Publications
976 results found
Koot MH, Grooten IJ, Sebert S, et al., 2017, Hyperemesis gravidarum and cardiometabolic risk factors in adolescents: a follow-up of the Northern Finland Birth Cohort 1986., BJOG - An International Journal of Obstetrics and Gynaecology, Vol: 124, Pages: 1107-1114, ISSN: 1470-0328
OBJECTIVE: To investigate the long-term consequences of prenatal exposure to maternal hyperemesis gravidarum upon offspring cardiometabolic risk factors. DESIGN: This study is part of the prospective follow-up of the Northern Finland Birth Cohort 1986. SETTING: Between 1 July 1985 and 30 June 1986 all pregnant women in two provinces of Finland were recruited at first antenatal visit (99% of eligible participated). POPULATION: A total of 8953 women with liveborn singleton offspring who consented to having their children followed-up were included. METHODS: Hyperemesis gravidarum (HG) was defined as hospitalisation during pregnancy for HG based on the International Classification of Disease (ICD) code. Women who were not hospitalised for HG during pregnancy were used as a reference group. Data on pregnancy and birth outcomes were obtained via medical records and questionnaires; 6462 adolescents, aged 16 years, underwent anthropometric measurements (HG n = 42, reference n = 6420) and 5648 adolescents had a fasting blood sample taken (HG n = 36, reference n = 5612). MAIN OUTCOME MEASURES: Body mass index (BMI), blood pressure, fasting glucose, and lipid levels in offspring. RESULTS: Multivariate regression analyses showed no differences in offspring BMI (kg/m(2) ; adjusted percentage difference HG versus reference, 2.2; 95% CI -0.1, 4.6), systolic blood pressure (adjusted difference 2.1 mmHg; 95% CI -1.5, 5.6), and fasting blood glucose (mmol/l; adjusted percentage difference, 2.3; 95% CI -0.6, 5.4), between adolescents born to mothers with and without HG. CONCLUSIONS: We found no evidence that prenatal exposure to HG has negative consequences for cardiometabolic health of offspring at the age of 16 years.
Poobalasingam T, Yates LL, Walker SA, et al., 2017, Heterozygous Vangl2 looptail mice reveal novel roles for the planar cell polarity pathway in adult lung homeostasis and repair, Disease Models & Mechanisms, Vol: 10, Pages: 409-423, ISSN: 1754-8403
Lung diseases impose a huge economic and health burden worldwide. A key aspect of several adult lung diseases, such as Idiopathic pulmonary fibrosis (IPF) and Chronic Obstructive pulmonary Disease (COPD), including emphysema, is aberrant tissue repair, which leads to an accumulation of damage and impaired respiratory function. Currently, there are few effective treatments available for these diseases and their incidence is rising.The Planar Cell Polarity (PCP) pathway is critical for the embryonic development of many organs, including kidney and lung. We have previously shown that perturbation of the PCP pathway impairs tissue morphogenesis, which disrupts the number and shape of epithelial tubes formed within these organs during embryogenesis. However, very little is known about the role of the PCP pathway beyond birth, partly due to the perinatal lethality of many PCP mouse mutant lines.Here we have investigated heterozygous Looptail (Lp) mice, in which a single copy of the core PCP gene, Vangl2, is disrupted. We show that these mice are viable but display severe airspace enlargement and impaired adult lung function. Underlying these defects, we find that Vangl2Lp/+ lungs exhibit altered distribution of actin microfilaments and abnormal regulation of the actin modifying protein cofilin. In addition, we show that Vangl2Lp/+ lungs exhibit many of the hallmarks of tissue damage including an altered macrophage population, abnormal elastin deposition and elevated levels of the elastin-modifying enzyme, Mmp12, all of which are observed in the lung disease, emphysema.In vitro, VANGL2 disruption impairs directed cell migration and reduces the rate of repair following scratch wounding of human alveolar epithelial cells. Moreover, using population data from a birth cohort of young adults, all aged 31, we found evidence of an interactive effect between VANGL2 and smoking (a tissue damaging insult) on lung function. Finally, we show that that PCP genes VANGL2 and SCRIBBLE (SC
Kumar D, Puan KJ, Andiappan AK, et al., 2017, A functional SNP associated with atopic dermatitis controls cell type-specific methylation of the VSTM1 gene locus, GENOME MEDICINE, Vol: 9, ISSN: 1756-994X
