273 results found
Pattaro C, Teumer A, Gorski M, et al., 2016, Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function., Nat Commun, Vol: 7
Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
de Vries PS, Chasman DI, Sabater-Lleal M, et al., 2016, A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration, HUMAN MOLECULAR GENETICS, Vol: 25, Pages: 358-370, ISSN: 0964-6906
LeBlanc M, Zuber V, Andreassen BK, et al., 2016, Identifying Novel Gene Variants in Coronary Artery Disease and Shared Genes With Several Cardiovascular Risk Factors, CIRCULATION RESEARCH, Vol: 118, Pages: 83-94, ISSN: 0009-7330
Sedaghat S, Mattace-Raso FUS, Hoorn EJ, et al., 2015, Arterial Stiffness and Decline in Kidney Function, CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, Vol: 10, Pages: 2190-2197, ISSN: 1555-9041
Nino PKB, Durik M, Danser AHJ, et al., 2015, Phosphodiesterase 1 regulation is a key mechanism in vascular aging, CLINICAL SCIENCE, Vol: 129, Pages: 1061-1075, ISSN: 0143-5221
van Leeuwen EM, Huffman JE, Bis JC, et al., 2015, Fine mapping the CETP region reveals a common intronic insertion associated to HDL-C, npj Aging and Mechanisms of Disease, Vol: 1
© 2015 Japanese Society of Anti-Aging Medicine/Macmillan Publishers Limited. BACKGROUND: Individuals with exceptional longevity and their offspring have significantly larger high-density lipoprotein concentrations (HDL-C) particle sizes due to the increased homozygosity for the I405V variant in the cholesteryl ester transfer protein (CETP) gene. In this study, we investigate the association of CETP and HDL-C further to identify novel, independent CETP variants associated with HDL-C in humans. METHODS: We performed a meta-analysis of HDL-C within the CETP region using 59,432 individuals imputed with 1000 Genomes data. We performed replication in an independent sample of 47,866 individuals and validation was done by Sanger sequencing. RESULTS: The meta-analysis of HDL-C within the CETP region identified five independent variants, including an exonic variant and a common intronic insertion. We replicated these 5 variants significantly in an independent sample of 47,866 individuals. Sanger sequencing of the insertion within a single family confirmed segregation of this variant. The strongest reported association between HDL-C and CETP variants, was rs3764261; however, after conditioning on the five novel variants we identified the support for rs3764261 was highly reduced (βunadjusted = 3.179 mg/dl (P value = 5.25 × 10−509), βadjusted = 0.859 mg/dl (P value = 9.51 × 10− 25)), and this finding suggests that these five novel variants may partly explain the association of CETP with HDL-C. Indeed, three of the five novel variants (rs34065661, rs5817082, rs7499892) are independent of rs3764261. CONCLUSIONS: The causal variants in CETP that account for the association with HDL-C remain unknown. We used studies imputed to the 1000 Genomes reference panel for fine mapping of the CETP region. We identified and validated five variants within this region that may partly account for the association of the known variant (rs3764261), as well as o
Ligthart S, van Herpt TTW, Leening MJG, et al., 2015, Lifetime risk of developing impaired glucose metabolism and eventual progression from prediabetes to type 2 diabetes: a prospective cohort study, Lancet Diabetes and Endocrinology, Vol: 4, Pages: 44-51, ISSN: 2213-8595
