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Search Results: 1 - 10 of 192007 matches for " Andre G. Uitterlinden "
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Type 2 diabetes gene TCF7L2 polymorphism is not associated with fetal and postnatal growth in two birth cohort studies
Dennis O Mook-Kanamori, Sandra WK de Kort, Cornelia M van Duijn, Andre G Uitterlinden, Albert Hofman, Henri?tte A Moll, Eric AP Steegers, Anita CS Hokken-Koelega, Vincent WV Jaddoe
BMC Medical Genetics , 2009, DOI: 10.1186/1471-2350-10-67
Abstract: This study was performed in two independent birth cohort studies, one prospective population-based (Generation R), and one of subjects born small-for-gestational-age (SGA cohort). Fetal growth was assessed by ultrasounds in second and third trimesters of pregnancy in Generation R. Growth in infancy was assessed in both cohorts at birth and at 6, 12 and 24 months postnatally. TCF7L2 genotype was determined in 3,419 subjects in Generation R and in 566 subjects in the SGA cohort.Minor allele frequency did not differ significantly (p = 0.47) between Generation R (T-allele: 28.7%) and the SGA cohort (T-allele: 29.8%). No differences at birth were found in gestational age or size (head circumference, length, weight) between the genotypes in either cohort. TCF7L2 genotype was also not associated with any pre- or postnatal growth characteristic in either Generation R or the SGA cohort.We found no evidence for an association between TCF7L2 genotype and fetal and early postnatal growth. Furthermore, this TCF7L2 polymorphism was not associated with an increased risk of SGA.Several epidemiological studies have shown inverse associations between birth weight and metabolic diseases, including type 2 diabetes (T2D) in adulthood [1,2]. These associations may be influenced by common genetic variants [2]. Insulin is the most important fetal growth factor and insulin-mediated fetal growth might be affected by genetic polymorphisms that regulate fetal insulin secretion or insulin sensitivity [2]. Therefore, gene variants associated with T2D have been suggested as candidate genes for influencing early growth [2].Genome-wide association (GWA) studies have consistently shown that the C>T substitution in TCF7L2 gene (rs7903146) increases the risk of T2D approximately 2-fold when two risk allele copies (TT) are present [3-5]. The T-allele of this TCF7L2 polymorphisms has been suggest to reduce proinsulin to insulin conversion [6], though the exact mechanism has not been elucidated yet. Othe
BMI-Associated Alleles Do Not Constitute Risk Alleles for Polycystic Ovary Syndrome Independently of BMI: A Case-Control Study
Yvonne V. Louwers, Nigel W. Rayner, Blanca M. Herrera, Lisette Stolk, Christopher J. Groves, Thomas M. Barber, Andre G. Uitterlinden, Stephen Franks, Joop S. E. Laven, Mark I. McCarthy
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0087335
Abstract: Introduction Polycystic Ovary Syndrome (PCOS) has a strong genetic background and the majority of patients with PCOS have elevated BMI levels. The aim of this study was to determine to which extent BMI-increasing alleles contribute to risk of PCOS when contemporaneous BMI is taken into consideration. Methods Patients with PCOS and controls were recruited from the United Kingdom (563 cases and 791 controls) and The Netherlands (510 cases and 2720 controls). Cases and controls were of similar BMI. SNPs mapping to 12 BMI-associated loci which have been extensively replicated across different ethnicities, i.e., BDNF, FAIM2, ETV5, FTO, GNPDA2, KCTD15, MC4R, MTCH2, NEGR1, SEC16B, SH2B1, and TMEM18, were studied in association with PCOS within each cohort using the additive genetic model followed by a combined analysis. A genetic allelic count risk score model was used to determine the risk of PCOS for individuals carrying increasing numbers of BMI-increasing alleles. Results None of the genetic variants, including FTO and MC4R, was associated with PCOS independently of BMI in the meta-analysis. Moreover, no differences were observed between cases and controls in the number of BMI-risk alleles present and no overall trend across the risk score groups was observed. Conclusion In this combined analysis of over 4,000 BMI-matched individuals from the United Kingdom and the Netherlands, we observed no association of BMI risk alleles with PCOS independent of BMI.