Background:Expression quantitative trait loci (eQTL) databases represent a valuable resource to link disease-associated SNPs to specific candidate genes whose gene expression is significantly modulated by the SNP under investigation. We previously identified signal inhibitory receptor on leukocytes-1 (SIRL-1) as a powerful regulator of human innate immune cell function. While it is constitutively high expressed on neutrophils, on monocytes the SIRL-1 surface expression varies strongly between individuals. The underlying mechanism of regulation, its genetic control as well as potential clinical implications had not been explored yet.Methods:Whole blood eQTL data of a Chinese cohort was used to identify SNPs regulating the expression of VSTM1, the gene encoding SIRL-1. The genotype effect was validated by flow cytometry (cell surface expression), correlated with electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP) and bisulfite sequencing (C-methylation) and its functional impact studied the inhibition of reactive oxygen species (ROS).Results:We found a significant association of a single CpG-SNP, rs612529T/C, located in the promoter of VSTM1. Through flow cytometry analysis we confirmed that primarily in the monocytes the protein level of SIRL-1 is strongly associated with genotype of this SNP. In monocytes, the T allele of this SNP facilitates binding of the transcription factors YY1 and PU.1, of which the latter has been recently shown to act as docking site for modifiers of DNA methylation. In line with this notion rs612529T associates with a complete demethylation of the VSTM1 promoter correlating with the allele-specific upregulation of SIRL-1 expression. In monocytes, this upregulation strongly impacts the IgA-induced production of ROS by these cells. Through targeted association analysis we found a significant Meta P value of 1.14 × 10–6 for rs612529 for association to atopic dermatitis (AD).Conclusion:Low
Bousquet J, Farrell J, Crooks G, et al., 2017, Erratum to: Scaling up strategies of the chronic respiratory disease programme of the European Innovation Partnership on Active and Healthy Ageing (Action Plan B3: Area 5), CLINICAL AND TRANSLATIONAL ALLERGY, Vol: 7, ISSN: 2045-7022
Kaakinen M, Magi R, Fischer K, et al., 2017, MARV: a tool for genome-wide multi-phenotype analysis of rare variants, BMC BIOINFORMATICS, Vol: 18, ISSN: 1471-2105
Background:Genome-wide association studies have enabled identification of thousands of loci for hundreds of traits. Yet, for most human traits a substantial part of the estimated heritability is unexplained. This and recent advances in technology to produce high-dimensional data cost-effectively have led to method development beyond standard common variant analysis, including single-phenotype rare variant and multi-phenotype common variant analysis, with the latter increasing power for locus discovery and providing suggestions of pleiotropic effects. However, there are currently no optimal methods and tools for the combined analysis of rare variants and multiple phenotypes.Results:We propose a user-friendly software tool MARV for Multi-phenotype Analysis of Rare Variants. The tool is based on a method that collapses rare variants within a genomic region and models the proportion of minor alleles in the rare variants on a linear combination of multiple phenotypes. MARV provides analyses of all phenotype combinations within one run and calculates the Bayesian Information Criterion to facilitate model selection. The running time increases with the size of the genetic data while the number of phenotypes to analyse has little effect both on running time and required memory. We illustrate the use of MARV with analysis of triglycerides (TG), fasting insulin (FI) and waist-to-hip ratio (WHR) in 4,721 individuals from the Northern Finland Birth Cohort 1966. The analysis suggests novel multi-phenotype effects for these metabolic traits at APOA5 and ZNF259, and at ZNF259 provides stronger support for association (P TG+FI = 1.8 × 10−9) than observed in single phenotype rare variant analyses (P TG = 6.5 × 10−8 and P FI = 0.27).Conclusions:MARV is a computationally efficient, flexible and user-friendly software tool allowing rapid identification of rare variant effects on multiple phenot
Tikanmaki M, Tammelin T, Kaseva N, et al., 2017, Objectively measured physical activity and sedentary time in young adults born preterm-The ESTER study, PEDIATRIC RESEARCH, Vol: 81, Pages: 550-555, ISSN: 0031-3998
