Showing papers by "Henry Völzke published in 2011"
TL;DR: A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function, and these findings suggest potential novel therapeutic pathways for cardiovascular disease prevention.
Abstract: Blood pressure is a heritable trait(1) influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (>= 140 mm Hg systolic blood pressure or >= 90 mm Hg diastolic blood pressure)(2). Even small increments in blood pressure are associated with an increased risk of cardiovascular events(3). This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
1,829 citations
TL;DR: Henry Volzke, y Dietrich Alte,1y Carsten Oliver Schmidt, Dorte Radke, Roberto Lorbeer, Nele Friedrich, Nicole Aumann, Katharina Lau, Michael Piontek, Gabriele Born, Christoph Havemann, Till Ittermann, Sabine Schipf, Robin Haring, Sebastian E Baumeister, Henri Wallaschofski, Matthias Nauck, Stephanie Frick, Andreas Arnold.
Abstract: Henry Volzke, y Dietrich Alte,1y Carsten Oliver Schmidt, Dorte Radke, Roberto Lorbeer, Nele Friedrich, Nicole Aumann, Katharina Lau, Michael Piontek, Gabriele Born, Christoph Havemann, Till Ittermann, Sabine Schipf, Robin Haring, Sebastian E Baumeister, Henri Wallaschofski, Matthias Nauck, Stephanie Frick, Andreas Arnold, Michael Junger, Julia Mayerle, Matthias Kraft, Markus M Lerch, Marcus Dorr, Thorsten Reffelmann, Klaus Empen, Stephan B Felix, Anne Obst, Beate Koch, Sven Glaser, Ralf Ewert, Ingo Fietze, Thomas Penzel, Martina Doren, Wolfgang Rathmann, Johannes Haerting, Mario Hannemann, Jurgen Ropcke, Ulf Schminke, Clemens Jurgens, Frank Tost, Rainer Rettig, Jan A Kors, Saskia Ungerer, Katrin Hegenscheid, Jens-Peter Kuhn, Julia Kuhn, Norbert Hosten, Ralf Puls, Jorg Henke, Oliver Gloger, Alexander Teumer, Georg Homuth, Uwe Volker, Christian Schwahn, Birte Holtfreter, Ines Polzer, Thomas Kohlmann, Hans J Grabe, Dieter Rosskopf, Heyo K Kroemer, Thomas Kocher, Reiner Biffar,17,y Ulrich John20y and Wolfgang Hoffmann1y
925 citations
Erasmus University Rotterdam1, National Institutes of Health2, Boston University3, University of Texas Health Science Center at Houston4, University of Washington5, University of Greifswald6, Wellcome Trust Sanger Institute7, Leiden University8, University of London9, University of Edinburgh10, Harvard University11, Wake Forest University12, University of Helsinki13, VU University Amsterdam14, University of Mainz15, Baylor College of Medicine16, University of Texas at Austin17, University of Oulu18, University of Minnesota19, Imperial College London20, University of North Carolina at Chapel Hill21, Martin Luther University of Halle-Wittenberg22, German Cancer Research Center23, Leipzig University24, Guy's and St Thomas' NHS Foundation Trust25, Amgen26, University of Iceland27, Cedars-Sinai Medical Center28, University of Split29, University of Ulm30
TL;DR: A genome-wide association analysis of CRP identified 18 loci that were associated with CRP levels and highlighted immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation.
Abstract: Background—C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels. Methods and Results—We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1) or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found a significant interaction of body ...
463 citations
Sébastien Jacquemont1, Alexandre Reymond, Flore Zufferey, Louise Harewood +179 more•Institutions (11)
TL;DR: In this article, the reciprocal duplication is associated with being clinically underweight, which is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa.
Abstract: Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m(2) in adults and ≤ -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance.
414 citations
TL;DR: This article identified new regions showing association with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2.
