (cross-sectional root-mean-square error: 16.27 mmHg; longitudinal: 17.61 mmHg) in the model with clinical measures (cross-sectional: 16.70 mmHg; longitudinal 18.52 mmHg) improved the machine learning model fit. Glucose, albumin, triglycerides in LDL, glycerol, VLDL particle size, and acetoacetate had the highest importance scores in models related to current or future BP. Conclusion: Our results suggest that serum lipids, and particularly LDL-derived and VLDL-derived cholesterol measures, and glucose metabolism abnormalities are associated with hypertension onset. Use of serum metabolite determination could improve identification of individuals at high risk of developing hypertension.Peer reviewe

Association Between the Gut Microbiota and Blood Pressure in a Population Cohort of 6953 Individuals

Background Several small-scale animal studies have suggested that gut microbiota and blood pressure (BP) are linked. However, results from human studies remain scarce and conflicting. We wanted to elucidate the multivariable-adjusted association between gut metagenome and BP in a large, representative, well-phenotyped population sample. We performed a focused analysis to examine the previously reported inverse associations between sodium intake and Lactobacillus abundance and between Lactobacillus abundance and BP. Methods and Results We studied a population sample of 6953 Finns aged 25 to 74 years (mean age, 49.212.9 years; 54.9% women). The participants underwent a health examination, which included BP measurement, stool collection, and 24-hour urine sampling (N=829). Gut microbiota was analyzed using shallow shotgun metagenome sequencing. In age- and sex-adjusted models, the alpha (within-sample) and beta (between-sample) diversities of taxonomic composition were strongly related to BP indexes (P diversity was only associated with diastolic BP (P=0.032). However, we observed significant, mainly positive, associations between BP indexes and 45 microbial genera (P Conclusions Although the associations between overall gut taxonomic composition and BP are weak, individuals with hypertension demonstrate changes in several genera. We demonstrate strong negative associations of certain Lactobacillus species with sodium intake and BP, highlighting the need for experimental studies.Peer reviewe

Viljasta verkostoihin : Huoltovarmuuskeskuksen arviointi

Tämän arviointiraportin tavoitteena on tuottaa kattavaan analyysiin perustuva näkemys huoltovarmuusorganisaation toiminnasta, johtamisesta ja toiminnan vaikuttavuudesta kansallisessa huoltovarmuusjärjestelmässä sekä esittää johtopäätöksiä ja suosituksia näiden kehittämiseksi. Arviointi peräänkuuluttaa laaja-alaisempaa näkökulmaa huoltovarmuuteen. Koronakriisin kokemukset ovat vahvistaneet sen, mitä jatkuvasti kasvanut globaali keskinäisriippuvuus on antanut koko 2000-luvun ajan odottaa: varautumista ei voida tehdä enää kapeiden, toisistaan erillään olevien sektoreiden tai toimialojen näkökulmasta. Huoltovarmuuskeskus (HVK) profiloituu vahvasti elinkeinoelämän kanssa tehtävään yhteistyöhön jatkuvuuden hallinnassa. Tätä työtä toteutetaan pääasiassa poolitoiminnan kautta. Poolikeskusteluista ja kyselystä saadun palautteen perusteella HVK:n voidaan katsoa onnistuneen tässä tehtävässä kohtuullisen hyvin. Sen sijaan Huoltovarmuuskeskuksen yhteistyöstä ministeriöiden kanssa ei piirry kovin selkeää ja johdonmukaista kokonaiskuvaa. Selkeästi lakisääteisiä tehtäviä kattavien toimialojen kohdalla yhteistyö ministeriöiden kanssa on tiiviimpää. Muussa ministeriöiden varautumisen kehittämistoiminnassa Huoltovarmuuskeskus ei näyttäydy läheisenä kumppanina. Arviointiraportissa kiinnitetään erityistä huomiota huoltovarmuusorganisaation ohjaukseen ja johtamisjärjestelmään. Nykyisellään ohjaus- ja päätöksentekojärjestelmä näyttäytyy jossain määrin jäsentymättömänä niin huoltovarmuuden tavoitepäätösten, työ- ja elinkeinoministeriön ja Huoltovarmuuskeskuksen tulosohjauksen kuin HVK:n hallituksen ohjausroolin osalta. Erityistä huomiota raportissa kiinnitetään huoltovarmuusrahaston varainkäytön avoimuuden puutteeseen. Ohjelmatoiminnan monivuotinen rahoittaminen rahaston kautta HVK:n hallituksen päätöksillä ei noudata valtion talousarviolain henkeä ja budjetin täydellisyysperiaatetta. Arviointiraportissa esitetään kolme ideaalimallia, joiden kautta suomalaista huoltovarmuusjärjestelmää olisi mahdollista kehittää tulevaisuudessa. Mallit ovat: 1) nykymalli pienin parannuksin, 2) Huoltovarmuusvirasto ja 3) Kansallinen varautumiskeskus. Kunkin mallin kohdalla on erikseen tarkastelu niiden vahvuuksia ja heikkouksia. Arviointiraportin lopussa on lisäksi 8 kehittämissuositusta, jotka ovat edellä kuvatuista malleista riippumattomia

