Publications by authors named "Pasi Soininen"

132 Publications

Reply to: "Methodological issues regarding: "A third of nonfasting plasma cholesterol is in remnant lipoproteins: Lipoprotein subclass profiling in 9293 individuals".

Atherosclerosis 2020 06 20;302:59-61. Epub 2020 Apr 20.

Nightingale Health Ltd, Helsinki, Finland.

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http://dx.doi.org/10.1016/j.atherosclerosis.2020.03.028DOI Listing
June 2020

Metabolic Profiles Help Discriminate Mild Cognitive Impairment from Dementia Stage in Alzheimer's Disease.

J Alzheimers Dis 2020 ;74(1):277-286

Institute of Clinical Medicine - Neurology, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.

Accurate differentiation between neurodegenerative diseases is developing quickly and has reached an effective level in disease recognition. However, there has been less focus on effectively distinguishing the prodromal state from later dementia stages due to a lack of suitable biomarkers. We utilized the Disease State Index (DSI) machine learning classifier to see how well quantified metabolomics data compares to clinically used cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD). The metabolic profiles were quantified for 498 serum and CSF samples using proton nuclear magnetic resonance spectroscopy. The patient cohorts in this study were dementia (with a clinical AD diagnosis) (N = 359), mild cognitive impairment (MCI) (N = 96), and control patients with subjective memory complaints (N = 43). DSI classification was conducted for MCI (N = 51) and dementia (N = 214) patients with low CSF amyloid-β levels indicating AD pathology and controls without such amyloid pathology (N = 36). We saw that the conventional CSF markers of AD were better at classifying controls from both dementia and MCI patients. However, quantified metabolic subclasses were more effective in classifying MCI from dementia. Our results show the consistent effectiveness of traditional CSF biomarkers in AD diagnostics. However, these markers are relatively ineffective in differentiating between MCI and the dementia stage, where the quantified metabolomics data provided significant benefit.
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http://dx.doi.org/10.3233/JAD-191226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175942PMC
January 2020

Low Serum High-Density Lipoprotein Cholesterol Levels Associate with the C9orf72 Repeat Expansion in Frontotemporal Lobar Degeneration Patients.

J Alzheimers Dis 2019 ;72(1):127-137

Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, Finland.

Decreased levels of serum high-density lipoprotein (HDL) cholesterol have previously been linked to systemic inflammation and neurodegenerative diseases, such as Alzheimer's disease. Here, we aimed to analyze the lipoprotein profile and inflammatory indicators, the high-sensitivity C-reactive peptide (hs-CRP) and glycoprotein acetyls (GlycA), in sporadic and C9orf72 repeat expansion-associated frontotemporal lobar degeneration (FTLD) patients. The C9orf72 hexanucleotide repeat expansion is the most frequent genetic etiology underlying FTLD. The concentrations of different lipid measures in the sera of 67 FTLD patients (15 C9orf72 repeat expansion carriers), including GlycA, were analyzed by nuclear magnetic resonance spectroscopy. To verify the state of systemic inflammation, hs-CRP was also quantified from patient sera. We found that the total serum HDL concentration was decreased in C9orf72 repeat expansion carriers when compared to non-carriers. Moreover, decreased concentrations of HDL particles of different sizes and subclass were consistently observed. No differences were detected in the very low- and low-density lipoprotein subclasses between the C9orf72 repeat expansion carriers and non-carriers. Furthermore, hs-CRP and GlycA levels did not differ between the C9orf72 repeat expansion carriers and non-carriers. In conclusion, the HDL-related changes were linked with C9orf72 repeat expansion associated FTLD but were not seen to associate with systemic inflammation. The underlying reason for the HDL changes remains unclear.
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http://dx.doi.org/10.3233/JAD-190132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839456PMC
November 2020

Total liver phosphatidylcholine content associates with non-alcoholic steatohepatitis and glycine N-methyltransferase expression.

Liver Int 2019 10 8;39(10):1895-1905. Epub 2019 Jul 8.

Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.

Background & Aims: Alterations in liver phosphatidylcholine (PC) metabolism have been implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Although genetic variation in the phosphatidylethanolamine N-methyltransferase (PEMT) enzyme synthesizing PC has been associated with disease, the functional mechanism linking PC metabolism to the pathogenesis of non-alcoholic steatohepatitis (NASH) remains unclear.

Methods: Serum PC levels and liver PC contents were measured using proton nuclear magnetic resonance (NMR) spectroscopy in 169 obese individuals [age 46.6 ± 10 (mean ± SD) years, BMI 43.3 ± 6 kg/m , 53 men and 116 women] with histological assessment of NAFLD; 106 of these had a distinct liver phenotype. All subjects were genotyped for PEMT rs7946 and liver mRNA expression of PEMT and glycine N-methyltransferase (GNMT) was analysed.

Results: Liver PC content was lower in those with NASH (P = 1.8 x 10 ) while serum PC levels did not differ between individuals with NASH and normal liver (P = 0.591). Interestingly, serum and liver PC did not correlate (r  = -0.047, P = 0.557). Serum PC and serum cholesterol levels correlated strongly (r  = 0.866, P = 7.1 x 10 ), while liver PC content did not correlate with serum cholesterol (r  = 0.065, P = 0.413). Neither PEMT V175M genotype nor PEMT expression explained the association between liver PC content and NASH. Instead, liver GNMT mRNA expression was decreased in those with NASH (P = 3.8 x 10 ) and correlated with liver PC content (r  = 0.265, P = 0.001).

Conclusions: Decreased liver PC content in individuals with the NASH is independent of PEMT V175M genotype and could be partly linked to decreased GNMT expression.
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http://dx.doi.org/10.1111/liv.14174DOI Listing
October 2019

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

Sci Rep 2018 06 5;8(1):8620. Epub 2018 Jun 5.

Department of Epidemiology and Public Health, London, University College London, London, United Kingdom.

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.
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http://dx.doi.org/10.1038/s41598-018-26441-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988716PMC
June 2018

NAFLD risk alleles in PNPLA3, TM6SF2, GCKR and LYPLAL1 show divergent metabolic effects.

Hum Mol Genet 2018 06;27(12):2214-2223

Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.