Abstract: Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
394 citations
Brigham and Women's Hospital1, University Hospital Bonn2, University of Helsinki3, Wellcome Trust Sanger Institute4, Leiden University5, National Institutes of Health6, Griffith University7, Helsinki University Central Hospital8, Ludwig Maximilian University of Munich9, University of Ulm10, French Institute of Health and Medical Research11
TL;DR: In a population-based genome-wide analysis including 5,122 migraineurs and 18,108 non-migraineurs, rs2651899, rs10166942 and rs11172113 were among the top seven associations with migraine, plausibly linking both genes to migraine pathophysiology.
Abstract: Migraine is a common, heterogeneous and heritable neurological disorder. Its pathophysiology is incompletely understood, and its genetic influences at the population level are unknown. In a population-based genome-wide analysis including 5,122 migraineurs and 18,108 non-migraineurs, rs2651899 (1p36.32, PRDM16), rs10166942 (2q37.1, TRPM8) and rs11172113 (12q13.3, LRP1) were among the top seven associations (P < 5 × 10(-6)) with migraine. These SNPs were significant in a meta-analysis among three replication cohorts and met genome-wide significance in a meta-analysis combining the discovery and replication cohorts (rs2651899, odds ratio (OR) = 1.11, P = 3.8 × 10(-9); rs10166942, OR = 0.85, P = 5.5 × 10(-12); and rs11172113, OR = 0.90, P = 4.3 × 10(-9)). The associations at rs2651899 and rs10166942 were specific for migraine compared with non-migraine headache. None of the three SNP associations was preferential for migraine with aura or without aura, nor were any associations specific for migraine features. TRPM8 has been the focus of neuropathic pain models, whereas LRP1 modulates neuronal glutamate signaling, plausibly linking both genes to migraine pathophysiology.
344 citations
University of Nottingham1, University of Leicester2, Ludwig Institute for Cancer Research3, Queen Mary University of London4, National Institutes of Health5, Imperial College London6, King's College London7, Western General Hospital8, Uppsala University9, University of Oulu10, Ontario Institute for Cancer Research11, University of Toronto12, Sir Charles Gairdner Hospital13, University of Western Australia14, St George's, University of London15, University of South Florida16, University of Bristol17, University of Cambridge18, Wellcome Trust Sanger Institute19, University of Greifswald20, University of Split21, University of Zagreb22, University of Edinburgh23, University of Basel24, Swiss Tropical and Public Health Institute25, University of Helsinki26, University of Jyväskylä27
TL;DR: Polymorphisms spanning previously associated lung function genes did not show strong evidence for association with lung function measures in the SpiroMeta consortium population of 20,288 individuals from the general population.
Abstract: Rationale: Lung function measures are heritable traits that predict population morbidity and mortality and are essential for the diagnosis of chronic obstructive pulmonary disease (COPD). Variations in many genes have been reported to affect these traits, but attempts at replication have provided conflicting results. Recently, we undertook a meta-analysis of Genome Wide Association Study (GWAS) results for lung function measures in 20,288 individuals from the general population (the SpiroMeta consortium).
274 citations
TL;DR: Genotype PNPLA3 rs738409(GG) is associated with alcoholic liver cirrhosis and elevated aminotransferase levels in alcoholic Caucasians.
263 citations
TL;DR: A genome-wide association study of metabolic traits in human urine, designed to investigate the detoxification capacity of the human body, identifies rs37369 in AGXT2 as the genetic basis of hyper-β-aminoisobutyric aciduria and identifies five loci with joint P values of association.
Abstract: Karsten Suhre and colleagues report a genome-wide association study of metabolic traits in human urine, using NMR spectrometry to measure 59 metabolites in urine from participants. They identify five loci influencing urine metabolite levels and point to a missense variant in AGXT2 as the likely cause of hyper-β-aminoisobutyric aciduria, a common inborn error of metabolism.