Background:Young adults born preterm have higher levels of cardio metabolic risk factors and they report less physical activity than their peers born at term. Physical activity provides important cardio metabolic health benefits. We hypothesized that objectively measured physical activity levels are lower and time spent sedentary is higher among preterm-born individuals compared with controls.Methods:We studied unimpaired participants of the ESTER birth cohort study at age 23.3 y (SD: 1.2): 60 born early preterm (<34 wk), 108 late preterm (34–36 wk), and 178 at term (controls). Physical activity and sedentary time were measured by hip-worn accelerometer (ActiGraph).Results:As compared with controls’ (mean physical activity, 303 counts per minute (cpm; SD 129)), physical activity was similar among adults born early preterm (mean difference = 21 cpm, 95% CI −61, 19) or late preterm (5 cpm, −27, 38). Time spent sedentary was also similar. Adjustments for early life confounders or current mediating characteristics did not change the results.Conclusion:In contrast to our hypothesis, we found no difference in objectively measured physical activity or time spent sedentary between adults born preterm and at term. The previously reported differences may be limited to physical activity captured by self-report.Follow-up studies of adolescents and adults born preterm suggest that those born smallest report less physical activity and are less fit than term-born individuals (1,2,3,4). The differences can be substantial: as assessed by a comprehensive 12-mo physical activity questionnaire, unimpaired adults born preterm at very low birth weight (< 1,500 g) report over 50% lower energy expenditure from leisure-time conditioning physical activity than controls born at term (3). This may contribute to the increased cardio metabolic risk profile reported in this group (5,6). However, these infants constitute only a minority of preterm
Kreiner E, Waage J, Standl M, et al., 2017, Shared genetic variants suggest common pathways in allergy and autoimmune diseases., Journal of Allergy and Clinical Immunology, Vol: 140, Pages: 771-781, ISSN: 1097-6825
BACKGROUND: The relationship between allergy and autoimmune disorders is complex and poorly understood. OBJECTIVE: We sought to investigate commonalities in genetic loci and pathways between allergy and autoimmune diseases to elucidate shared disease mechanisms. METHODS: We meta-analyzed 2 genome-wide association studies on self-reported allergy and sensitization comprising a total of 62,330 subjects. These results were used to calculate enrichment for single nucleotide polymorphisms (SNPs) previously associated with autoimmune diseases. Furthermore, we probed for enrichment within genetic pathways and of transcription factor binding sites and characterized commonalities in variant burden on tissue-specific regulatory sites by calculating the enrichment of allergy SNPs falling in gene regulatory regions in various cells using Encode Roadmap DNase-hypersensitive site data. Finally, we compared the allergy data with those of all known diseases. RESULTS: Among 290 loci previously associated with 16 autoimmune diseases, we found a significant enrichment of loci also associated with allergy (P = 1.4e-17) encompassing 29 loci at a false discovery rate of less than 0.05. Such enrichment seemed to be a general characteristic for autoimmune diseases. Among the common loci, 48% had the same direction of effect for allergy and autoimmune diseases. Additionally, we observed an enrichment of allergy SNPs falling within immune pathways and regions of chromatin accessible in immune cells that was also represented in patients with autoimmune diseases but not those with other diseases. CONCLUSION: We identified shared susceptibility loci and commonalities in pathways between allergy and autoimmune diseases, suggesting shared disease mechanisms. Further studies of these shared genetic mechanisms might help in understanding the complex relationship between these diseases, including the parallel increase in disease prevalence.
Wain LV, Shrine N, Artigas MS, et al., 2017, Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets, Nature Genetics, Vol: 49, Pages: 416-425, ISSN: 1061-4036
Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (~6 alleles) (95% confidence interval) = 1.24 (1.20–1.27), P = 5.05 × 10−49), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.
Ollila M-ME, West S, Keinanen-Kiukaanniemi S, et al., 2017, Overweight and obese but not normal weight women with PCOS are at increased risk of Type 2 diabetes mellitus-a prospective, population-based cohort study, Human Reproduction, Vol: 32, Pages: 423-431, ISSN: 1460-2350
