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Hellings PW, Fokkens WJ, Bachert C, et al., 2017, Positioning the principles of precision medicine in care pathways for allergic rhinitis and chronic rhinosinusitis - A EUFOREA-ARIA-EPOS-AIRWAYS ICP statement, Allergy, Vol: 72, Pages: 1297-1305, ISSN: 0105-4538
Precision medicine (PM) is increasingly recognized as the way forward for optimizing patient care. Introduced in the field of oncology, it is now considered of major interest in other medical domains like allergy and chronic airway diseases, which face an urgent need to improve the level of disease control, enhance patient satisfaction and increase effectiveness of preventive interventions. The combination of personalized care, prediction of treatment success, prevention of disease and patient participation in the elaboration of the treatment plan is expected to substantially improve the therapeutic approach for individuals suffering from chronic disabling conditions. Given the emerging data on the impact of patient stratification on treatment outcomes, European and American regulatory bodies support the principles of PM and its potential advantage over current treatment strategies. The aim of the current document was to propose a consensus on the position and gradual implementation of the principles of PM within existing adult treatment algorithms for allergic rhinitis (AR) and chronic rhinosinusitis (CRS). At the time of diagnosis, prediction of success of the initiated treatment and patient participation in the decision of the treatment plan can be implemented. The second‐level approach ideally involves strategies to prevent progression of disease, in addition to prediction of success of therapy, and patient participation in the long‐term therapeutic strategy. Endotype‐driven treatment is part of a personalized approach and should be positioned at the tertiary level of care, given the efforts needed for its implementation and the high cost of molecular diagnosis and biological treatment.
Wijga AH, Schipper M, Brunekreef B, et al., 2017, Asthma diagnosis in a child and cessation of smoking in the child's home: the PIAMA birth cohort., J Expo Sci Environ Epidemiol, Vol: 27, Pages: 521-525
Second hand smoke (SHS) exposure is associated with increased incidence and severity of childhood asthma. We investigated whether, in turn, asthma diagnosis in a child is associated with cessation of smoking exposure in the child's home. In the PIAMA birth cohort (n=3963), parents reported on smoking in their home and on asthma diagnosis in their child, annually from birth to 8 years. We used generalized estimating equations to assess the association between asthma diagnosis in a child and cessation of smoking in the child's home. Among children with residential SHS exposure, smoking stopped in 23.7% of the homes of children with newly diagnosed asthma as compared with 16.2% of the homes of children without asthma diagnosis (P=0.014). For children with an asthma diagnosis, the relative risk of smoking cessation in their home was 1.36 (one-sided 95% confidence interval: 1.09, inf.) and changed little after adjustment for maternal education, parental allergy and child's age. In most smokers' households (76.3%), smoking continued when the child got an asthma diagnosis. Nevertheless, an asthma diagnosis in the child increased the probability of a smoke-free home for the child and its parents and siblings. Cross-sectional associations between SHS exposure and asthma may underestimate true associations, because exposure may have been reduced following diagnosis of the disease.