Fatty liver has been associated with unfavourable metabolic changes in circulation. To provide insights in fatty liver-related metabolic deviations, we compared metabolic association profile of fatty liver versus metabolic association profiles of genotypes increasing the risk of non-alcoholic fatty liver disease (NAFLD). The cross-sectional associations of ultrasound-ascertained fatty liver with 123 metabolic measures were determined in 1810 (Nfatty liver = 338) individuals aged 34-49 years from The Cardiovascular Risk in Young Finns Study. The association profiles of NAFLD-risk alleles in PNPLA3, TM6SF2, GCKR, and LYPLAL1 with the corresponding metabolic measures were obtained from a publicly available metabolomics GWAS including up to 24 925 Europeans. The risk alleles showed different metabolic effects: PNPLA3 rs738409-G, the strongest genetic NAFLD risk factor, did not associate with metabolic changes. Metabolic effects of GCKR rs1260326-T were comparable in many respects to the fatty liver associations. Metabolic effects of LYPLAL1 rs12137855-C were similar, but statistically less robust, to the effects of GCKR rs1260326-T. TM6SF2 rs58542926-T displayed opposite metabolic effects when compared with the fatty liver associations. The metabolic effects of the risk alleles highlight heterogeneity of the molecular pathways leading to fatty liver and suggest that the fatty liver-related changes in the circulating lipids and metabolites may vary depending on the underlying pathophysiological mechanism. Despite the robust cross-sectional associations on population level, the present results showing neutral or cardioprotective metabolic effects for some of the NAFLD risk alleles advocate that hepatic lipid accumulation by itself may not increase the level of circulating lipids or other metabolites.
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http://dx.doi.org/10.1093/hmg/ddy124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985737PMC
June 2018

Association of branched-chain amino acids and other circulating metabolites with risk of incident dementia and Alzheimer's disease: A prospective study in eight cohorts.

Alzheimers Dement 2018 06 6;14(6):723-733. Epub 2018 Mar 6.

Department of Health, National Institute for Health and Welfare, Helsinki, Finland. Electronic address:

Introduction: Metabolite, lipid, and lipoprotein lipid profiling can provide novel insights into mechanisms underlying incident dementia and Alzheimer's disease.

Methods: We studied eight prospective cohorts with 22,623 participants profiled by nuclear magnetic resonance or mass spectrometry metabolomics. Four cohorts were used for discovery with replication undertaken in the other four to avoid false positives. For metabolites that survived replication, combined association results are presented.

Results: Over 246,698 person-years, 995 and 745 cases of incident dementia and Alzheimer's disease were detected, respectively. Three branched-chain amino acids (isoleucine, leucine, and valine), creatinine and two very low density lipoprotein (VLDL)-specific lipoprotein lipid subclasses were associated with lower dementia risk. One high density lipoprotein (HDL; the concentration of cholesterol esters relative to total lipids in large HDL) and one VLDL (total cholesterol to total lipids ratio in very large VLDL) lipoprotein lipid subclass was associated with increased dementia risk. Branched-chain amino acids were also associated with decreased Alzheimer's disease risk and the concentration of cholesterol esters relative to total lipids in large HDL with increased Alzheimer's disease risk.

Discussion: Further studies can clarify whether these molecules play a causal role in dementia pathogenesis or are merely markers of early pathology.
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http://dx.doi.org/10.1016/j.jalz.2018.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082422PMC
June 2018

Identification of seven novel loci associated with amino acid levels using single-variant and gene-based tests in 8545 Finnish men from the METSIM study.

Hum Mol Genet 2018 05;27(9):1664-1674

Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.

Comprehensive metabolite profiling captures many highly heritable traits, including amino acid levels, which are potentially sensitive biomarkers for disease pathogenesis. To better understand the contribution of genetic variation to amino acid levels, we performed single variant and gene-based tests of association between nine serum amino acids (alanine, glutamine, glycine, histidine, isoleucine, leucine, phenylalanine, tyrosine, and valine) and 16.6 million genotyped and imputed variants in 8545 non-diabetic Finnish men from the METabolic Syndrome In Men (METSIM) study with replication in Northern Finland Birth Cohort (NFBC1966). We identified five novel loci associated with amino acid levels (P = < 5×10-8): LOC157273/PPP1R3B with glycine (rs9987289, P = 2.3×10-26); ZFHX3 (chr16:73326579, minor allele frequency (MAF) = 0.42%, P = 3.6×10-9), LIPC (rs10468017, P = 1.5×10-8), and WWOX (rs9937914, P = 3.8×10-8) with alanine; and TRIB1 with tyrosine (rs28601761, P = 8×10-9). Gene-based tests identified two novel genes harboring missense variants of MAF <1% that show aggregate association with amino acid levels: PYCR1 with glycine (Pgene = 1.5×10-6) and BCAT2 with valine (Pgene = 7.4×10-7); neither gene was implicated by single variant association tests. These findings are among the first applications of gene-based tests to identify new loci for amino acid levels. In addition to the seven novel gene associations, we identified five independent signals at established amino acid loci, including two rare variant signals at GLDC (rs138640017, MAF=0.95%, Pconditional = 5.8×10-40) with glycine levels and HAL (rs141635447, MAF = 0.46%, Pconditional = 9.4×10-11) with histidine levels. Examination of all single variant association results in our data revealed a strong inverse relationship between effect size and MAF (Ptrend<0.001). These novel signals provide further insight into the molecular mechanisms of amino acid metabolism and potentially, their perturbations in disease.
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http://dx.doi.org/10.1093/hmg/ddy067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5905595PMC
May 2018

Effect of Dietary Counseling on a Comprehensive Metabolic Profile from Childhood to Adulthood.

J Pediatr 2018 04 1;195:190-198.e3. Epub 2018 Feb 1.

Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.

Objectives: To study the effects of repeated, infancy-onset dietary counseling on a detailed metabolic profile. Effects of dietary saturated fat replacement on circulating concentrations of metabolic biomarkers still remain unknown.

Study Design: The Special Turku Coronary Risk Factor Intervention Project (STRIP) study is a longitudinal, randomized atherosclerosis prevention trial in which repeated dietary counseling aimed at reducing the proportion of saturated fat intake. Nuclear magnetic resonance metabolomics quantified circulating metabolites from serum samples assessed at age 9 (n = 554), 11 (n = 553), 13 (n = 508), 15 (n = 517), 17 (n = 457), and 19 (n = 417) years.

Results: The intervention reduced dietary intake of saturated fat (mean difference in daily percentage of total energy intake: -2.1 [95% CI -1.9 to -2.3]) and increased intake of polyunsaturated fat (0.6 [0.5-0.7]). The dietary counseling intervention led to greater serum proportions of polyunsaturated fatty acids (P < .001), with greater proportions of both circulating omega-3 (P = .02) and omega-6 (P < .001) fatty acids. The proportion of saturated fatty acids in serum was lower for both boys and girls in the intervention group (P < .001), whereas the serum proportion of monounsaturated fat was lower for boys in the intervention group only (P < .001). The intervention also reduced circulating intermediate-density lipoprotein and low-density lipoprotein lipid concentrations (P < .01). Dietary intervention effects on nonlipid biomarkers were minor except from greater concentrations of glutamine in the intervention group.