STUDY QUESTIONWhat are the respective roles of polycystic ovary syndrome (PCOS), long-term weight gain and obesity for the development of prediabetes or Type 2 diabetes mellitus (T2DM) by age 46 years?SUMMARY ANSWERThe risk of T2DM in women with PCOS is mainly due to overweight and obesity, although these two factors have a synergistic effect on the development of T2DM.WHAT IS KNOWN ALREADYPCOS is associated with an increased risk of prediabetes and T2DM. However, the respective roles of PCOS per se and BMI for the development of T2DM have remained unclear.STUDY DESIGN, SIZE, DURATIONIn a prospective, general population-based follow-up birth cohort 1966 (n = 5889), postal questionnaires were sent at ages 14 (95% answered), 31 (80% answered) and 46 years (72% answered). Questions about oligoamenorrhoea and hirsutism were asked at age 31 years, and a question about PCOS diagnosis at 46 years. Clinical examination and blood sampling were performed at 31 years in 3127 women, and at 46 years in 3280 women. A 2-h oral glucose tolerance test (OGTT) was performed at 46 years of age in 2780 women.PARTICIPANTS/MATERIALS, SETTING, METHODSWomen reporting both oligoamenorrhoea and hirsutism at age 31 years and/or diagnosis of PCOS by 46 years were considered as women with PCOS (n = 279). Women without any symptoms at 31 years and without PCOS diagnosis by 46 years were considered as controls (n = 1577). The level of glucose metabolism was classified according to the results of the OGTT and previous information of glucose metabolism status from the national drug and hospital discharge registers.MAIN RESULTS AND THE ROLE OF CHANCEPCOS per se significantly increased the risk of T2DM in overweight/obese (BMI ≥ 25.0 kg/m2) women with PCOS when compared to overweight/obese controls (odds ratio: 2.45, 95% CI: 1.28–4.67). Normal weight women with PCOS did not present with an increased risk of prediabetes or T2DM. The increase in weight between ages 14, 31 and 46 years was signi
Mutt SJ, Shere RG, Jarvelin M, et al., 2017, Effect of vitamin D on mesenteric artery function in vitamin D-deficient mice, Publisher: WILEY-BLACKWELL, Pages: 36-36, ISSN: 1748-1708
Hinney A, Kesselmeier M, Jall S, et al., 2017, Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index., Mol Psychiatry, Vol: 22, Pages: 192-201
The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single-nucleotide polymorphisms (SNPs) with the lowest P-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI-related loci was performed in the AN GWAMA. We detected significant associations (P-values <5 × 10(-5), Bonferroni-corrected P<0.05) for nine SNP alleles at three independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; Poverall: 2.47 × 10(-06)/Pfemales: 3.45 × 10(-07)/Pmales: 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet-induced obese (DIO) mice as compared with age-matched lean controls. We observed no evidence for associations for the look-up of BMI-related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly pr
Warren HR, Evangelou E, Cabrera CP, et al., 2017, Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk, Nature Genetics, Vol: 49, Pages: 403-415, ISSN: 1546-1718
Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk.
Aschard H, Tobin MD, Hancock DB, et al., 2017, Evidence for large-scale gene-by-smoking interaction effects on pulmonary function., International Journal of Epidemiology, Vol: 46, Pages: 894-904, ISSN: 1464-3685
BACKGROUND: Smoking is the strongest environmental risk factor for reduced pulmonary function. The genetic component of various pulmonary traits has also been demonstrated, and at least 26 loci have been reproducibly associated with either FEV1 (forced expiratory volume in 1 second) or FEV1/FVC (FEV1/forced vital capacity). Although the main effects of smoking and genetic loci are well established, the question of potential gene-by-smoking interaction effect remains unanswered. The aim of the present study was to assess, using a genetic risk score approach, whether the effect of these 26 loci on pulmonary function is influenced by smoking. METHODS: We evaluated the interaction between smoking exposure, considered as either ever vs never or pack-years, and a 26-single nucleotide polymorphisms (SNPs) genetic risk score in relation to FEV1 or FEV1/FVC in 50 047 participants of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and SpiroMeta consortia. RESULTS: We identified an interaction (βint = -0.036, 95% confidence interval, -0.040 to -0.032, P = 0.00057) between an unweighted 26 SNP genetic risk score and smoking status (ever/never) on the FEV1/FVC ratio. In interpreting this interaction, we showed that the genetic risk of falling below the FEV 1: /FVC threshold used to diagnose chronic obstructive pulmonary disease is higher among ever smokers than among never smokers. A replication analysis in two independent datasets, although not statistically significant, showed a similar trend in the interaction effect. CONCLUSIONS: This study highlights the benefit of using genetic risk scores for identifying interactions missed when studying individual SNPs and shows, for the first time, that persons with the highest genetic risk for low FEV1/FVC may be more susceptible to the deleterious effects of smoking.