Ferreira DLS, Williams DM, Kangas AJ, et al., 2017, Association of pre-pregnancy body mass index with offspring metabolic profile: Analyses of 3 European prospective birth cohorts, PLoS Medicine, Vol: 14, ISSN: 1549-1277
BackgroundA high proportion of women start pregnancy overweight or obese. According to the developmentalovernutrition hypothesis, this could lead offspring to have metabolic disruptionthroughout their lives and thus perpetuate the obesity epidemic across generations. Concernsabout this hypothesis are influencing antenatal care. However, it is unknown whethermaternal pregnancy adiposity is associated with long-term risk of adverse metabolic profilesin offspring, and if so, whether this association is causal, via intrauterine mechanisms, orexplained by shared familial (genetic, lifestyle, socioeconomic) characteristics. We aimed todetermine if associations between maternal body mass index (BMI) and offspring systemiccardio-metabolic profile are causal, via intrauterine mechanisms, or due to shared familialfactors.Methods and findingsWe 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 offspringserum metabolome from 3 European birth cohorts (offspring age at blood collection:16, 17, and 31 years). Circulating metabolic traits were quantified by high-throughputnuclear magnetic resonance metabolomics. Results from 1-stage IPD meta-analysis (N =5327 to 5377 mother-father-offspring trios) showed that increasing maternal and paternalBMI was associated with an adverse cardio-metabolic profile in offspring. We observed strong positive associations with very-low-density lipoprotein (VLDL)-lipoproteins, VLDLcholesterol(C), VLDL-triglycerides, VLDL-diameter, branched/aromatic amino acids, glycoproteinacetyls, 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 strongermagnitudes of associations were present for maternal compared with paternal BMI acrossthese associations; however, there was no strong statistical evidence for heterogeneitybetween them (all
Mason WA, Patwardhan I, Smith GL, et al., 2017, Cumulative contextual risk at birth and adolescent substance initiation: Peer mediation tests, DRUG AND ALCOHOL DEPENDENCE, Vol: 177, Pages: 291-298, ISSN: 0376-8716
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- Citations: 7
Nasanen-Gilmore P, Sipola-Leppanen M, Tikanmaki M, et al., 2017, Late preterm birth protects against atopies in adulthood, Congress of the European-Academy-of-Allergy-and-Clinical-Immunology, Publisher: WILEY, Pages: 14-14, ISSN: 0105-4538
Poulter NR, et al, 2017, Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney, Hypertension, Vol: 70, Pages: e4-e19, ISSN: 0194-911X
Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project–based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.
Gill D, Sheehan NA, Wielscher M, et al., 2017, Age at menarche and lung function: a Mendelian randomization study., European Journal of Epidemiology, Vol: 32, Pages: 701-710, ISSN: 0393-2990
A trend towards earlier menarche in women has been associated with childhood factors (e.g. obesity) and hypothesised environmental exposures (e.g. endocrine disruptors present in household products). Observational evidence has shown detrimental effects of early menarche on various health outcomes including adult lung function, but these might represent spurious associations due to confounding. To address this we used Mendelian randomization where genetic variants are used as proxies for age at menarche, since genetic associations are not affected by classical confounding. We estimated the effects of age at menarche on forced vital capacity (FVC), a proxy for restrictive lung impairment, and ratio of forced expiratory volume in one second to FVC (FEV1/FVC), a measure of airway obstruction, in both adulthood and adolescence. We derived SNP-age at menarche association estimates for 122 variants from a published genome-wide meta-analysis (N = 182,416), with SNP-lung function estimates obtained by meta-analysing three studies of adult women (N = 46,944) and two of adolescent girls (N = 3025). We investigated the impact of departures from the assumption of no pleiotropy through sensitivity analyses. In adult women, in line with previous evidence, we found an effect on restrictive lung impairment with a 24.8 mL increase in FVC per year increase in age at menarche (95% CI 1.8-47.9; p = 0.035); evidence was stronger after excluding potential pleiotropic variants (43.6 mL; 17.2-69.9; p = 0.001). In adolescent girls we found an opposite effect (-56.5 mL; -108.3 to -4.7; p = 0.033), suggesting that the detrimental effect in adulthood may be preceded by a short-term post-pubertal benefit. Our secondary analyses showing results in the same direction in men and boys, in whom age at menarche SNPs have also shown association with sexual development, suggest a role for pubertal timing in general rather than me
Nolte IM, Munoz ML, Tragante V, et al., 2017, Genetic loci associated with heart rate variability and their effects on cardiac disease risk, NATURE COMMUNICATIONS, Vol: 8, ISSN: 2041-1723
Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (−0.74<rg<−0.55) and blood pressure (−0.35<rg<−0.20). These findings provide clinically relevant biological insight into heritable variation in vagal heart rhythm regulation, with a key role for genetic variants (GNG11, RGS6) that influence G-protein heterotrimer action in GIRK-channel induced pacemaker membrane hyperpolarization.