Comprehensive biomarker profiling of hypertension in 36 985 Finnish individuals

Objective: Previous studies on the association between metabolic biomarkers and hypertension have been limited by small sample sizes, low number of studied biomarkers, and cross-sectional study design. In the largest study to date, we assess the cross-sectional and longitudinal associations between high-abundance serum biomarkers and blood pressure (BP).Methods: We studied cross-sectional (N = 36 985; age 50.5 ± 14.2; 53.1% women) and longitudinal (N = 4197; age 49.4 ± 11.8, 55.3% women) population samples of Finnish individuals. We included 53 serum biomarkers and other detailed lipoprotein subclass measures in our analyses. We studied the associations between serum biomarkers and BP using both conventional statistical methods and a machine learning algorithm (gradient boosting) while adjusting for clinical risk factors.Results: Fifty-one of 53 serum biomarkers were cross-sectionally related to BP (adjusted P Conclusion: Our results suggest that serum lipids, and particularly LDL-derived and VLDL-derived cholesterol measures, and glucose metabolism abnormalities are associated with hypertension onset. Use of serum metabolite determination could improve identification of individuals at high risk of developing hypertension.</p

Association Between the Gut Microbiota and Blood Pressure in a Population Cohort of 6953 Individuals

Background:Several small-scale animal studies have suggested that gut microbiota and blood pressure (BP) are linked. However, results from human studies remain scarce and conflicting. We wanted to elucidate the multivariable-adjusted association between gut metagenome and BP in a large, representative, well-phenotyped population sample. We performed a focused analysis to examine the previously reported inverse associations between sodium intake and Lactobacillus abundance and between Lactobacillus abundance and BP.Methods and Results:We studied a population sample of 6953 Finns aged 25 to 74 years (mean age, 49.212.9 years; 54.9% women). The participants underwent a health examination, which included BP measurement, stool collection, and 24-hour urine sampling (N=829). Gut microbiota was analyzed using shallow shotgun metagenome sequencing. In age- and sex-adjusted models, the alpha (within-sample) and beta (between-sample) diversities of taxonomic composition were strongly related to BP indexes (PConclusions:Although the associations between overall gut taxonomic composition and BP are weak, individuals with hypertension demonstrate changes in several genera. We demonstrate strong negative associations of certain Lactobacillus species with sodium intake and BP, highlighting the need for experimental studies.</div

Are coronary event rates declining slower in women than in men – evidence from two population-based myocardial infarction registers in Finland?

<p>Abstract</p> <p>Background</p> <p>Studies have suggested that the prevention and treatment of coronary heart disease may not have been as effective in women as in men. Therefore, we aimed to examine whether the incidence, attack rate and mortality of myocardial infarction (MI) events have declined less in women than in men.</p> <p>Methods</p> <p>Two large population-based MI registers, the FINAMI register and the Finnish Cardiovascular Disease Register (CVDR) were used for comparing the event rates among men and women aged ≥35 years in two time periods, 1994–1996 and 2000–2002.</p> <p>Results</p> <p>In the FINAMI register a total of 5,252 events were recorded in men and 4,898 in women. Corresponding numbers in the CVDR were 78,709 and 70,464. Both FINAMI and CVDR data suggested smaller declines in incidence and attack rate of MI events in women than in men. In CVDR data the decline in mortality was also smaller in women than in men, while in FINAMI data this difference did not reach statistical significance. In the large CVDR data set, negative binomial regression models revealed smaller declines in incidence (p = 0.006), attack rate (p = 0.008) and mortality (p = 0.04) in women than in men aged <55 years. In persons ≥55 years no difference was observed between women and men.</p> <p>Conclusion</p> <p>The incidence and attack rate of MI events have declined less in women aged <55 than in men of similar age. In older persons no significant differences were observed. Further studies are warranted to find out the reasons why the development has been less favourable for young women than for men.</p

CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits

Funding Information: This research has been conducted using the UK Biobank Resource. This research has been conducted using the Danish National Biobank resource. The authors are grateful to the Raine Study participants and their families, and to the Raine Study research staff for cohort co-ordination and data collection. QIMR is grateful to the twins and their families for their generous participation in these studies. We would like to thank staff at the Queensland Institute of Medical Research: Anjali Henders, Dixie Statham, Lisa Bowdler, Ann Eldridge, and Marlene Grace for sample collection, processing and genotyping, Scott Gordon, Brian McEvoy, Belinda Cornes and Beben Benyamin for data QC and preparation, and David Smyth and Harry Beeby for IT support. HBCS Acknowledgements: We thank all study participants as well as everybody involved in the Helsinki Birth Cohort Study. Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Folkhälsan Research Foundation, Novo Nordisk Foundation, Finska Läkaresällskapet, Juho Vainio Foundation, Signe and Ane Gyllenberg Foundation, University of Helsinki, Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation. Finrisk study is grateful for the THL DNA laboratory for its skillful work to produce the DNA samples used in this study and thanks the Sanger Institute and FIMM genotyping facilities for genotyping the samples. We thank the MOLGENIS team and Genomics Coordination Center of the University Medical Center Groningen for software development and data management, in particular Marieke Bijlsma and Edith Adriaanse. This work was supported by the Leenards Foundation (to Z.K.), the Swiss National Science Foundation (31003A_169929 to Z.K., Sinergia grant CRSII33-133044 to AR), Simons Foundation (SFARI274424 to AR) and SystemsX.ch (51RTP0_151019 to Z.K.). A.R.W., H.Y. and T.M.F. are supported by the European Research Council grant: 323195:SZ-245. M.A.T., M.N.W. and An.M. are supported by the Wellcome Trust Institutional Strategic Support Award (WT097835MF). For full funding information of all participating cohorts see Supplementary Note 2. Publisher Copyright: © 2017 The Author(s).There are few examples of robust associations between rare copy number variants (CNVs) and complex continuous human traits. Here we present a large-scale CNV association meta-analysis on anthropometric traits in up to 191,161 adult samples from 26 cohorts. The study reveals five CNV associations at 1q21.1, 3q29, 7q11.23, 11p14.2, and 18q21.32 and confirms two known loci at 16p11.2 and 22q11.21, implicating at least one anthropometric trait. The discovered CNVs are recurrent and rare (0.01-0.2%), with large effects on height (> 2.4 cm), weight ( 5 kg), and body mass index (BMI) (> 3.5 kg/m(2)). Burden analysis shows a 0.41 cm decrease in height, a 0.003 increase in waist-to-hip ratio and increase in BMI by 0.14 kg/m2 for each Mb of total deletion burden (P = 2.5 x 10(-10), 6.0 x 10(-5), and 2.9 x 10(-3)). Our study provides evidence that the same genes (e.g., MC4R, FIBIN, and FMO5) harbor both common and rare variants affecting body size and that anthropometric traits share genetic loci with developmental and psychiatric disorders.Peer reviewe

Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies

BACKGROUND: Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies. METHODS: For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84 961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45·8 years to 76·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p<5 × 10(-6)) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70 804 participants, of whom 19 816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed-effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at p<5 × 10(-8)), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants. FINDINGS: We replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with risk of all-stroke (odds ratio [OR] 1·08, 95% CI 1·05-1·12, p=1·48 × 10(-8); minor allele frequency 21%). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensity-a marker of cerebral small vessel disease-in stroke-free adults (n=21 079; p=0·0025). Consistently, young patients (aged 2-32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity. Deletion of Foxf2 in adult mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The orthologs of FOXF2 in zebrafish (foxf2b and foxf2a) are expressed in brain pericytes and mutant foxf2b(-/-) cerebral vessels show decreased smooth muscle cell and pericyte coverage. INTERPRETATION: We identified common variants near FOXF2 that are associated with increased stroke susceptibility. Epidemiological and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells. Further expression studies in appropriate human tissues, and further functional experiments with long follow-up periods are needed to fully understand the underlying mechanisms

Bayesian Variable Selection in Searching for Additive and Dominant Effects in Genome-Wide Data

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