Sanders AE, Jain D, Sofer T, et al., 2017, GWAS Identifies New Loci for Painful Temporomandibular Disorder: Hispanic Community Health Study/Study of Latinos., Journal of Dental Research, Vol: 96, Pages: 277-284, ISSN: 0022-0345
Temporomandibular disorder (TMD) is a musculoskeletal condition characterized by pain and reduced function in the temporomandibular joint and/or associated masticatory musculature. Prevalence in the United States is 5% and twice as high among women as men. We conducted a discovery genome-wide association study (GWAS) of TMD in 10,153 participants (769 cases, 9,384 controls) of the US Hispanic Community Health Study/Study of Latinos (HCHS/SOL). The most promising single-nucleotide polymorphisms (SNPs) were tested in meta-analysis of 4 independent cohorts. One replication cohort was from the United States, and the others were from Germany, Finland, and Brazil, totaling 1,911 TMD cases and 6,903 controls. A locus near the sarcoglycan alpha ( SGCA), rs4794106, was suggestive in the discovery analysis ( P = 2.6 × 10(6)) and replicated (i.e., 1-tailed P = 0.016) in the Brazilian cohort. In the discovery cohort, sex-stratified analysis identified 2 additional genome-wide significant loci in females. One lying upstream of the relaxin/insulin-like family peptide receptor 2 ( RXP2) (chromosome 13, rs60249166, odds ratio [OR] = 0.65, P = 3.6 × 10(-8)) was replicated among females in the meta-analysis (1-tailed P = 0.052). The other (chromosome 17, rs1531554, OR = 0.68, P = 2.9 × 10(-8)) was replicated among females (1-tailed P = 0.002), as well as replicated in meta-analysis of both sexes (1-tailed P = 0.021). A novel locus at genome-wide level of significance (rs73460075, OR = 0.56, P = 3.8 × 10(-8)) in the intron of the dystrophin gene DMD (X chromosome), and a suggestive locus on chromosome 7 (rs73271865, P = 2.9 × 10(-7)) upstream of the Sp4 Transcription Factor ( SP4) gene were identified in the discovery cohort, but neither of these was replicated. The SGCA gene encodes SGCA, which is involved in the cellular structure of muscle fibers and, along with DMD, forms part of the dystrophin-glycoprotein complex. Functional annotation suggested tha
Bousquet J, Bewick M, Cano A, et al., 2017, Building bridges for innovation in ageing: Synergies between action groups of the EIP on AHA, Journal of Nutrition, Health and Aging, Vol: 21, Pages: 92-104, ISSN: 1279-7707
The Strategic Implementation Plan of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) proposed six Action Groups. After almost three years of activity, many achievements have been obtained through commitments or collaborative work of the Action Groups. However, they have often worked in silos and, consequently, synergies between Action Groups have been proposed to strengthen the triple win of the EIP on AHA. The paper presents the methodology and current status of the Task Force on EIP on AHA synergies. Synergies are in line with the Action Groups’ new Renovated Action Plan (2016-2018) to ensure that their future objectives are coherent and fully connected. The outcomes and impact of synergies are using the Monitoring and Assessment Framework for the EIP on AHA (MAFEIP). Eight proposals for synergies have been approved by the Task Force: Five cross-cutting synergies which can be used for all current and future synergies as they consider overarching domains (appropriate polypharmacy, citizen empowerment, teaching and coaching on AHA, deployment of synergies to EU regions, Responsible Research and Innovation), and three cross-cutting synergies focussing on current Action Group activities (falls, frailty, integrated care and chronic respiratory diseases).
Bousquet J, Hellings PW, Agache I, et al., 2016, ARIA 2016: Care pathways implementing emerging technologies for predictive medicine in rhinitis and asthma across the life cycle, Clinical and Translational Allergy, Vol: 6, ISSN: 2045-7022
The Allergic Rhinitis and its Impact on Asthma (ARIA) initiative commenced during a World Health Organization workshop in 1999. The initial goals were (1) to propose a new allergic rhinitis classification, (2) to promote the concept of multi-morbidity in asthma and rhinitis and (3) to develop guidelines with all stakeholders that could be used globally for all countries and populations. ARIA—disseminated and implemented in over 70 countries globally—is now focusing on the implementation of emerging technologies for individualized and predictive medicine. MASK [MACVIA (Contre les Maladies Chroniques pour un Vieillissement Actif)-ARIA Sentinel NetworK] uses mobile technology to develop care pathways for the management of rhinitis and asthma by a multi-disciplinary group and by patients themselves. An app (Android and iOS) is available in 20 countries and 15 languages. It uses a visual analogue scale to assess symptom control and work productivity as well as a clinical decision support system. It is associated with an inter-operable tablet for physicians and other health care professionals. The scaling up strategy uses the recommendations of the European Innovation Partnership on Active and Healthy Ageing. The aim of the novel ARIA approach is to provide an active and healthy life to rhinitis sufferers, whatever their age, sex or socio-economic status, in order to reduce health and social inequalities incurred by the disease.