242 citations
University of Regensburg1, Boston University2, Johns Hopkins University3, University of Freiburg4, University of Washington5, University of Lübeck6, Harvard University7, University of Greifswald8, University of Maryland, Baltimore9, Memorial Hospital of South Bend10, National Institutes of Health11, University of California, San Francisco12, University of Lausanne13, Swiss Institute of Bioinformatics14, Cambridge University Hospitals NHS Foundation Trust15, Jackson State University16, Loyola University Chicago17, University of Groningen18, University of Iceland19, Wake Forest University20, Mayo Clinic21, Western General Hospital22, Innsbruck Medical University23, Leipzig University24, Karolinska Institutet25, University of North Carolina at Chapel Hill26, University of Texas Health Science Center at Houston27, University of Pennsylvania28, Group Health Cooperative29, Cedars-Sinai Medical Center30, GlaxoSmithKline31, Broad Institute32, University of Pittsburgh33, Norwegian University of Science and Technology34, Uppsala University35, University of Ulm36, Heidelberg University37, Université catholique de Louvain38, University of Oxford39, University of Edinburgh40, University of Michigan41, University of Toronto42, Ludwig Maximilian University of Munich43, University of Mississippi44
TL;DR: A missense CUBN variant is identified that associates with levels of albuminuria in both the general population and in individuals with diabetes.
Abstract: Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 × 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.
219 citations
TL;DR: Interactions between physical abuse and rs1360780 of the FKBP5 gene, confirming its role in the individual susceptibility to depression, could be included into prediction models for depression in individuals exposed to childhood abuse.
University of Gothenburg1, University of Greifswald2, National Institutes of Health3, Boston University4, Erasmus University Rotterdam5, University of Exeter6, Wellcome Trust Centre for Human Genetics7, University of Tampere8, Imperial College London9, University of British Columbia10, University of Parma11, University of Manchester12, Harvard University13, Lund University14, Wake Forest University15, Uppsala University16, Technische Universität München17, University of Pittsburgh18, VU University Medical Center19, Ludwig Maximilian University of Munich20, University of Turku21, University of California, San Francisco22, Turku University Hospital23
TL;DR: A meta-analysis of genome-wide association data in 8,938 men from seven cohorts identified genetic loci significantly associated with serum testosterone concentration in men that could influence the calculation of free testosterone using law-of-mass-action equation.
Abstract: Testosterone concentrations in men are associated with cardiovascular morbidity, osteoporosis, and mortality and are affected by age, smoking, and obesity. Because of serum testosterone's high heritability, we performed a meta-analysis of genome-wide association data in 8,938 men from seven cohorts and followed up the genome-wide significant findings in one in silico (n = 871) and two de novo replication cohorts (n = 4,620) to identify genetic loci significantly associated with serum testosterone concentration in men. All these loci were also associated with low serum testosterone concentration defined as,300 ng/dl. Two single-nucleotide polymorphisms at the sex hormone-binding globulin (SHBG) locus (17p13-p12) were identified as independently associated with serum testosterone concentration (rs12150660, p = 1.2x10(-41) and rs6258, p = 2.3x10(-22)). Subjects with >= 3 risk alleles of these variants had 6.5-fold higher risk of having low serum testosterone than subjects with no risk allele. The rs5934505 polymorphism near FAM9B on the X chromosome was also associated with testosterone concentrations (p = 5.6610216). The rs6258 polymorphism in exon 4 of SHBG affected SHBG's affinity for binding testosterone and the measured free testosterone fraction (p<0.01). Genetic variants in the SHBG locus and on the X chromosome are associated with a substantial variation in testosterone concentrations and increased risk of low testosterone. rs6258 is the first reported SHBG polymorphism, which affects testosterone binding to SHBG and the free testosterone fraction and could therefore influence the calculation of free testosterone using law-of-mass-action equation.
University of Washington1, Erasmus University Rotterdam2, University of North Carolina at Chapel Hill3, University of Michigan4, University of Greifswald5, Johns Hopkins University6, National Institutes of Health7, Boston University8, St George's, University of London9, Medical University of Graz10, University of Edinburgh11, University of Mainz12, Group Health Cooperative13, University of Turku14, National Research Council15, University of Maryland, Baltimore16, Harvard University17, Baylor College of Medicine18, Houston Methodist Hospital19, University of California, Berkeley20, Tel Aviv University21, Wellcome Trust22, University of Helsinki23, University of Iceland24, Broad Institute25, University of Pennsylvania26, Cedars-Sinai Medical Center27, University of Tampere28, Hannover Medical School29, Veterans Health Administration30, Ludwig Maximilian University of Munich31, Tufts University32, Leipzig University33, University of Düsseldorf34, University of Texas Health Science Center at Houston35, University of Ulm36, University of Pittsburgh37
TL;DR: A meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium identified three genomic regions associated with common carotid intima media thickness and two different areas associated with the presence of carotids plaque.