Aguilar D, Pinart M, Koppelman GH, et al., 2017, Computational analysis of multimorbidity between asthma, eczema and rhinitis, PLoS One, Vol: 12, ISSN: 1932-6203
BACKGROUND: The mechanisms explaining the co-existence of asthma, eczema and rhinitis (allergic multimorbidity) are largely unknown. We investigated the mechanisms underlying multimorbidity between three main allergic diseases at a molecular level by identifying the proteins and cellular processes that are common to them. METHODS: An in silico study based on computational analysis of the topology of the protein interaction network was performed in order to characterize the molecular mechanisms of multimorbidity of asthma, eczema and rhinitis. As a first step, proteins associated to either disease were identified using data mining approaches, and their overlap was calculated. Secondly, a functional interaction network was built, allowing to identify cellular pathways involved in allergic multimorbidity. Finally, a network-based algorithm generated a ranked list of newly predicted multimorbidity-associated proteins. RESULTS: Asthma, eczema and rhinitis shared a larger number of associated proteins than expected by chance, and their associated proteins exhibited a significant degree of interconnectedness in the interaction network. There were 15 pathways involved in the multimorbidity of asthma, eczema and rhinitis, including IL4 signaling and GATA3-related pathways. A number of proteins potentially associated to these multimorbidity processes were also obtained. CONCLUSIONS: These results strongly support the existence of an allergic multimorbidity cluster between asthma, eczema and rhinitis, and suggest that type 2 signaling pathways represent a relevant multimorbidity mechanism of allergic diseases. Furthermore, we identified new candidates contributing to multimorbidity that may assist in identifying new targets for multimorbid allergic diseases.
Karjula S, Morin-Papunen L, Auvinen J, et al., 2017, Psychological distress is more prevalent in fertile age and premenopausal women with PCOS symptoms: 15-year follow-up, Journal of Clinical Endocrinology & Metabolism, Vol: 102, Pages: 1861-1869, ISSN: 1945-7197
Context:Polycystic ovary syndrome (PCOS) is associated with increased psychological distress, obesity and hyperandrogenism being suggested as key promoters.Objectives:To investigate the prevalence of anxiety/depression and their coexistence in women with PCOS/PCOS-related symptoms at ages 31 and 46. The roles of obesity, hyperandrogenism, and awareness of PCOS on psychological distress were also assessed.Design:Population-based follow-up.Setting:Northern Finland Birth Cohort 1966 with 15-year follow-up.Participants:At age 31, a questionnaire-based screening for oligoamenorrhea (OA) and hirsutism (H): 2188 asymptomatic (controls), 331 OA, 323 H, and 125 OA plus H (PCOS). Follow-up at age 46: 1576 controls, 239 OA, 231 H, and 85 PCOS.Interventions:Questionnaire-based screening for anxiety and depression symptoms (Hopkins Symptom Checklist-25) and previously diagnosed/treated depression at ages 31 and 46. Body mass index (BMI), serum testosterone/free androgen index, and awareness of polycystic ovaries/PCOS on psychological distress were also assessed.Main Outcomes:Population-based prevalence of anxiety and/or depression in women with PCOS/PCOS-related symptoms at ages 31 and 46.Results:Anxiety and/or depression symptoms, their coexistence, and rate of depression were increased at ages 31 and 46 in women with PCOS or isolated H compared with controls. High BMI or hyperandrogenism did not associate with increased anxiety or depression symptoms. The awareness of PCOS was associated with increased anxiety.Conclusions:Women with PCOS or isolated H present more often with anxiety and/or depression symptoms and their coexistence compared with controls. High BMI or hyperandrogenism did not provoke psychological distress in PCOS. The awareness of PCOS increased anxiety but did not associate with severe anxiety or depression.
Day FR, Thompson DJ, Helgason H, et al., 2017, Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk, NATURE GENETICS, Vol: 49, Pages: 834-+, ISSN: 1061-4036
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- Citations: 171
Couto Alves A, Valcarcel B, Makinen V, et al., 2017, Metabolic profiling of polycystic ovary syndrome reveals interactions with abdominal obesity, International Journal of Obesity, Vol: 41, Pages: 1331-1340, ISSN: 1476-5497
Background: Polycystic ovary syndrome (PCOS) is a common reproductive disorder associated with metabolic disturbances including obesity, insulin resistance, and diabetes mellitus. Here we investigate whether changes in the metabolic profile of PCOS women are driven by increased tendency to obesity or are specific features of PCOS related to increased testosterone levels.Design and Methods: We conducted an NMR metabolomics association study of PCOS cases (n=145) and controls (n=687) nested in a population-based birth cohort (n=3,127). Subjects were 31 years old at examination. The main analyses were adjusted for waist circumference (WC) as a proxy measure of central obesity. Subsequently, metabolite concentrations were compared between cases and controls within pre-defined WC strata. On each stratum, additional metabolomics association analyses with testosterone levels were conducted separately among cases and controls.Results: Overall, women with PCOS showed more adverse metabolite profiles than the controls. Four lipid fractions in different subclasses of very low density lipoprotein (VLDL) were associated with PCOS, after adjusting for WC and correction for multiple testing (P<0.002). In stratified analysis the PCOS women within large WC strata (≥98 cm) had significantly lower high density lipoprotein (HDL) levels, ApoA1 and albumin values compared to the controls. Testosterone levels were significantly associated with VLDL and serum lipids in PCOS cases with large WC but not in the controls. The higher testosterone levels, adjusted for WC, adversely associated with insulin levels and HOMA IR in cases but not in the controls.Conclusions: Our findings show that both abdominal obesity and hyperandrogenism contribute to the dyslipidaemia and other metabolic traits of PCOS which all may negatively contribute to the long term health of women with PCOS.