BackgroundData are scarce for the lifetime risk of developing impaired glucose metabolism, including prediabetes, as are data for the risk of eventual progression from prediabetes to diabetes and for initiation of insulin treatment in previously untreated patients with diabetes. We aimed to calculate the lifetime risk of the full range of glucose impairments, from normoglycaemia to prediabetes, type 2 diabetes, and eventual insulin use.MethodsIn this prospective population-based cohort analysis, we used data from the population-based Rotterdam Study. We identified diagnostic events by use of general practitioners' records, hospital discharge letters, pharmacy dispensing data, and serum fasting glucose measurements taken at the study centre (Rotterdam, Netherlands) visits. Normoglycaemia, prediabetes, and diabetes were defined on the basis of WHO criteria for fasting glucose (normoglycaemia: ≤6·0 mmol/L; prediabetes: >6·0 mmol/L and <7·0 mmol/L; and diabetes ≥7·0 mmol/L or use of glucose-lowering drug). We calculated lifetime risk using a modified version of survival analysis adjusted for the competing risk of death. We also estimated the lifetime risk of progression from prediabetes to overt diabetes and from diabetes free of insulin treatment to insulin use. Additionally, we calculated years lived with healthy glucose metabolism.FindingsWe used data from 10 050 participants from the Rotterdam Study. During a follow-up of up to 14·7 years (between April 1, 1997, and Jan 1, 2012), 1148 participants developed prediabetes, 828 developed diabetes, and 237 started insulin treatment. At age 45 years, the remaining lifetime risk was 48·7% (95% CI 46·2–51·3) for prediabetes, 31·3% (29·3–33·3) for diabetes, and 9·1% (7·8–10·3) for insulin use. In individuals aged 45 years, the lifetime risk to progress from prediabetes to diabetes was 74·0% (
Tamar Silva C, Kors JA, Amin N, et al., 2015, Heritabilities, proportions of heritabilities explained by GWAS findings, and implications of cross-phenotype effects on PR interval, HUMAN GENETICS, Vol: 134, Pages: 1211-1219, ISSN: 0340-6717
Laugsand LE, Ix JH, Bartz TM, et al., 2015, Fetuin-A and risk of coronary heart disease: A Mendelian randomization analysis and a pooled analysis of AHSG genetic variants in 7 prospective studies, ATHEROSCLEROSIS, Vol: 243, Pages: 44-52, ISSN: 0021-9150
van Loon J, Dehghan A, Tang W, et al., 2015, Genome-wide association studies identify genetic loci for low von Willebrand factor levels, EUROPEAN JOURNAL OF HUMAN GENETICS, Vol: 24, Pages: 1035-1040, ISSN: 1018-4813
Maksimovic A, Hanewinckel R, Verlinden VJA, et al., 2015, Gait characteristics in older adults with diabetes and impaired fasting glucose: The Rotterdam Study, Journal of Diabetes and its Complications, Vol: 30, Pages: 61-66, ISSN: 1056-8727
AimsTo investigate the association of diabetes mellitus and impaired fasting glucose with gait in the general middle-aged and elderly population.MethodsWe performed a cross-sectional study on 3019 participants from the population-based Rotterdam Study (aged > 45 years, 54% women). The presence of diabetes mellitus and impaired fasting glucose was evaluated by measuring serum glucose levels and by documenting anti-diabetic treatment. Participants underwent gait analysis using an electronic walkway. Thirty gait variables were summarized into five independent gait domains for normal walking (Rhythm, Variability, Phases, Pace and Base of Support), one for turning (Turning) and one for walking heel to toe (Tandem), which were averaged into Global Gait. Linear regression analyses were performed to determine the association of diabetes, impaired fasting glucose and continuous glucose levels within the normal range with gait.ResultsDiabetes mellitus was associated with worse Global Gait (Z-score difference − 0.19, 95% confidence interval (CI) − 0.30; − 0.07), worse Pace (− 0.20, 95% CI − 0.30; − 0.10) and worse Tandem (− 0.21, 95% CI − 0.33; − 0.09), after adjusting for age, sex, height and weight. The association with Tandem remained significant after additional adjustment for cardiovascular risk factors. Impaired fasting glucose and continuous glucose levels within the normal range were not associated with any of the gait domains.ConclusionIn our population-based study diabetes mellitus was associated with worse Global Gait, which was mostly reflected in Pace and Tandem. These associations were partly driven by other cardiovascular risk factors, emphasizing the importance of optimal control of cardiovascular risk factor profiles in patients with diabetes.