Conclusions: Repeated dietary counseling from infancy to early adulthood yielded favorable effects on multiple circulating fatty acids and lipoprotein subclass lipids, particularly in boys. These molecular effects substantiate the beneficial role of saturated fat replacement on the metabolic risk profile.

Trial Registration: ClinicalTrials.gov: NCT00223600.
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http://dx.doi.org/10.1016/j.jpeds.2017.11.057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5864506PMC
April 2018

Nuclear magnetic resonance-based metabolomics identifies phenylalanine as a novel predictor of incident heart failure hospitalisation: results from PROSPER and FINRISK 1997.

Eur J Heart Fail 2018 04 11;20(4):663-673. Epub 2017 Dec 11.

Institute of Cardiovascular and Medical Sciences (ICAMS), BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.

Aims: We investigated the association between quantified metabolite, lipid and lipoprotein measures and incident heart failure hospitalisation (HFH) in the elderly, and examined whether circulating metabolic measures improve HFH prediction.

Methods And Results: Overall, 80 metabolic measures from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial were measured by proton nuclear magnetic resonance spectroscopy (n = 5341; 182 HFH events during 2.7-year follow-up). We repeated the work in FINRISK 1997 (n = 7330; 133 HFH events during 5-year follow-up). In PROSPER, the circulating concentrations of 13 metabolic measures were found to be significantly different in those who were later hospitalised for heart failure after correction for multiple comparisons. These included creatinine, phenylalanine, glycoprotein acetyls, 3-hydroxybutyrate, and various high-density lipoprotein measures. In Cox models, two metabolites were associated with risk of HFH after adjustment for clinical risk factors and N-terminal pro-B-type natriuretic peptide (NT-proBNP): phenylalanine [hazard ratio (HR) 1.29, 95% confidence interval (CI) 1.10-1.53; P = 0.002] and acetate (HR 0.81, 95% CI 0.68-0.98; P = 0.026). Both were retained in the final model after backward elimination. Compared to a model with established risk factors and NT-proBNP, this model did not improve the C-index but did improve the overall continuous net reclassification index (NRI 0.21; 95% CI 0.06-0.35; P = 0.007) due to improvement in classification of non-cases (NRI 0.14; 95% CI 0.12-0.17; P < 0.001). Phenylalanine was replicated as a predictor of HFH in FINRISK 1997 (HR 1.23, 95% CI 1.03-1.48; P = 0.023).

Conclusion: Our findings identify phenylalanine as a novel predictor of incident HFH, although prediction gains are low. Further mechanistic studies appear warranted.
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http://dx.doi.org/10.1002/ejhf.1076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947152PMC
April 2018

DHA mediates the protective effect of fish consumption on new episodes of depression among women.

Br J Nutr 2017 Nov;118(9):743-749

1Menzies Institute for Medical Research,University of Tasmania,Private Bag 23, Hobart, Tasmania 7000,Australia.

In a longitudinal cohort study of young Australian adults, we reported that for women higher baseline levels of fish consumption were associated with reduced incidence of new depressive episodes during the 5-year follow-up. Fish are high in both n-3 fatty acids and tyrosine. In this study, we seek to determine whether n-3 fatty acids or tyrosine explain the observed association. During 2004-2006, a FFQ (nine fish items) was used to estimate weekly fish consumption among 546 women aged 26-36 years. A fasting blood sample was taken and high-throughput NMR spectroscopy was used to measure 233 metabolites, including serum n-3 fatty acids and tyrosine. During 2009-2011, new episodes of depression since baseline were identified using the lifetime version of the Composite International Diagnostic Interview. Relative risks were calculated using log-binomial regression and indirect effects estimated using the STATA binary_mediation command. Potential mediators were added to separate models, and mediation was quantified as the proportion of the total effect due to the mediator. The n-3 DHA mediated 25·3 % of the association between fish consumption and depression when fish consumption was analysed as a continuous variable and 16·6 % when dichotomised (reference group: <2 serves/week). Tyrosine did not mediate the association (<0·1 %). Components in fish other than n-3 fatty acids and tyrosine might be beneficial for women's mental health.
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http://dx.doi.org/10.1017/S0007114517002768DOI Listing
November 2017

Quantitative Serum Nuclear Magnetic Resonance Metabolomics in Large-Scale Epidemiology: A Primer on -Omic Technologies.

Am J Epidemiol 2017 Nov;186(9):1084-1096

Detailed metabolic profiling in large-scale epidemiologic studies has uncovered novel biomarkers for cardiometabolic diseases and clarified the molecular associations of established risk factors. A quantitative metabolomics platform based on nuclear magnetic resonance spectroscopy has found widespread use, already profiling over 400,000 blood samples. Over 200 metabolic measures are quantified per sample; in addition to many biomarkers routinely used in epidemiology, the method simultaneously provides fine-grained lipoprotein subclass profiling and quantification of circulating fatty acids, amino acids, gluconeogenesis-related metabolites, and many other molecules from multiple metabolic pathways. Here we focus on applications of magnetic resonance metabolomics for quantifying circulating biomarkers in large-scale epidemiology. We highlight the molecular characterization of risk factors, use of Mendelian randomization, and the key issues of study design and analyses of metabolic profiling for epidemiology. We also detail how integration of metabolic profiling data with genetics can enhance drug development. We discuss why quantitative metabolic profiling is becoming widespread in epidemiology and biobanking. Although large-scale applications of metabolic profiling are still novel, it seems likely that comprehensive biomarker data will contribute to etiologic understanding of various diseases and abilities to predict disease risks, with the potential to translate into multiple clinical settings.
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http://dx.doi.org/10.1093/aje/kwx016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860146PMC
November 2017

Common, low-frequency, and rare genetic variants associated with lipoprotein subclasses and triglyceride measures in Finnish men from the METSIM study.

PLoS Genet 2017 Oct 30;13(10):e1007079. Epub 2017 Oct 30.

Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States of America.

Lipid and lipoprotein subclasses are associated with metabolic and cardiovascular diseases, yet the genetic contributions to variability in subclass traits are not fully understood. We conducted single-variant and gene-based association tests between 15.1M variants from genome-wide and exome array and imputed genotypes and 72 lipid and lipoprotein traits in 8,372 Finns. After accounting for 885 variants at 157 previously identified lipid loci, we identified five novel signals near established loci at HIF3A, ADAMTS3, PLTP, LCAT, and LIPG. Four of the signals were identified with a low-frequency (0.005
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http://dx.doi.org/10.1371/journal.pgen.1007079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679656PMC
October 2017

Differential Associations of Inflammatory Markers With Insulin Sensitivity and Secretion: The Prospective METSIM Study.