Song C, Burgess S, Eicher JD, et al., 2017, Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease, Journal of the American Heart Association, Vol: 6, ISSN: 2047-9980
Background--Plasminogen activator inhibitor type 1 (PAI-1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI-1 levels are associated with increased risk of coronary heart disease (CHD). However, it is unclear whether the association reflects a causal influence of PAI-1 on CHD risk. Methods and Results--To evaluate the association between PAI-1 and CHD, we applied a 3-step strategy. First, we investigated the observational association between PAI-1 and CHD incidence using a systematic review based on a literature search for PAI-1 and CHD studies. Second, we explored the causal association between PAI-1 and CHD using a Mendelian randomization approach using summary statistics from large genome-wide association studies. Finally, we explored the causal effect of PAI-1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta-analysis, the highest quantile of blood PAI-1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age- and sex-adjusted model. The effect size was reduced in studies using a multivariable-adjusted model (odds ratio=1.46; 95% CI: 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI-1 level on CHD risk (odds ratio=1.22 per unit increase of log-transformed PAI-1; 95% CI: 1.01, 1.47). In addition, we also detected a causal effect of PAI-1 on elevating blood glucose and high-density lipoprotein cholesterol. Conclusions--Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction.
Kaakinen M, Magi R, Fischer K, et al., 2017, A rare-variant test for high-dimensional data, European Journal of Human Genetics, Vol: 25, Pages: 988-994, ISSN: 1018-4813
Genome-wide association studies have facilitated the discovery of thousands of loci for hundreds of phenotypes. However, the issue of missing heritability remains unsolved for most complex traits. Locus discovery could be enhanced with both improved power through multi-phenotype analysis (MPA) and use of a wider allele frequency range, including rare variants (RVs). MPA methods for single-variant association have been proposed, but given their low power for RVs, more efficient approaches are required. We propose multi-phenotype analysis of rare variants (MARV), a burden test-based method for RVs extended to the joint analysis of multiple phenotypes through a powerful reverse regression technique. Specifically, MARV models the proportion of RVs at which minor alleles are carried by individuals within a genomic region as a linear combination of multiple phenotypes, which can be both binary and continuous, and the method accommodates directly the genotyped and imputed data. The full model, including all phenotypes, is tested for association for discovery, and a more thorough dissection of the phenotype combinations for any set of RVs is also enabled. We show, via simulations, that the type I error rate is well controlled under various correlations between two continuous phenotypes, and that the method outperforms a univariate burden test in all considered scenarios. Application of MARV to 4876 individuals from the Northern Finland Birth Cohort 1966 for triglycerides, high- and low-density lipoprotein cholesterols highlights known loci with stronger signals of association than those observed in univariate RV analyses and suggests novel RV effects for these lipid traits.