Abstract: Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10(-8)). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events.
Morris J. Bown1, Gregory T. Jones2, Seamus C. Harrison3, Benjamin J. Wright1 +504 more•Institutions (64)
TL;DR: This study has identified a biologically plausible genetic variant associated specifically with AAA, and it is suggested that this variant has a possible functional role in LRP1 expression.
Abstract: Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10(-5)) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10(-5)). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10(-10), odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression.
National Institutes of Health1, University of North Carolina at Chapel Hill2, Erasmus University Rotterdam3, Boston University4, University of Iceland5, National Research Council6, University of Vermont7, University of Greifswald8, University of Exeter9, Wake Forest University10, University of Washington11, University of Minnesota12, University of Oxford13, German Cancer Research Center14, Broad Institute15, Harvard University16, NHS Blood and Transplant17, Cedars-Sinai Medical Center18, University of Mississippi19, Université de Montréal20, Technische Universität München21, University of Tokyo22, Leipzig University23, King's College London24, Johns Hopkins University25, Ludwig Maximilian University of Munich26, Wellcome Trust Sanger Institute27, University of Texas Health Science Center at Houston28, University College London29, Group Health Cooperative30, University of Michigan31
TL;DR: Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression.
Abstract: White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count—6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count—17q21; basophil count- 3p21 near RPN1 and C3orf27; lymphocyte count—6p21, 19p13 at EPS15L1; monocyte count—2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds.
TL;DR: Low serum Mg(++) levels are associated with higher all-cause mortality and cardiovascular mortality, which corresponds well with recent findings that hypomagnesemia is associated with the increase of left ventricular mass over the following years.
King's College London1, University of Greifswald2, Erasmus University Rotterdam3, University of Exeter4, Wellcome Trust Centre for Human Genetics5, University of Gothenburg6, Boston University7, National Institutes of Health8, Wellcome Trust Sanger Institute9, Harvard University10, Wake Forest University11, University of Parma12, University of Pittsburgh13, University of Geneva14, VU University Medical Center15, Sir Charles Gairdner Hospital16, University of Western Australia17, Pfizer18
TL;DR: A meta-analysis of genome-wide association data with 14,846 individuals found several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing.
Abstract: Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands—yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p=3.15610 236 ), SULT2A1 (rs2637125; p=2.61610 219 ), ARPC1A (rs740160; p=1.56610 216 ), TRIM4 (rs17277546; p=4.50610 211 ), BMF (rs7181230; p=5.44610 211 ), HHEX (rs2497306; p=4.64610 29 ), BCL2L11 (rs6738028; p=1.72610 28 ), and CYP2C9 (rs2185570; p=2.29610 28 ). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS.
TL;DR: Adding biomarker information did not affect the association of subjective health measures with mortality, but significantly improved risk stratification, which may be useful to identify high-risk individuals for intensified monitoring.