J Clin Endocrinol Metab 2017 09;102(9):3600-3609

Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio 70210, Finland.

Context: Low-grade inflammation is involved in the development of type 2 diabetes and cardiovascular disease (CVD); however, prospective studies evaluating inflammatory markers as predictors of changes in insulin secretion and insulin sensitivity are lacking.

Objective: We investigated the associations of glycoprotein acetyls (GlycA), interleukin-1 receptor antagonist (IL-1RA), and high-sensitivity C-reactive protein (hs-CRP) with insulin secretion, insulin sensitivity, incident type 2 diabetes, hypertension, CVD events, and total mortality in the prospective Metabolic Syndrome in Men (METSIM) study.

Design: A prospective study.

Participants: The cross-sectional METSIM study included 8749 nondiabetic Finnish men aged 45 to 73 years, who had been randomly selected from the population register of Kuopio, Finland. A total of 5401 men participated in the 6.8-year follow-up study.

Main Outcome Measures: Changes in insulin secretion, insulin sensitivity, and cardiometabolic traits during the follow-up period and the incidence of type 2 diabetes, hypertension, CVD events, and total mortality.

Results: During the follow-up period, GlycA was associated with impaired insulin secretion, hyperglycemia, incident type 2 diabetes (hazard ratio, 1.37; 95% confidence interval, 1.29 to 1.46) and CVD (hazard ratio, 1.21; 95% confidence interval, 1.12 to 1.32). IL-1RA and hs-CRP were associated with adverse changes in insulin sensitivity and obesity-related traits and with total mortality (hazard ratio, 1.13; 95% confidence interval, 1.07 to 1.20; and hazard ratio, 1.08; 95% confidence interval, 1.04 to 1.11, respectively).

Conclusions: Inflammatory markers differentially predicted changes in insulin secretion and insulin sensitivity. GlycA predicted impaired insulin secretion, and IL-1RA and hs-CRP predicted changes in insulin sensitivity. Combining the three markers improved the prediction of disease outcomes, suggesting that they capture different aspects of low-grade inflammation.
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http://dx.doi.org/10.1210/jc.2017-01057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587063PMC
September 2017

Association of pre-pregnancy body mass index with offspring metabolic profile: Analyses of 3 European prospective birth cohorts.

PLoS Med 2017 Aug 22;14(8):e1002376. Epub 2017 Aug 22.

MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom.

Background: A high proportion of women start pregnancy overweight or obese. According to the developmental overnutrition hypothesis, this could lead offspring to have metabolic disruption throughout their lives and thus perpetuate the obesity epidemic across generations. Concerns about this hypothesis are influencing antenatal care. However, it is unknown whether maternal pregnancy adiposity is associated with long-term risk of adverse metabolic profiles in offspring, and if so, whether this association is causal, via intrauterine mechanisms, or explained by shared familial (genetic, lifestyle, socioeconomic) characteristics. We aimed to determine if associations between maternal body mass index (BMI) and offspring systemic cardio-metabolic profile are causal, via intrauterine mechanisms, or due to shared familial factors.

Methods And Findings: We used 1- and 2-stage individual participant data (IPD) meta-analysis, and a negative-control (paternal BMI) to examine the association between maternal pre-pregnancy BMI and offspring serum metabolome from 3 European birth cohorts (offspring age at blood collection: 16, 17, and 31 years). Circulating metabolic traits were quantified by high-throughput nuclear magnetic resonance metabolomics. Results from 1-stage IPD meta-analysis (N = 5327 to 5377 mother-father-offspring trios) showed that increasing maternal and paternal BMI was associated with an adverse cardio-metabolic profile in offspring. We observed strong positive associations with very-low-density lipoprotein (VLDL)-lipoproteins, VLDL-cholesterol (C), VLDL-triglycerides, VLDL-diameter, branched/aromatic amino acids, glycoprotein acetyls, and triglycerides, and strong negative associations with high-density lipoprotein (HDL), HDL-diameter, HDL-C, HDL2-C, and HDL3-C (all P < 0.003). Slightly stronger magnitudes of associations were present for maternal compared with paternal BMI across these associations; however, there was no strong statistical evidence for heterogeneity between them (all bootstrap P > 0.003, equivalent to P > 0.05 after accounting for multiple testing). Results were similar in each individual cohort, and in the 2-stage analysis. Offspring BMI showed similar patterns of cross-sectional association with metabolic profile as for parental pre-pregnancy BMI associations but with greater magnitudes. Adjustment of parental BMI-offspring metabolic traits associations for offspring BMI suggested the parental associations were largely due to the association of parental BMI with offspring BMI. Limitations of this study are that inferences cannot be drawn about the role of circulating maternal fetal fuels (i.e., glucose, lipids, fatty acids, and amino acids) on later offspring metabolic profile. In addition, BMI may not reflect potential effects of maternal pregnancy fat distribution.

Conclusion: Our findings suggest that maternal BMI-offspring metabolome associations are likely to be largely due to shared genetic or familial lifestyle confounding rather than to intrauterine mechanisms.
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http://dx.doi.org/10.1371/journal.pmed.1002376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568725PMC
August 2017

An interaction map of circulating metabolites, immune gene networks, and their genetic regulation.

Genome Biol 2017 08 1;18(1):146. Epub 2017 Aug 1.

Department of Microbiology and Immunology, The University of Melbourne, Parkville, 3010, Victoria, Australia.

Background: Immunometabolism plays a central role in many cardiometabolic diseases. However, a robust map of immune-related gene networks in circulating human cells, their interactions with metabolites, and their genetic control is still lacking. Here, we integrate blood transcriptomic, metabolomic, and genomic profiles from two population-based cohorts (total N = 2168), including a subset of individuals with matched multi-omic data at 7-year follow-up.

Results: We identify topologically replicable gene networks enriched for diverse immune functions including cytotoxicity, viral response, B cell, platelet, neutrophil, and mast cell/basophil activity. These immune gene modules show complex patterns of association with 158 circulating metabolites, including lipoprotein subclasses, lipids, fatty acids, amino acids, small molecules, and CRP. Genome-wide scans for module expression quantitative trait loci (mQTLs) reveal five modules with mQTLs that have both cis and trans effects. The strongest mQTL is in ARHGEF3 (rs1354034) and affects a module enriched for platelet function, independent of platelet counts. Modules of mast cell/basophil and neutrophil function show temporally stable metabolite associations over 7-year follow-up, providing evidence that these modules and their constituent gene products may play central roles in metabolic inflammation. Furthermore, the strongest mQTL in ARHGEF3 also displays clear temporal stability, supporting widespread trans effects at this locus.