Ortega-Alonso A, Ekelund J, Sarin A, et al., 2017, Genome-wide association study of psychosis proneness in the Finnish population, Schizophrenia Bulletin, Vol: 43, Pages: 1304-1314, ISSN: 1745-1701
The current study examined quantitative measures of psychosis proneness in a nonpsychoticpopulation, in order to elucidate their underlying genetic architecture and to observeif there is any commonality to that already detected in the studies of individuals with overtpsychotic conditions, such as schizophrenia and bipolar disorder.Heritability, univariate and multivariate genome-wide association tests, including a series ofcomprehensive gene-based association analyses, were developed in 4269 non-psychoticpersons participating in the Northern Finland Birth Cohort 1966 study with information on thefollowing psychometric measures: Hypomanic Personality, Perceptual Aberration, Physicaland Social Anhedonia (a.k.a. Chapman’s Schizotypia scales), and Schizoidia scale. Genomewidegenetic data was available for ~9.84 million SNPs.Heritability estimates ranged from 16% to 27%. Phenotypic, genetic and environmentalcorrelations ranged from 0.04-0.43, 0.25-0.73, and 0.12-0.43, respectively. Univariate GWAStests revealed an intronic SNP (rs12449097) at the TMC7 gene (16p12.3) that significantlyassociated (p=3.485 × 10-8) with the hypomanic scale. Bivariate GWAs tests including thehypomanic and physical anhedonia scales suggested a further borderline significant SNP(rs188320715; p-value=5.261 × 10-8, ~572kb downstream the ARID1B gene at 6q25.3).Gene-based tests highlighted 20 additional genes of which 5 had previously been associatedto schizophrenia and/or bipolar disorder: CSMD1, CCDC141, SLC1A2, CACNA1C andSNAP25. Altogether the findings explained from 3.7% to 14.1% of the corresponding traitheritability.In conclusion, this study provides preliminary genomic evidence suggesting that qualitativelysimilar biological factors may underlie different psychosis proneness measures, some ofwhich could further predispose to schizophrenia and bipolar disorder.
Gref A, Merid SK, Gruzieva O, et al., 2017, Genome-Wide Interaction Analysis of Air Pollution Exposure and Childhood Asthma with Functional Follow-up, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 195, Pages: 1373-1383, ISSN: 1073-449X
Rationale: The evidence supporting an association between traffic-related air pollution exposure and incident childhood asthma is inconsistent and may depend on genetic factors.Objectives: To identify gene–environment interaction effects on childhood asthma using genome-wide single-nucleotide polymorphism (SNP) data and air pollution exposure. Identified loci were further analyzed at epigenetic and transcriptomic levels.Methods: We used land use regression models to estimate individual air pollution exposure (represented by outdoor NO2 levels) at the birth address and performed a genome-wide interaction study for doctors’ diagnoses of asthma up to 8 years in three European birth cohorts (n = 1,534) with look-up for interaction in two separate North American cohorts, CHS (Children’s Health Study) and CAPPS/SAGE (Canadian Asthma Primary Prevention Study/Study of Asthma, Genetics and Environment) (n = 1,602 and 186 subjects, respectively). We assessed expression quantitative trait locus effects in human lung specimens and blood, as well as associations among air pollution exposure, methylation, and transcriptomic patterns.Measurements and Main Results: In the European cohorts, 186 SNPs had an interaction P < 1 × 10−4 and a look-up evaluation of these disclosed 8 SNPs in 4 loci, with an interaction P < 0.05 in the large CHS study, but not in CAPPS/SAGE. Three SNPs within adenylate cyclase 2 (ADCY2) showed the same direction of the interaction effect and were found to influence ADCY2 gene expression in peripheral blood (P = 4.50 × 10−4). One other SNP with P < 0.05 for interaction in CHS, rs686237, strongly influenced UDP-Gal:betaGlcNAc β-1,4-galactosyltransferase, polypeptide 5 (B4GALT5) expression in lung tissue (P = 1.18 × 10−17). Air pollution exposure was associ
Graff M, Scott RA, Justice AE, et al., 2017, Genome-wide physical activity interactions in adiposity. A meta-analysis of 200,452 adults, PLOS GENETICS, Vol: 13, ISSN: 1553-7404
Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
Justice AE, Winkler TW, Feitosa MF, et al., 2017, Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits, NATURE COMMUNICATIONS, Vol: 8, ISSN: 2041-1723
Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.