Abstract: Associations between measures of subjective health and mortality risk have previously been shown. We assessed the impact and comparative predictive performance of a multi-biomarker panel on this association. Data from 4,261 individuals aged 20-79 years recruited for the population-based Study of Health in Pomerania was used. During an average 9.7 year follow-up, 456 deaths (10.7%) occurred. Subjective health was assessed by SF-12 derived physical (PCS-12) and mental component summaries (MCS-12), and a single-item self-rated health (SRH) question. We implemented Cox proportional-hazards regression models to investigate the association of subjective health with mortality and to assess the impact of a combination of 10 biomarkers on this association. Variable selection procedures were used to identify a parsimonious set of subjective health measures and biomarkers, whose predictive ability was compared using receiver operating characteristic (ROC) curves, C-statistics, and reclassification methods. In age- and gender-adjusted Cox models, poor SRH (hazard ratio (HR), 2.07; 95% CI, 1.34-3.20) and low PCS-12 scores (lowest vs. highest quartile: HR, 1.75; 95% CI, 1.31-2.33) were significantly associated with increased risk of all-cause mortality; an association independent of various covariates and biomarkers. Furthermore, selected subjective health measures yielded a significantly higher C-statistic (0.883) compared to the selected biomarker panel (0.872), whereas a combined assessment showed the highest C-statistic (0.887) with a highly significant integrated discrimination improvement of 1.5% (p < 0.01). Adding biomarker information did not affect the association of subjective health measures with mortality, but significantly improved risk stratification. Thus, a combined assessment of self-reported subjective health and measured biomarkers may be useful to identify high-risk individuals for intensified monitoring.
TL;DR: Low total testosterone concentrations are prospectively associated with an adverse lipid profile and increased risk of incident dyslipidemia, which may contribute to an explanation for the higher cardiovascular disease risk in men with lower totalosterone concentrations.
Abstract: Background Earlier studies have suggested that total testosterone concentrations influence the lipid metabolism. Whether these concentrations are prospectively associated with an adverse lipid profile and an increased risk of incident dyslipidemia has not yet been investigated. Methods and results Our study population consisted of 1468 men, aged 20–79 years, who were repeatedly examined as part of the population-based Study of Health in Pomerania. Serum total testosterone concentrations measured by the chemiluminescent enzyme immunoassays were categorized into age-specific quartiles. We used generalized estimating equations models to assess the prospective association between total testosterone concentrations and lipid profile components including total cholesterol (TC), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride (TG) concentrations, as well as incident dyslipidemia after 5 years of follow-up. Multivariate models revealed that total testosterone concentrations in the lowest quartile were associated with higher TC and TG concentrations in both cross-sectional [TC: 0.23mmol/l (95% confidence interval, CI, 0.02–0.42); TG: 0.73mmol/l (95% CI, 0.53–0.94)] and longitudinal analyses [TC: 0.20mmol/l (95% CI, 0.03–0.27); TG: 0.62mmol/l (95% CI, 0.43–0.80)], but not with high-density lipoprotein cholesterol or low-density lipoprotein cholesterol concentrations. Baseline prevalence of dyslipidemia was 57.1% with a crude incidence rate of 46.6 per 1000 person-years. Total testosterone concentrations in the lowest quartile predicted dyslipidemia; age-adjusted relative risks (RR) for men in quartiles 1, 2, and 3 as compared to quartile 4 (highest, reference) were 1.28 (95% CI, 1.06–1.54), 1.10 (95% CI, 0.91–1.33), and 1.05 (95% CI, 0.86–1.29), respectively. This effect was particularly strong among men aged 20–39 years (relative risk, 1.51; 95% CI, 1.08–2.10). Conclusion Low total testosterone concentrations are prospectively associated with an adverse lipid profile and increased risk of incident dyslipidemia. These findings are particularly interesting and may contribute to an explanation for the higher cardiovascular disease risk in men with lower total testosterone concentrations. Eur J Cardiovasc Prev Rehabil 00:000–000 � c 2010 The European Society of Cardiology
TL;DR: In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, a known association of single nucleotide polymorphisms in the IGFBP3 gene region on chromosome 7p12.3 is confirmed and a borderline statistically significant association between IGF-I concentration and FOXO3 is observed.