Conclusions: This study provides a detailed map of natural variation at the blood immunometabolic interface and its genetic basis, and may facilitate subsequent studies to explain inter-individual variation in cardiometabolic disease.
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http://dx.doi.org/10.1186/s13059-017-1279-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540552PMC
August 2017

-ancestry Fine Mapping and Molecular Assays Identify Regulatory Variants at the HDL-C GWAS Locus.

G3 (Bethesda) 2017 09 7;7(9):3217-3227. Epub 2017 Sep 7.

Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599

Recent genome-wide association studies (GWAS) have identified variants associated with high-density lipoprotein cholesterol (HDL-C) located in or near the gene. Given the extensive sharing of GWAS loci across populations, we hypothesized that at least one shared variant at this locus affects HDL-C. The HDL-C-associated variants are coincident with expression quantitative trait loci for and in subcutaneous adipose tissue; however, only expression levels are associated with HDL-C levels. We identified a 400-bp promoter region of and enhancer regions within 5 kb that contribute to regulating expression in liver and adipose. To identify variants functionally responsible for the HDL-C association, we performed fine-mapping analyses and selected 13 candidate variants that overlap putative regulatory regions to test for allelic differences in regulatory function. Of these variants, rs12463177-G increased transcriptional activity (1.5-fold, = 0.004) and showed differential protein binding. Six additional variants (rs17699089, rs200788077, rs56322906, rs3760782, rs737337, and rs3745683) showed evidence of allelic differences in transcriptional activity and/or protein binding. Taken together, these data suggest a regulatory mechanism at the HDL-C GWAS locus involving tissue-selective expression and at least one functional variant.
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http://dx.doi.org/10.1534/g3.117.300088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5592946PMC
September 2017

Experimental and Human Evidence for Lipocalin-2 (Neutrophil Gelatinase-Associated Lipocalin [NGAL]) in the Development of Cardiac Hypertrophy and heart failure.

J Am Heart Assoc 2017 Jun 14;6(6). Epub 2017 Jun 14.

School of Applied and Biomedical Sciences, Faculty of Science and Technology, Federation University Australia, Ballarat, Victoria, Australia

Background: Cardiac hypertrophy increases the risk of developing heart failure and cardiovascular death. The neutrophil inflammatory protein, lipocalin-2 (LCN2/NGAL), is elevated in certain forms of cardiac hypertrophy and acute heart failure. However, a specific role for LCN2 in predisposition and etiology of hypertrophy and the relevant genetic determinants are unclear. Here, we defined the role of LCN2 in concentric cardiac hypertrophy in terms of pathophysiology, inflammatory expression networks, and genomic determinants.

Methods And Results: We used 3 experimental models: a polygenic model of cardiac hypertrophy and heart failure, a model of intrauterine growth restriction and -knockout mouse; cultured cardiomyocytes; and 2 human cohorts: 114 type 2 diabetes mellitus patients and 2064 healthy subjects of the YFS (Young Finns Study). In hypertrophic heart rats, cardiac and circulating was significantly overexpressed before, during, and after development of cardiac hypertrophy and heart failure. expression was increased in hypertrophic hearts in a model of intrauterine growth restriction, whereas -knockout mice had smaller hearts. In cultured cardiomyocytes, activated molecular hypertrophic pathways and increased cell size, but reduced proliferation and cell numbers. Increased LCN2 was associated with cardiac hypertrophy and diastolic dysfunction in diabetes mellitus. In the YFS, expression was associated with body mass index and cardiac mass and with levels of inflammatory markers. The single-nucleotide polymorphism, rs13297295, located near defined a significant -eQTL for expression.

Conclusions: Direct effects of LCN2 on cardiomyocyte size and number and the consistent associations in experimental and human analyses reveal a central role for LCN2 in the ontogeny of cardiac hypertrophy and heart failure.
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http://dx.doi.org/10.1161/JAHA.117.005971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669193PMC
June 2017

Novel association of rs58542926 genotype with increased serum tyrosine levels and decreased apoB-100 particles in Finns.

J Lipid Res 2017 07 24;58(7):1471-1481. Epub 2017 May 24.

Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI

A glutamate-to-lysine variant (rs58542926-T) in transmembrane 6 superfamily member 2 () is associated with increased fatty liver disease and diabetes in conjunction with decreased cardiovascular disease risk. To identify mediators of the effects of , we tested for associations between rs58542926-T and serum lipoprotein/metabolite measures in cross-sectional data from nondiabetic statin-naïve participants. We identified independent associations between rs58542926-T and apoB-100 particles (β = -0.057 g/l, = 1.99 × 10) and tyrosine levels (β = 0.0020 mmol/l, = 1.10 × 10), controlling for potential confounders, in 6,929 Finnish men. The association between rs58542926-T and apoB-100 was confirmed in an independent sample of 2,196 Finnish individuals from the FINRISK study (β = -0.029, = 0.029). Secondary analyses demonstrated an rs58542926-T dose-dependent decrease in particle concentration, cholesterol, and triglyceride (TG) content for VLDL and LDL particles ( < 0.001 for all). No significant associations between rs58542926-T and HDL measures were observed. SNP rs58542926-T and tyrosine levels were associated with increased incident T2D risk in both METSIM and FINRISK. Decreased liver production/secretion of VLDL, decreased cholesterol and TGs in VLDL/LDL particles in serum, and increased tyrosine levels identify possible mechanisms by which rs58542926-T exerts its effects on increasing risk of fatty liver disease, decreasing cardiovascular disease, and increasing diabetes risk, respectively.
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http://dx.doi.org/10.1194/jlr.P076034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496043PMC
July 2017

The biomarker and causal roles of homoarginine in the development of cardiometabolic diseases: an observational and Mendelian randomization analysis.

Sci Rep 2017 04 25;7(1):1130. Epub 2017 Apr 25.

Department of Clinical Chemistry, Fimlab Laboratories, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.