Chaker L, Heeringa J, Dehghan A, et al., 2015, Normal Thyroid Function and the Risk of Atrial Fibrillation: the Rotterdam Study, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 100, Pages: 3718-3724, ISSN: 0021-972X
Kato N, Loh M, Takeuchi F, et al., 2015, Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation, Nature Genetics, Vol: 47, Pages: 1282-1293, ISSN: 1546-1718
We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10−11 to 5.0 × 10−21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10−6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.
Huffman JE, de Vries PS, Morrison AC, et al., 2015, Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF, BLOOD, Vol: 126, Pages: E19-E29, ISSN: 0006-4971
Nikpay M, Goel A, Won H-H, et al., 2015, A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease, Nature Genetics, Vol: 47, Pages: 1121-1130, ISSN: 1061-4036
Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largelybased on genome-wide association studies (GWAS) analysis of common SNPs. Leveragingphased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of 185thousand CAD cases and controls, interrogating 6.7 million common (MAF>0.05) as well as 2.7million low frequency (0.005<MAF<0.05) variants. In addition to confirmation of most knownCAD loci, we identified 10 novel loci, eight additive and two recessive, that contain candidategenes that newly implicate biological processes in vessel walls. We observed intra-locus allelicheterogeneity but little evidence of low frequency variants with larger effects and no evidence ofsynthetic association. Our analysis provides a comprehensive survey of the fine geneticarchitecture of CAD showing that genetic susceptibility to this common disease is largelydetermined by common SNPs of small effect size
Sedaghat S, Cremers LGM, de Groot M, et al., 2015, Kidney function and microstructural integrity of brain white matter, NEUROLOGY, Vol: 85, Pages: 154-161, ISSN: 0028-3878
Liefaard MC, Ligthart S, Vitezova A, et al., 2015, Vitamin D and C-Reactive Protein: A Mendelian Randomization Study, PLOS ONE, Vol: 10, ISSN: 1932-6203
Milaneschi Y, Lamers F, Peyrot WJ, et al., 2015, Polygenic dissection of major depression clinical heterogeneity., Mol Psychiatry, Vol: 21, Pages: 516-522
The molecular mechanisms underlying major depressive disorder (MDD) are largely unknown. Limited success of previous genetics studies may be attributable to heterogeneity of MDD, aggregating biologically different subtypes. We examined the polygenic features of MDD and two common clinical subtypes (typical and atypical) defined by symptom profiles in a large sample of adults with established diagnoses. Data were from 1530 patients of the Netherlands Study of Depression and Anxiety (NESDA) and 1700 controls mainly from the Netherlands Twin Register (NTR). Diagnoses of MDD and its subtypes were based on DSM-IV symptoms. Genetic overlap of MDD and subtypes with psychiatric (MDD, bipolar disorder, schizophrenia) and metabolic (body mass index (BMI), C-reactive protein, triglycerides) traits was evaluated via genomic profile risk scores (GPRS) generated from meta-analysis results of large international consortia. Single nucleotide polymorphism (SNP)-heritability of MDD and subtypes was also estimated. MDD was associated with psychiatric GPRS, while no association was found for GPRS of metabolic traits. MDD subtypes had differential polygenic signatures: typical was strongly associated with schizophrenia GPRS (odds ratio (OR)=1.54, P=7.8e-9), while atypical was additionally associated with BMI (OR=1.29, P=2.7e-4) and triglycerides (OR=1.21, P=0.006) GPRS. Similar results were found when only the highly discriminatory symptoms of appetite/weight were used to define subtypes. SNP-heritability was 32% for MDD, 38% and 43% for subtypes with, respectively, decreased (typical) and increased (atypical) appetite/weight. In conclusion, MDD subtypes are characterized by partially distinct polygenic liabilities and may represent more homogeneous phenotypes. Disentangling MDD heterogeneity may help the psychiatric field moving forward in the search for molecular roots of depression.