Abstract: Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known association of single nucleotide polymorphisms in the IGFBP3 gene region on chromosome 7p12.3 with IGFBP-3 concentrations using a significance threshold of P < 5 × 10(-8) (P = 3.3 × 10(-101)). Furthermore, the same IGFBP3 gene locus (e.g. rs11977526) that was associated with IGFBP-3 concentrations was also associated with the opposite direction of effect, with IGF-I concentration after adjustment for IGFBP-3 concentration (P = 1.9 × 10(-26)). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 (P = 4.4 × 10(-21)) and higher IGF-I (P = 4.9 × 10(-9)) concentrations; when the two measurements were adjusted for one another, the IGF-I association was attenuated but the IGFBP-3 association was not. Two additional loci demonstrated genome-wide significant associations with IGFBP-3 concentration (rs1065656, chromosome 16p13.3, P = 1.2 × 10(-11), IGFALS, a confirmatory finding; and rs4234798, chromosome 4p16.1, P = 4.5 × 10(-10), SORCS2, a novel finding). Together, the four genome-wide significant loci explained 6.5% of the population variation in IGFBP-3 concentration. Furthermore, we observed a borderline statistically significant association between IGF-I concentration and FOXO3 (rs2153960, chromosome 6q21, P = 5.1 × 10(-7)), a locus associated with longevity. These genetic loci deserve further investigation to elucidate the biological basis for the observed associations and clarify their possible role in IGF-mediated regulation of cell growth and metabolism.
TL;DR: Low male TT concentrations are predictive of hypertension, suggesting TT as a potential biomarker of increased cardiovascular risk, and a significant inverse association of TT concentrations and blood pressure.
Abstract: Background. Studies on the relationship between testosterone concentrations and blood pressure have yielded inconsistent results. Therefore, this study investigated the prospective association of total testosterone (TT) concentrations with risk of incident hypertension and blood pressure change in 1484 men aged 20–79 years.Methods. Data from the population-based Study of Health in Pomerania, Germany, were used. Serum TT concentrations, measured by chemiluminescent enzyme immunoassays, were categorised into age-specific quartiles. Generalised Estimating Equation (GEE) models, adjusted for age, waist circumference, physical activity, smoking and alcohol consumption were specified.Results. During a median follow-up time of 5.0 years, the prevalence of hypertension increased from 50.6% to 57.1%. TT concentrations were significantly lower in men with baseline and incident hypertension. Analyses revealed that men with baseline TT concentrations in the lowest quartile had an increased risk of incident hypertensi...
TL;DR: Subjects with low- or high-IGF1 level are at increased risk of developing diabetes after exclusion of patients with onset of new diabetes within 1 year or with borderline glucose or HbA1c levels at baseline.
Abstract: Objective: IGF1 is associated with metabolic parameters and involved in glucose metabolism. Low-IGF1 has been implicated in the etiology of glucose intolerance and subjects with pathological causes of either low- or high-IGF1 are at risk of diabetes. We hypothesized that both low- and high-IGF1 levels increase the risk of diabetes and aimed to assess the role of IGF1 in the risk of developing diabetes in a large prospective study. Design: An analysis of two prospective cohort studies, the DETECT study and SHIP. Methods: We measured IGF1 levels in 7777 nondiabetic subjects and assessed incident diabetes mellitus during follow-up. Results: There were 464 cases of incident diabetes during 32 229 person-years (time of follow-up in the DETECT study and SHIP: 4.5 and 5 years respectively). There was no heterogeneity between both studies (PO0.4). The hazard ratios (HRs) of incident diabetes in subjects with IGF1 levels below the 10th or above the 90th age- and sex-specific percentile, compared to subjects with intermediate IGF1 levels, were 1.44 (95% confidence interval (CI) 1.07–1.94) and 1.55 (95% CI 1.06–2.06) respectively, after multiple adjustment. After further adjustment for metabolic parameters, the HR for low-IGF1 became insignificant. Analysis of IGF1 quintiles revealed a U-shaped association of IGF1 with risk of diabetes. Results remained similar after exclusion of patients with onset of new diabetes within 1 year or with borderline glucose or HbA1c levels at baseline. Conclusions: Subjects with low- or high-IGF1 level are at increased risk of developing diabetes.
TL;DR: A genome-wide association study of the thyroid phenotype by analyzing a discovery cohort consisting of 3620 participants of the Study of Health in Pomerania and finding four genetic loci associated with thyroid volume, increasing the knowledge about genetic factors and physiological mechanisms influencing thyroid volume.