High L-homoarginine (hArg) levels are directly associated with several risk factors for cardiometabolic diseases whereas low levels predict increased mortality in prospective studies. The biomarker role of hArg in young adults remains unknown. To study the predictive value of hArg in the development of cardiometabolic risk factors and diseases, we utilized data on high-pressure liquid chromatography-measured hArg, cardiovascular risk factors, ultrasound markers of preclinical atherosclerosis and type 2 diabetes from the population-based Young Finns Study involving 2,106 young adults (54.6% females, aged 24-39). We used a Mendelian randomization approach involving tens to hundreds of thousands of individuals to test causal associations. In our 10-year follow-up analysis, hArg served as an independent predictor for future hyperglycaemia (OR 1.31, 95% CI 1.06-1.63) and abdominal obesity (OR 1.60, 95% 1.14-2.30) in men and type 2 diabetes in women (OR 1.55, 95% CI 1.02-2.41). The MR analysis revealed no evidence of causal associations between serum hArg and any of the studied cardiometabolic outcomes. In conclusion, lifetime exposure to higher levels of circulating hArg does not seem to alter cardiometabolic disease risk. Whether hArg could be used as a biomarker for identification of individuals at risk developing cardiometabolic abnormalities merits further investigation.
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http://dx.doi.org/10.1038/s41598-017-01274-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430630PMC
April 2017

Relationships between gut microbiota, plasma metabolites, and metabolic syndrome traits in the METSIM cohort.

Genome Biol 2017 04 13;18(1):70. Epub 2017 Apr 13.

Department of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.

Background: The gut microbiome is a complex and metabolically active community that directly influences host phenotypes. In this study, we profile gut microbiota using 16S rRNA gene sequencing in 531 well-phenotyped Finnish men from the Metabolic Syndrome In Men (METSIM) study.

Results: We investigate gut microbiota relationships with a variety of factors that have an impact on the development of metabolic and cardiovascular traits. We identify novel associations between gut microbiota and fasting serum levels of a number of metabolites, including fatty acids, amino acids, lipids, and glucose. In particular, we detect associations with fasting plasma trimethylamine N-oxide (TMAO) levels, a gut microbiota-dependent metabolite associated with coronary artery disease and stroke. We further investigate the gut microbiota composition and microbiota-metabolite relationships in subjects with different body mass index and individuals with normal or altered oral glucose tolerance. Finally, we perform microbiota co-occurrence network analysis, which shows that certain metabolites strongly correlate with microbial community structure and that some of these correlations are specific for the pre-diabetic state.

Conclusions: Our study identifies novel relationships between the composition of the gut microbiota and circulating metabolites and provides a resource for future studies to understand host-gut microbiota relationships.
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http://dx.doi.org/10.1186/s13059-017-1194-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5390365PMC
April 2017

Corrigendum: Chronic Pyruvate Supplementation Increases Exploratory Activity and Brain Energy Reserves in Young and Middle-Aged Mice.

Front Aging Neurosci 2017 20;9:67. Epub 2017 Mar 20.

A. I. Virtanen Institute, University of Eastern Finland Kuopio, Finland.

[This corrects the article on p. 41 in vol. 8, PMID: 27014054.].
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http://dx.doi.org/10.3389/fnagi.2017.00067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5357803PMC
March 2017

Impaired HDL2-mediated cholesterol efflux is associated with metabolic syndrome in families with early onset coronary heart disease and low HDL-cholesterol level.

PLoS One 2017 16;12(2):e0171993. Epub 2017 Feb 16.

Department of Internal Medicine, Institute of Clinical Medicine and Biocenter Oulu, University of Oulu, Oulu, Finland and Medical Research Center, Oulu University Hospital, Oulu, Finland.

Objective: The potential of high-density lipoproteins (HDL) to facilitate cholesterol removal from arterial foam cells is a key function of HDL. We studied whether cholesterol efflux to serum and HDL subfractions is impaired in subjects with early coronary heart disease (CHD) or metabolic syndrome (MetS) in families where a low HDL-cholesterol level (HDL-C) predisposes to early CHD.

Methods: HDL subfractions were isolated from plasma by sequential ultracentrifugation. THP-1 macrophages loaded with acetyl-LDL were used in the assay of cholesterol efflux to total HDL, HDL2, HDL3 or serum.

Results: While cholesterol efflux to serum, total HDL and HDL3 was unchanged, the efflux to HDL2 was 14% lower in subjects with MetS than in subjects without MetS (p<0.001). The efflux to HDL2 was associated with components of MetS such as plasma HDL-C (r = 0.76 in men and r = 0.56 in women, p<0.001 for both). The efflux to HDL2 was reduced in men with early CHD (p<0.01) only in conjunction with their low HDL-C. The phospholipid content of HDL2 particles was a major correlate with the efflux to HDL2 (r = 0.70, p<0.001). A low ratio of HDL2 to total HDL was associated with MetS (p<0.001).

Conclusion: Our results indicate that impaired efflux to HDL2 is a functional feature of the low HDL-C state and MetS in families where these risk factors predispose to early CHD. The efflux to HDL2 related to the phospholipid content of HDL2 particles but the phospholipid content did not account for the impaired efflux in cardiometabolic disease, where a combination of low level and poor quality of HDL2 was observed.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0171993PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5313225PMC
August 2017

Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity.

Authors:
Simone Wahl Alexander Drong Benjamin Lehne Marie Loh William R Scott Sonja Kunze Pei-Chien Tsai Janina S Ried Weihua Zhang Youwen Yang Sili Tan Giovanni Fiorito Lude Franke Simonetta Guarrera Silva Kasela Jennifer Kriebel Rebecca C Richmond Marco Adamo Uzma Afzal Mika Ala-Korpela Benedetta Albetti Ole Ammerpohl Jane F Apperley Marian Beekman Pier Alberto Bertazzi S Lucas Black Christine Blancher Marc-Jan Bonder Mario Brosch Maren Carstensen-Kirberg Anton J M de Craen Simon de Lusignan Abbas Dehghan Mohamed Elkalaawy Krista Fischer Oscar H Franco Tom R Gaunt Jochen Hampe Majid Hashemi Aaron Isaacs Andrew Jenkinson Sujeet Jha Norihiro Kato Vittorio Krogh Michael Laffan Christa Meisinger Thomas Meitinger Zuan Yu Mok Valeria Motta Hong Kiat Ng Zacharoula Nikolakopoulou Georgios Nteliopoulos Salvatore Panico Natalia Pervjakova Holger Prokisch Wolfgang Rathmann Michael Roden Federica Rota Michelle Ann Rozario Johanna K Sandling Clemens Schafmayer Katharina Schramm Reiner Siebert P Eline Slagboom Pasi Soininen Lisette Stolk Konstantin Strauch E-Shyong Tai Letizia Tarantini Barbara Thorand Ettje F Tigchelaar Rosario Tumino Andre G Uitterlinden Cornelia van Duijn Joyce B J van Meurs Paolo Vineis Ananda Rajitha Wickremasinghe Cisca Wijmenga Tsun-Po Yang Wei Yuan Alexandra Zhernakova Rachel L Batterham George Davey Smith Panos Deloukas Bastiaan T Heijmans Christian Herder Albert Hofman Cecilia M Lindgren Lili Milani Pim van der Harst Annette Peters Thomas Illig Caroline L Relton Melanie Waldenberger Marjo-Riitta Järvelin Valentina Bollati Richie Soong Tim D Spector James Scott Mark I McCarthy Paul Elliott Jordana T Bell Giuseppe Matullo Christian Gieger Jaspal S Kooner Harald Grallert John C Chambers

Nature 2017 01 21;541(7635):81-86. Epub 2016 Dec 21.

Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK.

Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation, a key regulator of gene expression and molecular phenotype. Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 × 10, range P = 9.2 × 10 to 6.0 × 10; n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 × 10, range P = 5.5 × 10 to 6.1 × 10, n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07-2.56); P = 1.1 × 10). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.
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http://dx.doi.org/10.1038/nature20784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570525PMC
January 2017

Metabolic profiling of pregnancy: cross-sectional and longitudinal evidence.

BMC Med 2016 Dec 13;14(1):205. Epub 2016 Dec 13.

Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland.

Background: Pregnancy triggers well-known alterations in maternal glucose and lipid balance but its overall effects on systemic metabolism remain incompletely understood.

Methods: Detailed molecular profiles (87 metabolic measures and 37 cytokines) were measured for up to 4260 women (24-49 years, 322 pregnant) from three population-based cohorts in Finland. Circulating molecular concentrations in pregnant women were compared to those in non-pregnant women. Metabolic profiles were also reassessed for 583 women 6 years later to uncover the longitudinal metabolic changes in response to change in the pregnancy status.

Results: Compared to non-pregnant women, all lipoprotein subclasses and lipids were markedly increased in pregnant women. The most pronounced differences were observed for the intermediate-density, low-density and high-density lipoprotein triglyceride concentrations. Large differences were also seen for many fatty acids and amino acids. Pregnant women also had higher concentrations of low-grade inflammatory marker glycoprotein acetyls, higher concentrations of interleukin-18 and lower concentrations of interleukin-12p70. The changes in metabolic concentrations for women who were not pregnant at baseline but pregnant 6 years later (or vice versa) matched (or were mirror-images of) the cross-sectional association pattern. Cross-sectional results were consistent across the three cohorts and similar longitudinal changes were seen for 653 women in 4-year and 497 women in 10-year follow-up. For multiple metabolic measures, the changes increased in magnitude across the three trimesters.

Conclusions: Pregnancy initiates substantial metabolic and inflammatory changes in the mothers. Comprehensive characterisation of normal pregnancy is important for gaining understanding of the key nutrients for fetal growth and development. These findings also provide a valuable molecular reference in relation to studies of adverse pregnancy outcomes.
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http://dx.doi.org/10.1186/s12916-016-0733-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5153817PMC
December 2016

Blood hsa-miR-122-5p and hsa-miR-885-5p levels associate with fatty liver and related lipoprotein metabolism-The Young Finns Study.

Sci Rep 2016 12 5;6:38262. Epub 2016 Dec 5.

Department of Clinical Chemistry, Pirkanmaa Hospital District, Fimlab Laboratories, and University of Tampere, School of Medicine, Tampere, Finland.

MicroRNAs are involved in disease development and may be utilized as biomarkers. We investigated the association of blood miRNA levels and a) fatty liver (FL), b) lipoprotein and lipid pathways involved in liver lipid accumulation and c) levels of predicted mRNA targets in general population based cohort. Blood microRNA profiling (TaqMan OpenArray), genome-wide gene expression arrays and nuclear magnetic resonance metabolomics were performed for Young Finns Study participants aged 34-49 years (n = 871). Liver fat status was assessed ultrasonographically. Levels of hsa-miR-122-5p and -885-5p were up-regulated in individuals with FL (fold change (FC) = 1.55, p = 1.36 * 10 and FC = 1.25, p = 4.86 * 10, respectively). In regression model adjusted with age, sex and BMI, hsa-miR-122-5p and -885-5p predicted FL (OR = 2.07, p = 1.29 * 10 and OR = 1.41, p = 0.002, respectively). Together hsa-miR-122-5p and -885-5p slightly improved the detection of FL beyond established risk factors. These miRNAs may be associated with FL formation through the regulation of lipoprotein metabolism as hsa-miR-122-5p levels associated with small VLDL, IDL, and large LDL lipoprotein subclass components, while hsa-miR-885-5p levels associated inversely with XL HDL cholesterol levels. Hsa-miR-885-5p levels correlated inversely with oxysterol-binding protein 2 (OSBPL2) expression (r = -0.143, p = 1.00 * 10) and suppressing the expression of this lipid receptor and sterol transporter could link hsa-miR-885-5p with HDL cholesterol levels.
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http://dx.doi.org/10.1038/srep38262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5137183PMC
December 2016

Metabolic signatures of birthweight in 18 288 adolescents and adults.

Int J Epidemiol 2016 10;45(5):1539-1550

Department of Genomics and Biomarkers, National Institute for Health and Welfare, Helsinki, Finland.

Background: Lower birthweight is associated with increased susceptibility to cardiometabolic diseases in adulthood, but the underlying molecular pathways are incompletely understood. We examined associations of birthweight with a comprehensive metabolic profile measured in adolescents and adults.

Methods: High-throughput nuclear magnetic resonance metabolomics and biochemical assays were used to quantify 87 circulating metabolic measures in seven cohorts from Finland and the UK, comprising altogether 18 288 individuals (mean age 26 years, range 15-75). Metabolic associations with birthweight were assessed by linear regression models adjusted for sex, gestational age and age at blood sampling. The metabolic associations with birthweight were compared with the corresponding associations with adult body mass index (BMI).

Results: Lower birthweight adjusted for gestational age was adversely associated with cardiometabolic biomarkers, including lipoprotein subclasses, fatty acids, amino acids and markers of inflammation and impaired liver function (P < 0.0015 for 46 measures). Associations were consistent across cohorts with different ages at metabolic profiling, but the magnitudes were weak. The pattern of metabolic deviations associated with lower birthweight resembled the metabolic signature of higher adult BMI (R = 0.77) assessed at the same time as the metabolic profiling. The resemblance indicated that 1 kg lower birthweight is associated with similar metabolic aberrations as caused by 0.92 units higher BMI in adulthood.