Rautio N, Varanka-Ruuska T, Vaaramo E, et al., 2017, Accumulated exposure to unemployment is related to impaired glucose metabolism in middle-aged men: A follow-up of the Northern Finland Birth Cohort 1966, Primary Care Diabetes, Vol: 11, Pages: 365-372, ISSN: 1751-9918
Tikanmaki M, Tammelin T, Vaarasmaki M, et al., 2017, Prenatal determinants of physical activity and cardiorespiratory fitness in adolescence - Northern Finland Birth Cohort 1986 study, BMC PUBLIC HEALTH, Vol: 17, ISSN: 1471-2458
Background:Lower levels of physical activity and cardiorespiratory fitness are key risk factors of chronic adultdiseases. Physical activity and cardiorespiratory fitness are predicted by birth weight, but the underlying parentaland pregnancy-related factors remain largely unknown. We examined how prenatal determinants are associatedwith physical activity and cardiorespiratory fitness in adolescence.Methods:Of the 16-year-old members of the population-based Northern Finland Birth Cohort 1986 (NFBC 1986),6682 singletons with no major physical disability reported their amount of physical activity outside school hours,and 4706 completed a submaximal cycle ergometer test assessing cardiorespiratory fitness. Physical activity wasexpressed as metabolic equivalent hours per week (METh/week) and cardiorespiratory fitness as peak oxygenuptake (ml·kg−1·min−1). Prenatal determinants included birth weight, length of gestation, mother’s and father’s bodymass index (BMI), maternal gestational diabetes mellitus (GDM), and maternal hypertension and smoking duringpregnancy. Data were analyzed by multiple linear regression.Results:A higher birth weight and longer length of gestation predicted lower levels of physical activity andcardiorespiratory fitness at 16 years, although the association between length of gestation and physical activity wasinverse U-shaped. Mother’s or father’s overweight or obesity before pregnancy were associated with lower levels oftheir offspring’s physical activity and fitness in adolescence. Adjusting for maternal pregnancy disorders and theadolescent’s own BMI attenuated the associations with the mother’s but not the father’s overweight/obesity.Furthermore, maternal GDM predicted lower cardiorespiratory fitness.Conclusions:A high birth weight and parental overweight/obesity are associated with lower levels of bothphysical activity and cardiorespiratory fitness in adolescence, while ma
Ollila MM, West S, Keinanen-Kiukaaniemi S, et al., 2017, Correction: 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: 968-968, ISSN: 1460-2350
This is a correction to:Human Reproduction, Volume 32, Issue 2, 1 February 2017, Pages 423–431, https://doi.org/10.1093/humrep/dew329
Pettersson ME, Koppelman GH, Flokstra-de Blok BMJ, et al., 2017, Apolipoprotein B: a possible new biomarker for anaphylaxis., Ann Allergy Asthma Immunol, Vol: 118, Pages: 515-516
Miotla P, Cartwright R, Franklin-Nembhard L, et al., 2017, Urinary endothelin and endothelin pathway gene expression in overactive bladder, EUROPEAN JOURNAL OF OBSTETRICS & GYNECOLOGY AND REPRODUCTIVE BIOLOGY, Vol: 211, Pages: 205-205, ISSN: 0301-2115
Pirinen M, Benner C, Marttinen P, et al., 2017, biMM: Efficient estimation of genetic variances and covariances for cohorts with high-dimensional phenotype measurements., Bioinformatics, Vol: 33, Pages: 2405-2407, ISSN: 1367-4803
Summary: Genetic research utilizes a decomposition of trait variances and covariances into genetic and environmental parts. Our software package biMM is a computationally efficient implementation of a bivariate linear mixed model for settings where hundreds of traits have been measured on partially overlapping sets of individuals.
Machin M, Amaral AFS, Wielscher M, et al., 2017, Systematic review of lung function and COPD with peripheral blood DNA methylation in population based studies, BMC Pulmonary Medicine, Vol: 17, ISSN: 1471-2466
BackgroundEpigenetic variations in peripheral blood have potential as biomarkers for disease. This systematic review assesses the association of lung function and chronic obstructive pulmonary disease (COPD) with DNA methylation profiles in peripheral blood from population-based studies.MethodsOnline databases Medline, Embase, and Web of Science were searched. Google Scholar was searched to identify grey literature. After removing duplicate articles, 1155 articles were independently screened by two investigators. Peer reviewed reports on population-based studies that examined peripheral blood DNA methylation in participants with measured lung function (FEV1, FEV1/FVC ratio) or known COPD status were selected for full-text review. Six articles were suitable for inclusion. Information regarding study characteristics, designs, methodologies and conclusions was extracted. A narrative synthesis was performed based on published results.ResultsThree of the six articles assessed the association of COPD with DNA methylation, and two of these also included associations with lung function. Overall, five reports examined the association of lung function with DNA methylation profiles. Five of the six articles reported ‘significant’ results. However, no consistent CpG sites were identified across studies for COPD status or lung function values.ConclusionsDNA methylation patterns in peripheral blood from individuals with reduced lung function or COPD may be different to those in people with normal lung function. However, this systematic review did not find any consistent associations of lung function or COPD with differentially methylated CpG sites. Large studies with a longitudinal design to address reverse causality may prove a more fruitful area of research.