Abstract: Thyroid disorders such as goiters represent important diseases, especially in iodine-deficient areas. Sibling studies have demonstrated that genetic factors substantially contribute to the interindividual variation of thyroid volume. We performed a genome-wide association study of this phenotype by analyzing a discovery cohort consisting of 3620 participants of the Study of Health in Pomerania (SHIP). Four genetic loci were associated with thyroid volume on a genome-wide level of significance. Of these, two independent loci are located upstream of and within CAPZB, which encodes the β subunit of the barbed-end F-actin binding protein that modulates actin polymerization, a process crucial in the colloid engulfment during thyroglobulin mobilization in the thyroid. The third locus marks FGF7, which encodes fibroblast growth factor 7. Members of this protein family have been discussed as putative signal molecules involved in the regulation of thyroid development. The fourth locus represents a "gene desert" on chromosome 16q23, located directly downstream of the predicted coding sequence LOC440389, which, however, had already been removed from the NCBI database as a result of the standard genome annotation processing at the time that this study was initiated. Experimental proof of the formerly predicted mature mRNA, however, demonstrates that LOC440389 indeed represents a real gene. All four associations were replicated in an independent sample of 1290 participants of the KORA study. These results increase the knowledge about genetic factors and physiological mechanisms influencing thyroid volume.
TL;DR: Findings implicate a role of ESR2 in the risk for developing CRC in women and suggest that HSD17B 1, ABCB1, and SHBG genes may contribute to sex steroid-mediated effects on CRC development.
Abstract: The incidence rates and relative risks for colorectal cancer (CRC) are higher in men than in women. Sex steroids may play a role in this gender-associated difference in CRC risk. This study was conducted to explore the relationship of single nucleotide polymorphisms (SNPs) in steroid hormone signaling (ESR1, ESR2, PGR, NR1I2, and SHBG), phase I- and II-metabolizing enzyme (COMT, HSD17B1, CYP1A1, CYP17A1, CYP1A2, CYP1B1, CYP2C9, CYP3A4, CYP2C19, and GSTP1), and hormone transporter (ABCB1) genes with the risk of CRC in German women and men, separately. From the population-based DACHS study (South Germany), 47 putatively functional SNPs were genotyped in 1798 CRC cases (746 women and 1052 men) and 1810 controls (732 women and 1078 men). Significant allele dose-response associations were observed with ESR2_rs1255998, ESR2_rs928554, HSD17B1_rs605059, and ABCB1_rs2229109 in women (P trend=0.004, 0.05, 0.03, and 0.05 respectively) and with ABCB1_rs1045642, ABCB1_rs9282564, and SHBG_rs6259 in men (P trend=0.01, 0.03, and 0.02 respectively). The ESR2_rs1255998_G allele showed the most significant association with risk for CRC in women, with a per-allele odds ratio (OR) of 0.68 (95% confidence interval (CI) 0.52-0.88). This finding was replicated in an independent study from North Germany including 1076 female CRC cases and 1151 controls (OR=0.84, 95% CI 0.71-1.04), yielding a per-allele OR of 0.80 (95% CI 0.69-0.93, P trend=0.003) in the pooled sample. These findings implicate a role of ESR2 in the risk for developing CRC in women and suggest that HSD17B1, ABCB1, and SHBG genes may contribute to sex steroid-mediated effects on CRC development.
TL;DR: Associations of PAC with MetS, elevated triglycerides, and decreased HDL cholesterol in SHIP-1 and KORA F4 suggest that aldosterone may be involved in the pathophysiology of MetS and lipid metabolism disorders.