Wahl S, Drong A, Lehne B, et al., 2016, Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity, Nature, Vol: 541, Pages: 81-+, ISSN: 0028-0836
Approximately 1.5 billion people worldwide are overweight oraffected by obesity, and are at risk of developing type 2 diabetes,cardiovascular disease and related metabolic and inflammatorydisturbances1,2. Although the mechanisms linking adiposity toassociated clinical conditions are poorly understood, recent studiessuggest that adiposity may influence DNA methylation3–6, a keyregulator of gene expression and molecular phenotype7. Here weuse epigenome-wide association to show that body mass index(BMI; a key measure of adiposity) is associated with widespreadchanges in DNA methylation (187 genetic loci with P<1×10−7,range P=9.2×10−8 to 6.0×10−46; n=10,261 samples). Geneticassociation analyses demonstrate that the alterations in DNAmethylation are predominantly the consequence of adiposity,rather than the cause. We find that methylation loci are enrichedfor functional genomic features in multiple tissues (P<0.05), andshow that sentinel methylation markers identify gene expressionsignatures at 38 loci (P < 9.0 × 10−6, range P = 5.5 × 10−6 to6.1×10−35, n=1,785 samples). The methylation loci identify genesinvolved in lipid and lipoprotein metabolism, substrate transportand inflammatory pathways. Finally, we show that the disturbancesin DNA methylation predict future development of type 2 diabetes(relative risk per 1 standard deviation increase in methylation riskscore: 2.3 (2.07–2.56); P=1.1×10−54). Our results provide newinsights into the biologic pathways influenced by adiposity, and mayenable development of new strategies for prediction and preventionof type 2 diabetes and other adverse clinical consequences of obesity
Wang Q, Wurtz P, Auro K, et al., 2016, Metabolic profiling of pregnancy: cross-sectional and longitudinal evidence., BMC MEDICINE, Vol: 14, ISSN: 1741-7015
AbstractBackgroundPregnancy triggers well-known alterations in maternal glucose and lipid balance but its overall effects on systemic metabolism remain incompletely understood.MethodsDetailed 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.ResultsCompared 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.ConclusionsPregnancy 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.
Uimari O, Auvinen J, Jokelainen J, et al., 2016, Uterine fibroids and cardiovascular risk., Human Reproduction, Vol: 31, Pages: 2689-2703, ISSN: 1460-2350
STUDY QUESTION: Are uterine fibroids associated with increased cardiovascular risk? SUMMARY ANSWER: This study reports an association between increased serum lipids and metabolic syndrome with an increased risk of uterine fibroids. WHAT IS KNOWN ALREADY: Recent studies suggest similarities in biological disease mechanisms and risk factors for fibroids and atherosclerosis: obesity, hypertension and abnormal serum lipids. These findings are awaiting confirmation that a population-based follow-up study could offer with extensive health examination data collection linked with a national hospital discharge register. STUDY DESIGN, SIZE, DURATION: The Northern Finland Birth Cohort (NFBC1966) is a population-based long-term follow-up study including all children with estimated date of delivery in 1966 in the Northern Finland area. The data were collected from national registries, postal questionnaires and clinical health examinations. The study population for this study comprised all females included in the NFBC1966 that underwent an extensive clinical health examination at age 46 years (n = 3635). PARTICIPANTS/MATERIALS, SETTING, METHODS: All females included in the NFBC1966 who were alive and traceable (n = 5118) were invited for the 46-year follow-up study; 3268 (63.9%) responded, returned the postal questionnaire and attended the clinical examination. Uterine fibroid cases were identified through the national hospital discharge register that has data on disease diagnoses based on WHO ICD-codes. Uterine fibroid codes, ICD-9: 218 and ICD-10: D25 were used for case identification. Self-reported fibroid cases were identified through the postal questionnaire. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 729 fibroid cases were identified, including 293 based on hospital discharge registries. With adjustment for BMI, parity, education and current use of exogenous hormones the risk of prevalent fibroids rose significantly for every 1 mmol/l increase in LD
Schumann G, Liu C, O'Reilly P, et al., 2016, KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference, Proceedings of the National Academy of Sciences of the United States of America, Vol: 113, Pages: 14372-14377, ISSN: 1091-6490
Alcohol is a widely consumed drug in western societies that can lead to addiction. A small shift in consumption can have dramatic consequences on public health. We performed the largest genome-wide association metaanalysis and replication study to date (>105,000 individuals) and identified a genetic basis for alcohol consumption during nonaddictive drinking. We found that a locus in the gene encoding β-Klotho is associated with alcohol consumption. β-Klotho is an essential receptor component for the endocrine FGFs, FGF19 and FGF21. Using mouse models and pharmacologic administration of FGF21, we show that β-Klotho in the brain controls alcohol drinking. These findings reveal a mechanism regulating alcohol consumption in humans that may be pharmacologically tractable for reducing alcohol intake.