Ezzati M, Danaei G, Fahimi S, et al., 2015, Effects of diabetes definition on global surveillance of diabetes prevalence and diagnosis: a pooled analysis of 96 population-based studies with 331 288 participants, The Lancet Diabetes & Endocrinology, Vol: 3, Pages: 624-637, ISSN: 2213-8587
Background: Over time, diabetes has been defined based on different biomarkers, includingfasting plasma glucose (FPG) or 2-hour plasma glucose in an oral glucose tolerance test (2hOGTT) and,more recently, haemoglobin A1c (HbA1c). We examined the influence of diagnostic definitions on boththe population prevalence of diabetes and the classification of previously-undiagnosed individuals aswith vs. without diabetes in a pooled analysis of data from population-based health examinationsurveys in different world regions.
de Vries PS, Boender J, Sonneveld MAH, et al., 2015, Genetic variants in the ADAMTS13 and SUPT3H genes are associated with ADAMTS13 activity, BLOOD, Vol: 125, Pages: 3949-3955, ISSN: 0006-4971
Muka T, Trajanoska K, Kiefte-de Jong JC, et al., 2015, The Association between Metabolic Syndrome, Bone Mineral Density, Hip Bone Geometry and Fracture Risk: The Rotterdam Study, PLOS ONE, Vol: 10, ISSN: 1932-6203
Desikan RS, Schork AJ, Wang Y, et al., 2015, Polygenic Overlap Between C-Reactive Protein, Plasma Lipids, and Alzheimer Disease, CIRCULATION, Vol: 131, Pages: 2061-2069, ISSN: 0009-7322
Chaker L, Baumgartner C, den Elzen WPJ, et al., 2015, Subclinical Hypothyroidism and the Risk of Stroke Events and Fatal Stroke: An Individual Participant Data Analysis, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 100, Pages: 2181-2191, ISSN: 0021-972X
Ghanbari M, Franco OH, de Looper HWJ, et al., 2015, Genetic Variations in MicroRNA-Binding Sites Affect MicroRNA-Mediated Regulation of Several Genes Associated With Cardio-metabolic Phenotypes, CIRCULATION-CARDIOVASCULAR GENETICS, Vol: 8, Pages: 473-486, ISSN: 1942-325X
Muka T, Kiefte-de Jong JC, Hofman A, et al., 2015, Polyunsaturated Fatty Acids and Serum C-Reactive Protein The Rotterdam Study, AMERICAN JOURNAL OF EPIDEMIOLOGY, Vol: 181, Pages: 846-856, ISSN: 0002-9262
Steenaard RV, Ligthart S, Stolk L, et al., 2015, Tobacco smoking is associated with methylation of genes related to coronary artery disease, CLINICAL EPIGENETICS, Vol: 7, ISSN: 1868-7075
Fall T, Hagg S, Ploner A, et al., 2015, Age- and Sex-Specific Causal Effects of Adiposity on Cardiovascular Risk Factors, DIABETES, Vol: 64, Pages: 1841-1852, ISSN: 0012-1797
Gorski M, Tin A, Garnaas M, et al., 2015, Genome-wide association study of kidney function decline in individuals of European descent, KIDNEY INTERNATIONAL, Vol: 87, Pages: 1017-1029, ISSN: 0085-2538
Chaker L, Buitendijk GHS, Dehghan A, et al., 2015, Thyroid function and age-related macular degeneration: a prospective population-based cohort study - the Rotterdam Study, BMC MEDICINE, Vol: 13, ISSN: 1741-7015
de Vries PS, Kavousi M, Ligthart S, et al., 2015, Incremental predictive value of 152 single nucleotide polymorphisms in the 10-year risk prediction of incident coronary heart disease: the Rotterdam Study, INTERNATIONAL JOURNAL OF EPIDEMIOLOGY, Vol: 44, Pages: 682-688, ISSN: 0300-5771
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