Vonk JM, Scholtens S, Postma DS, et al., 2017, Adult onset asthma and interaction between genes and active tobacco smoking: The GABRIEL consortium, PLoS ONE, Vol: 12, ISSN: 1932-6203
BackgroundGenome-wide association studies have identified novel genetic associations for asthma, butwithout taking into account the role of active tobacco smoking. This study aimed to identifynovel genes that interact with ever active tobacco smoking in adult onset asthma.MethodsWe performed a genome-wide interaction analysis in six studies participating in theGABRIEL consortium following two meta-analyses approaches based on 1) the overall interaction effect and 2) the genetic effect in subjects with and without smoking exposure.We performed a discovery meta-analysis including 4,057 subjects of European descent andreplicated our findings in an independent cohort (LifeLines Cohort Study), including 12,475subjects.ResultsFirst approach: 50 SNPs were selected based on an overall interaction effect at p<10−4. Themost pronounced interaction effect was observed for rs9969775 on chromosome 9 (discoverymeta-analysis: ORint = 0.50, p = 7.63*10−5, replication: ORint = 0.65, p = 0.02). Secondapproach: 35 SNPs were selected based on the overall genetic effect in exposed subjects(p <10−4). The most pronounced genetic effect was observed for rs5011804 on chromosome12 (discovery meta-analysis ORint = 1.50, p = 1.21*10−4; replication: ORint = 1.40,p = 0.03).ConclusionsUsing two genome-wide interaction approaches, we identified novel polymorphisms in nonannotatedintergenic regions on chromosomes 9 and 12, that showed suggestive evidencefor interaction with active tobacco smoking in the onset of adult asthma.
Williams DM, Buxton JL, Kantomaa MT, et al., 2017, Associations of Leukocyte Telomere Length With Aerobic and Muscular Fitness in Young Adults, AMERICAN JOURNAL OF EPIDEMIOLOGY, Vol: 185, Pages: 529-537, ISSN: 0002-9262
Decline in both telomere length and physical fitness over the life course may contribute to increased risk of several chronic diseases. The relationship between telomere length and aerobic and muscular fitness is not well characterized. We examined whether there are cross-sectional associations of mean relative leukocyte telomere length (LTL) with objective measures of aerobic fitness, muscle strength, and muscle endurance, using data on 31-year-old participants of the Northern Finland Birth Cohort 1966 (n = 4,952–5,205, varying by exposure-outcome analysis). Aerobic fitness was assessed by means of heart rate measurement following a standardized submaximal step test; muscular fitness was assessed by means of a maximal isometric handgrip strength test and a test of lower-back trunk muscle endurance. Longer LTL was associated with higher aerobic fitness and better trunk muscle endurance in models including adjustment for age, sex, body mass index, socioeconomic position, diet, smoking, alcohol consumption, physical activity level, and C-reactive protein. In a sex-stratified analysis, LTL was not associated with handgrip strength in either men or women. LTL may relate to aspects of physical fitness in young adulthood, but replication of these findings is required, along with further studies to help assess directions and causality in these associations.