Conclusions: Lower birthweight adjusted for gestational age is associated with adverse biomarker aberrations across multiple metabolic pathways. Coherent metabolic signatures between lower birthweight and higher adult adiposity suggest that shared molecular pathways may potentially underpin the metabolic deviations. However, the magnitudes of metabolic associations with birthweight are modest in comparison to the effects of adiposity, implying that birthweight is only a weak indicator of the metabolic risk profile in adulthood.
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http://dx.doi.org/10.1093/ije/dyw255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5100627PMC
October 2016

Metabolic profiling of fatty liver in young and middle-aged adults: Cross-sectional and prospective analyses of the Young Finns Study.

Hepatology 2017 02 24;65(2):491-500. Epub 2016 Dec 24.

Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.

Nonalcoholic fatty liver is associated with obesity-related metabolic disturbances, but little is known about the metabolic perturbations preceding fatty liver disease. We performed comprehensive metabolic profiling to assess how circulating metabolites, such as lipoprotein lipids, fatty acids, amino acids, and glycolysis-related metabolites, reflect the presence of and future risk for fatty liver in young adults. Sixty-eight lipids and metabolites were quantified by nuclear magnetic resonance metabolomics in the population-based Young Finns Study from serum collected in 2001 (n = 1,575), 2007 (n = 1,509), and 2011 (n = 2,002). Fatty liver was diagnosed by ultrasound in 2011 when participants were aged 34-49 years (19% prevalence). Cross-sectional associations as well as 4-year and 10-year risks for fatty liver were assessed by logistic regression. Metabolites across multiple pathways were strongly associated with the presence of fatty liver (P < 0.0007 for 60 measures in age-adjusted and sex-adjusted cross-sectional analyses). The strongest direct associations were observed for extremely large very-low-density lipoprotein triglycerides (odds ratio [OR] = 4.86 per 1 standard deviation, 95% confidence interval 3.48-6.78), other very-low-density lipoprotein measures, and branched-chain amino acids (e.g., leucine OR = 2.94, 2.51-3.44). Strong inverse associations were observed for high-density lipoprotein measures, e.g., high-density lipoprotein size (OR = 0.36, 0.30-0.42) and several fatty acids including omega-6 (OR = 0.37, 0.32-0.42). The metabolic associations were attenuated but remained significant after adjusting for waist, physical activity, alcohol consumption, and smoking (P < 0.0007). Similar aberrations in the metabolic profile were observed already 10 years before fatty liver diagnosis.

Conclusion: Circulating lipids, fatty acids, and amino acids reflect fatty liver independently of routine metabolic risk factors; these metabolic aberrations appear to precede the development of fatty liver in young adults. (Hepatology 2017;65:491-500).
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http://dx.doi.org/10.1002/hep.28899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5299457PMC
February 2017

Temperature responsive porous silicon nanoparticles for cancer therapy - spatiotemporal triggering through infrared and radiofrequency electromagnetic heating.

J Control Release 2016 11 26;241:220-228. Epub 2016 Sep 26.

University of Eastern Finland, Department of Applied Physics, 70211, Kuopio, Finland. Electronic address:

One critical functionality of the carrier system utilized in targeted drug delivery is its ability to trigger the release of the therapeutic cargo once the carrier has reached its target. External triggering is an alluring approach as it can be applied in a precise spatiotemporal manner. In the present study, we achieved external triggering through the porous silicon (PSi) nanoparticles (NPs) by providing a pulse of infrared or radiofrequency radiation. The NPs were grafted with a temperature responsive polymer whose critical temperature was tailored to be slightly above 37°C. The polymer coating improved the biocompatibility of the NPs significantly in comparison with their uncoated counterparts. Radiation induced a rapid temperature rise, which resulted in the collapse of the polymer chains facilitating the cargo release. Both infrared and radiofrequency radiation were able to efficiently trigger the release of the encapsulated drug in vitro and induce significant cell death in comparison to the control groups. Radiofrequency radiation was found to be more efficient in vitro, and the treatment efficacy was verified in vivo in a lung carcinoma (3LL) mice model. After a single intratumoral administration of the carrier system combined with radiofrequency radiation, there was clear suppression of the growth of the carcinoma and a prolongation of the survival time of the animals.

Toc Image: The temperature responsive (TR) polymer grafted on the surface of porous silicon nanoparticles (PSi NPs) changes its conformation in response to the heating induced by infrared or radiofrequency radiation. The conformation change allows the loaded doxorubicin to escape from the pores, achieving controlled drug release from TR PSi NPs, which displayed efficacy against malignant cells both in vitro and in vivo.
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http://dx.doi.org/10.1016/j.jconrel.2016.09.028DOI Listing
November 2016

Characterization of the metabolic profile associated with serum 25-hydroxyvitamin D: a cross-sectional analysis in population-based data.

Int J Epidemiol 2016 10 7;45(5):1469-1481. Epub 2016 Sep 7.

Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany,

Background: Numerous observational studies have observed associations between vitamin D deficiency and cardiometabolic diseases, but these findings might be confounded by obesity. A characterization of the metabolic profile associated with serum 25-hydroxyvitamin D [25(OH)D] levels, in general and stratified by abdominal obesity, may help to untangle the relationship between vitamin D, obesity and cardiometabolic health.

Methods: Serum metabolomics measurements were obtained from a nuclear magnetic resonance spectroscopy (NMR)- and a mass spectrometry (MS)-based platform. The discovery was conducted in 1726 participants of the population-based KORA-F4 study, in which the associations of the concentrations of 415 metabolites with 25(OH)D levels were assessed in linear models. The results were replicated in 6759 participants (NMR) and 609 (MS) participants, respectively, of the population-based FINRISK 1997 study.

Results: Mean [standard deviation (SD)] 25(OH)D levels were 15.2 (7.5) ng/ml in KORA F4 and 13.8 (5.9) ng/ml in FINRISK 1997; 37 metabolites were associated with 25(OH)D in KORA F4 at P < 0.05/415. Of these, 30 associations were replicated in FINRISK 1997 at P < 0.05/37. Among these were constituents of (very) large very-low-density lipoprotein and small low-density lipoprotein subclasses and related measures like serum triglycerides as well as fatty acids and measures reflecting the degree of fatty acid saturation. The observed associations were independent of waist circumference and generally similar in abdominally obese and non-obese participants.

Conclusions: Independently of abdominal obesity, higher 25(OH)D levels were associated with a metabolite profile characterized by lower concentrations of atherogenic lipids and a higher degree of fatty acid polyunsaturation. These results indicate that the relationship between vitamin D deficiency and cardiometabolic diseases is unlikely to merely reflect obesity-related pathomechanisms.
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http://dx.doi.org/10.1093/ije/dyw222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5100623PMC
October 2016