Bousquet J, Bewick M, Cano A, et al., 2016, Erratum to: Building bridges for innovation in ageing: Synergies between action groups of the EIP on AHA, Journal of Nutrition, Health and Aging, Vol: 2016, Pages: 1-1, ISSN: 1279-7707
The authors would like to change and use the correct name of M. Khaitov which is M. Kaitov on this manuscript. The authors have incorrectly used her other name during the finalization of this research. With this, the authors hereby publish the correct author names as presented above.
Ried JS, Jeff JM, Chu AY, et al., 2016, A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape, Nature Communications, Vol: 7, ISSN: 2041-1723
Large consortia have revealed hundreds of genetic loci associated with anthropometric traits,one trait at a time. We examined whether genetic variants affect body shape as a compositephenotype that is represented by a combination of anthropometric traits. We developed anapproach that calculates averaged PCs (AvPCs) representing body shape derived fromsix anthropometric traits (body mass index, height, weight, waist and hip circumference,waist-to-hip ratio). The first four AvPCs explain499% of the variability, are heritable, andassociate with cardiometabolic outcomes. We performed genome-wide association analysesfor each body shape composite phenotype across 65 studies and meta-analysed summarystatistics. We identify six novel loci:LEMD2andCD47for AvPC1,RPS6KA5/C14orf159andGANABfor AvPC3, andARL15andANP32for AvPC4. Our findings highlight the value ofusing multiple traits to define complex phenotypes for discovery, which are not captured bysingle-trait analyses, and may shed light onto new pathways.
Nieuwenhuis MA, Vonk JM, Himes BE, et al., 2016, PTTG1IP and MAML3, novel GWAS genes for severity of hyperresponsiveness in adult asthma., Allergy, Vol: 72, Pages: 792-801, ISSN: 0105-4538
BACKGROUND: The severity of bronchial hyperresponsiveness (BHR) is a fundamental feature of asthma. The severity of BHR varies between asthmatics and is associated with lack of asthma control. The mechanisms underlying this trait are still unclear. This study aims to identify genes associated with BHR severity, using a genome wide association study (GWAS) on the slope of BHR in adult asthmatics. METHODS: We performed a GWAS on BHR severity in adult asthmatics from the Dutch Asthma GWAS cohort (n=650), adjusting for smoking and inhaled corticosteroid use, and verified results in 3 other cohorts. Furthermore, we performed eQTL and co-expression analyses in lung tissue. RESULTS: In the discovery cohort, one genome wide significant hit located in phosphodiesterase 4D, cAMP-specif (PDE4D) and 26 SNPs with p-values <1*10(-5) were found. None of our findings replicated in adult and childhood replication cohorts jointly. In adult cohorts separately, rs1344110 in pituitary tumor-transforming 1 interacting protein (PTTG1IP) and rs345983 in Mastermind-like 3 (MAML3) replicated nominally; minor alleles of rs345983 and rs1344110 were associated with less severe BHR and higher lung tissue gene expression. PTTG1IP showed significant co-expression with pituitary tumor-transforming 1, the binding factor of PTTG1lP, and with Vimentin and E-Cadherin1. MAML3 co-expressed significantly with Mastermind-like 2 (MAML2), both involved in Notch signalling. CONCLUSIONS: PTTG1IP and MAML3 are associated with BHR severity in adult asthma. The relevance of these genes is supported by the eQTL analyses and co-expression of PTTG1lP with Vimentin and E-Cadherin1, and MAML3 with MAML2. This article is protected by copyright. All rights reserved.
Wurtz P, Wang Q, Niironen M, et al., 2016, Metabolic signatures of birthweight in 18 288 adolescents and adults, International Journal of Epidemiology, Vol: 45, Pages: 1539-1550, ISSN: 1464-3685
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 (R2 = 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, implyi
Bousquet J, Anto JM, Akdis M, et al., 2016, Paving the way of systems biology and precision medicine in allergic diseases: the MeDALL success story: Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015., Allergy, Vol: 71, Pages: 1513-1525
MeDALL (Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015) has proposed an innovative approach to develop early indicators for the prediction, diagnosis, prevention and targets for therapy. MeDALL has linked epidemiological, clinical and basic research using a stepwise, large-scale and integrative approach: MeDALL data of precisely phenotyped children followed in 14 birth cohorts spread across Europe were combined with systems biology (omics, IgE measurement using microarrays) and environmental data. Multimorbidity in the same child is more common than expected by chance alone, suggesting that these diseases share causal mechanisms irrespective of IgE sensitization. IgE sensitization should be considered differently in monosensitized and polysensitized individuals. Allergic multimorbidities and IgE polysensitization are often associated with the persistence or severity of allergic diseases. Environmental exposures are relevant for the development of allergy-related diseases. To complement the population-based studies in children, MeDALL included mechanistic experimental animal studies and in vitro studies in humans. The integration of multimorbidities and polysensitization has resulted in a new classification framework of allergic diseases that could help to improve the understanding of genetic and epigenetic mechanisms of allergy as well as to better manage allergic diseases. Ethics and gender were considered. MeDALL has deployed translational activities within the EU agenda.