Palaniswamy S, Hyppoenen E, Williams DM, et al., 2017, Potential determinants of vitamin D in Finnish adults: a cross-sectional study from the Northern Finland birth cohort 1966, BMJ Open, Vol: 7, ISSN: 2044-6055
Objective: Evidence from randomised controlled trialssuggests that vitamin D may reduce multimorbidity,but very few studies have investigated specificdeterminants of vitamin D2 and D3 (two isoforms of25-hydroxyvitamin D). The aim of the study was toinvestigate the determinants of vitamin D2 and D3 andto identify the risk factors associated withhypovitaminosis D.Design: Cross-sectional study.Setting: Northern Finland Birth Cohort 1966.Participants: 2374 male and 2384 female participantswith data on serum 25(OH)D2 and 25(OH)D3concentrations measured at 31 years of age (1997),together with comprehensive measures of daylight,anthropometric, social, lifestyle and contraceptivecofactors.Methods: We assessed a wide range of potentialdeterminants prior to a nationwide fortificationprogramme introduced in Finland. The determinants of25(OH)D2, 25(OH)D3 and 25(OH)D concentrations wereanalysed by linear regression and risk factors for beingin lower tertile of 25(OH)D concentration by ordinallogistic regression.Results: At the time of sampling, 72% of theparticipants were vitamin D sufficient (≥50 nmol/L).Low sunlight exposure period (vs high) was associatedpositively with 25(OH)D2 and negatively with 25(OH)D3concentrations. Use of oral contraceptives (vs nonusers)was associated with an increase of 0.17 nmol/L(95% CI 0.08 to 0.27) and 0.48 nmol/L (95% CI 0.41to 0.56) in 25(OH)D2 and 25(OH)D3 concentrations.Sex, season, latitude, alcohol consumption andphysical activity were the factors most stronglyassociated with 25(OH)D concentration. Risk factorsfor low vitamin D status were low sunlight exposuredefined by time of sampling, residing in northernlatitudes, obesity, higher waist circumference, lowphysical activity and unhealthy diet.Conclusions: We demonstrate some differentialassociations of environmental and lifestyle factors with25(OH)D2 and 25(OH)D3 raising important questionsrelated to personalised healthcare. Future strategiescould implement lifestyle modification and s
Gallo V, Dijk FN, Holloway JW, et al., 2017, TRPA1 gene polymorphisms and childhood asthma., Pediatr Allergy Immunol, Vol: 28, Pages: 191-198
BACKGROUND: Animal data have suggested that the transient receptor potential ankyrin-1 (TRPA1) ion channel plays a key role in promoting airway inflammation in asthma and may mediate effects of paracetamol on asthma, yet confirmatory human data are lacking. To study associations of TRPA1 gene variants with childhood asthma and total IgE concentration, and interactions between TRPA1 and prenatal paracetamol exposure on these outcomes. METHODS: We analysed associations between 31 TRPA1 single nucleotide polymorphisms (SNPs) and current doctor-diagnosed asthma and total IgE concentration at 7.5 years in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. We sought to confirm the most significant associations with comparable outcomes in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) and Generation R birth cohorts. In ALSPAC, we explored interactions with prenatal paracetamol exposure. RESULTS: In ALSPAC, there was strong evidence for association between six SNPs and asthma: rs959974 and rs1384001 (per-allele odds ratio for both: 1.30 (95% CI: 1.15-1.47), p = 0.00001), rs7010969 (OR 1.28 (1.13-1.46), p = 0.00004), rs3735945 (OR 1.30 (1.09-1.55), p = 0.003), rs920829 (OR 1.30 (1.09-1.54), p = 0.004) and rs4738202 (OR 1.22 (1.07-1.39), p = 0.004). In a meta-analysis across the three cohorts, the pooled effect estimates confirmed that all six SNPs were significantly associated with asthma. In ALSPAC, TRPA1 associations with asthma were not modified by prenatal paracetamol, although associations with IgE concentration were. CONCLUSION: This study suggests that TRPA1 may play a role in the development of childhood asthma. (249 words).
Vijverberg SJ, Pijnenburg MW, Hövels AM, et al., 2017, The need for precision medicine clinical trials in childhood asthma: rationale and design of the PUFFIN trial., Pharmacogenomics, Vol: 18, Pages: 393-401
A 'one-size fits all'-approach does not fit all pediatric asthma patients. Current evidence suggests that in children with persistent asthma, ADRB2 genotype-guided treatment can improve treatment outcomes, yet this evidence is mainly derived from observational and genotype-stratified studies. Implementation of precision medicine-guided asthma treatment in clinical practice will only occur if randomized clinical trials can show that this approach will improve patient outcomes and is cost effective. In this paper, we will discuss why precision medicine trials are currently needed to improve childhood asthma management and present the rationale and design of the PUFFIN trial, that has been set up to address this need.
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