Abstract: Objective: The aim of this study was to analyze the potential association of the plasma aldosterone concentration (PAC) with the metabolic syndrome (MetS) and its components in two German population-based studies. Methods: We selected 2830 and 2901 participants (31–80 years) from the follow-ups of the Study of Health in Pomerania (SHIP)-1 and the Cooperative Health Research in the Region of Augsburg (KORA) F4 respectively. MetS was defined as the presence of at least three out of the following five criteria: waist circumference R94 cm (men (m)) and R80 cm (women (w)); high-density lipoprotein (HDL) cholesterol !1.0 mmol/l (m) and !1.3 mmol/l (w); blood pressure R130/85 mmHg or antihypertensive treatment; non-fasting glucose (SHIP-1) R8 mmol/l, fasting glucose (KORA F4) R5.55 mmol/l or antidiabetic treatment; non-fasting triglycerides (SHIP-1) R2.3 mmol/l, fasting triglycerides (KORA F4) R1.7 mmol/l, or lipid-lowering treatment. We calculated logistic regression models by comparing the highest study- and sex-specific PAC quintiles versus all lower quintiles. Results: MetS was common with 48.1% (m) and 34.8% (w) in SHIP-1 and 42.7% (m) and 27.5% (w) in KORA F4. Our logistic regression models revealed associations of PAC with MetS, elevated triglycerides, and decreased HDL cholesterol in SHIP-1 and KORA F4. Conclusions: Our findings add to the increasing evidence supporting a relation between aldosterone and MetS and suggest that aldosterone may be involved in the pathophysiology of MetS and lipid metabolism disorders.
Patent•
12 Oct 2011
TL;DR: In this article, a framework for predicting development of a cardiovascular condition of interest in a patient is proposed, which involves determining, based on prior domain knowledge relating to the cardiovascular conditions of interest, a risk score as a function of patient data.
Abstract: Described herein is a framework for predicting development of a cardiovascular condition of interest in a patient. The framework involves determining, based on prior domain knowledge relating to the cardiovascular condition of interest, a risk score as a function of patient data. The patient data may include both genetic data and non-genetic data. In one implementation, the risk score is used to categorize the patient into at least one of multiple risk categories, the multiple risk categories being associated with different strategies to prevent the onset of the cardiovascular condition. The results generated by the framework may be presented to a physician to facilitate interpretation, risk assessment and/or clinical decision support.
TL;DR: In the case of early loss of kidney function, measured TT concentrations might help to detect high-risk individuals for potential therapeutic interventions and to improve mortality risk assessment and outcome.
Abstract: Background: Chronic kidney disease (CKD) and low serum total testosterone (TT) concentrations are independent predictors of mortality risk in the general population, but their combi
TL;DR: This is the first study relating traumatic stress and PTSD, respectively, to objective parameters of lung function and suggests an association of trauma exposure and PTSD with airflow limitation, which may be mediated by inflammatory processes.
Abstract: Trauma exposure and post-traumatic stress disorder (PTSD) are associated with self-reported asthma and chronic obstructive pulmonary disease. However, these conditions have not yet been related to objective measures of lung function. 1,772 adults from the general population were assessed regarding their medical histories and spirometric lung function. Additionally, they were administered a PTSD interview, and assigned to three groups: no trauma; trauma, but no PTSD; and trauma with PTSD. Adjusting for sociodemographic, clinical and lifestyle factors, subjects with PTSD had significantly higher odds ratios for most asthma-related symptoms than PTSD-negative participants (OR 3.2-8.8). The mean ratio of forced expiratory volume in 1 s (FEV₁) to forced vital capacity (FVC) was lowest in the PTSD group and highest in those without trauma exposure. Traumatic stress was independently associated with FEV₁ and FEV₁/FVC. Participants with PTSD, compared with those without, had a significantly increased risk for airflow limitation independent of its definition (OR 4.2-7.8). This is the first study relating traumatic stress and PTSD, respectively, to objective parameters of lung function. Our findings suggest an association of trauma exposure and PTSD with airflow limitation, which may be mediated by inflammatory processes.
University of Würzburg1, University of Marburg2, Aarhus University Hospital3, University of Trier4, Goethe University Frankfurt5, Radboud University Nijmegen Medical Centre6, Haukeland University Hospital7, University of Bergen8, University of Greifswald9, University of Barcelona10, Radboud University Nijmegen11
TL;DR: Converging lines of evidence implicate genetic variance in the promoter region of DIRAS2 in the etiology of ADHD and co-morbid impulsive disorders.
TL;DR: An association of objective measure of airflow limitation to generalized anxiety and panic is suggested, while the causal relationship between obstructive lung disease, airflow limitation and anxiety remains to be determined.