Nasanen-Gilmore P, Sipola-Leppanen M, Tikanmaki M, et al., 2016, LATE PRETERM BIRTH PROTECTS AGAINST ALLERGIES IN ADULTHOOD, Publisher: SPRINGER, Pages: 1469-1470, ISSN: 0340-6199
Abass K, Koiranen M, Mazej D, et al., 2016, Arsenic, cadmium, lead and mercury levels in blood of Finnish adults and their relation to diet, lifestyle habits and sociodemographic variables, Environmental Science and Pollution Research, Vol: 24, Pages: 1347-1362, ISSN: 1614-7499
The Northern Finland Birth Cohort program (NFBC) is the epidemiological and longitudinal prospective general population research program, which was established to promote health and wellbeing of the population in northern Finland. The aim of present study, as a part of the NFBC program, was to analyze the blood levels of arsenic (B-As), cadmium (B-Cd), lead (B-Pb), total mercury (B-Hg) and selenium (B-Se); to compare these levels with threshold limits; to study sociodemographic factors; and to correlate these levels with calcium and haemoglobin. The study was comprised of 249 NFBC subjects, of which 123 were female and 126 were male (ages 31.1 ± 0.3 and 31.1 ± 0.4, respectively). All participants were asked to complete a questionnaire regarding diet and living habits. The geometric means (± SD) of B-As were 0.49 ± 2.80 μg/l and 0.44 ± 2.72 μg/l; B-Cd were 0.18 ± 4.02 μg/l and 0.12 ± 3.21 μg/l; B-Pb were 17.0 ± 1.8 μg/l and 9.06 ± 2.20 μg/l; B-Hg were 2.18 ± 2.02 μg/l and 1.85 ± 1.78 μg/l; and B-Se were 106.0 ± 1.3 and 94.3 ± 1.3 μg/l in males and females, respectively. Among the subjects in the present analysis, 23 % of males and 17.1 % of females had B-As levels above the ATSDR normal human levels of B-As in unexposed individuals (1.0 μg/l). The B-Pb geometric mean (12.44 μg/l) was approximately one eighth the CDC toxicological cut-off point of 100 μg/l. Twenty-one individuals (8.4 %) exceeded a B-Hg level of 5.8 μg/l. Fifty-eight females (47 %) had a B-Hg higher than 2.0 μg/l, the German Federal Environmental Agency cut-off point for women (18–69 years) who consume fish at least three times/month; therefore, their babies could be at risk of adverse effects during development.
Gormley P, Anttila V, Winsvold BS, et al., 2016, Correction: Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine, Nature Genetics, Vol: 48, Pages: 1296-1296, ISSN: 1061-4036
In the version of this article initially published online, the affiliations for Bertram Muller-Myhsok and Patricia Pozo-Rosich were incorrect or incomplete. These errors have been corrected for the print, PDF and HTML versions of this article.
Huovinen J, Rautio N, Isohanni M, et al., 2016, A 3-fold risk of metabolic syndrome with a susceptibility to impaired glucose tolerance in non-schizophrenic psychoses - a 46-year follow-up within the Northern Finland Birth Cohort 1966, 29th Congress of the European-College-of-Neuropsychopharmacology (ECNP), Publisher: ELSEVIER SCIENCE BV, Pages: S494-S494, ISSN: 0924-977X
Horikoshi M, Beaumont RN, Day FR, et al., 2016, Genome-wide associations for birth weight and correlations with adult disease, Nature, Vol: 538, Pages: 248-252, ISSN: 0028-0836
Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10(-8)). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (Rg = -0.22, P = 5.5 × 10(-13)), T2D (Rg = -0.27, P = 1.1 × 10(-6)) and coronary artery disease (Rg = -0.30, P = 6.5 × 10(-9)). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10(-4)). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.
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