A Genome-Wide Association Study of Optic Disc Parameters
Wishal D. Ramdas equal contributor,Leonieke M. E. van Koolwijk equal contributor,M. Kamran Ikram equal contributor,Nomdo M. Jansonius,Paulus T. V. M. de Jong,Arthur A. B. Bergen,Aaron Isaacs,Najaf Amin,Yurii S. Aulchenko,Roger C. W. Wolfs,Albert Hofman,Fernando Rivadeneira,Ben A. Oostra,Andre G. Uitterlinden,Pirro Hysi,Christopher J. Hammond,Hans G. Lemij,Johannes R. Vingerling ,Caroline C. W. Klaver equal contributor,Cornelia M. van Duijn equal contributor
PLOS Genetics , 2010, DOI: 10.1371/journal.pgen.1000978
Abstract: The optic nerve head is involved in many ophthalmic disorders, including common diseases such as myopia and open-angle glaucoma. Two of the most important parameters are the size of the optic disc area and the vertical cup-disc ratio (VCDR). Both are highly heritable but genetically largely undetermined. We performed a meta-analysis of genome-wide association (GWA) data to identify genetic variants associated with optic disc area and VCDR. The gene discovery included 7,360 unrelated individuals from the population-based Rotterdam Study I and Rotterdam Study II cohorts. These cohorts revealed two genome-wide significant loci for optic disc area, rs1192415 on chromosome 1p22 (p = 6.72×10?19) within 117 kb of the CDC7 gene and rs1900004 on chromosome 10q21.3-q22.1 (p = 2.67×10?33) within 10 kb of the ATOH7 gene. They revealed two genome-wide significant loci for VCDR, rs1063192 on chromosome 9p21 (p = 6.15×10?11) in the CDKN2B gene and rs10483727 on chromosome 14q22.3-q23 (p = 2.93×10?10) within 40 kbp of the SIX1 gene. Findings were replicated in two independent Dutch cohorts (Rotterdam Study III and Erasmus Rucphen Family study; N = 3,612), and the TwinsUK cohort (N = 843). Meta-analysis with the replication cohorts confirmed the four loci and revealed a third locus at 16q12.1 associated with optic disc area, and four other loci at 11q13, 13q13, 17q23 (borderline significant), and 22q12.1 for VCDR. ATOH7 was also associated with VCDR independent of optic disc area. Three of the loci were marginally associated with open-angle glaucoma. The protein pathways in which the loci of optic disc area are involved overlap with those identified for VCDR, suggesting a common genetic origin.
Mapping of Gene Expression Reveals CYP27A1 as a Susceptibility Gene for Sporadic ALS
Frank P. Diekstra, Christiaan G. J. Saris, Wouter van Rheenen, Lude Franke, Ritsert C. Jansen, Michael A. van Es, Paul W. J. van Vught, Hylke M. Blauw, Ewout J. N. Groen, Steve Horvath, Karol Estrada, Fernando Rivadeneira, Albert Hofman, Andre G. Uitterlinden, Wim Robberecht, Peter M. Andersen, Judith Melki, Vincent Meininger, Orla Hardiman, John E. Landers, Robert H. Brown, Aleksey Shatunov, Christopher E. Shaw, P. Nigel Leigh, Ammar Al-Chalabi, Roel A. Ophoff, Leonard H. van den Berg, Jan H. Veldink
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0035333
Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease characterized by loss of upper and lower motor neurons. ALS is considered to be a complex trait and genome-wide association studies (GWAS) have implicated a few susceptibility loci. However, many more causal loci remain to be discovered. Since it has been shown that genetic variants associated with complex traits are more likely to be eQTLs than frequency-matched variants from GWAS platforms, we conducted a two-stage genome-wide screening for eQTLs associated with ALS. In addition, we applied an eQTL analysis to finemap association loci. Expression profiles using peripheral blood of 323 sporadic ALS patients and 413 controls were mapped to genome-wide genotyping data. Subsequently, data from a two-stage GWAS (3,568 patients and 10,163 controls) were used to prioritize eQTLs identified in the first stage (162 ALS, 207 controls). These prioritized eQTLs were carried forward to the second sample with both gene-expression and genotyping data (161 ALS, 206 controls). Replicated eQTL SNPs were then tested for association in the second-stage GWAS data to find SNPs associated with disease, that survived correction for multiple testing. We thus identified twelve cis eQTLs with nominally significant associations in the second-stage GWAS data. Eight SNP-transcript pairs of highest significance (lowest p = 1.27×10?51) withstood multiple-testing correction in the second stage and modulated CYP27A1 gene expression. Additionally, we show that C9orf72 appears to be the only gene in the 9p21.2 locus that is regulated in cis, showing the potential of this approach in identifying causative genes in association loci in ALS. This study has identified candidate genes for sporadic ALS, most notably CYP27A1. Mutations in CYP27A1 are causal to cerebrotendinous xanthomatosis which can present as a clinical mimic of ALS with progressive upper motor neuron loss, making it a plausible susceptibility gene for ALS.
Best Practices and Joint Calling of the HumanExome BeadChip: The CHARGE Consortium
Megan L. Grove, Bing Yu, Barbara J. Cochran, Talin Haritunians, Joshua C. Bis, Kent D. Taylor, Mark Hansen, Ingrid B. Borecki, L. Adrienne Cupples, Myriam Fornage, Vilmundur Gudnason, Tamara B. Harris, Sekar Kathiresan, Robert Kraaij, Lenore J. Launer, Daniel Levy, Yongmei Liu, Thomas Mosley, Gina M. Peloso, Bruce M. Psaty, Stephen S. Rich, Fernando Rivadeneira, David S. Siscovick, Albert V. Smith, Andre Uitterlinden, Cornelia M. van Duijn, James G. Wilson, Christopher J. O’Donnell, Jerome I. Rotter, Eric Boerwinkle
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0068095
Abstract: Genotyping arrays are a cost effective approach when typing previously-identified genetic polymorphisms in large numbers of samples. One limitation of genotyping arrays with rare variants (e.g., minor allele frequency [MAF] <0.01) is the difficulty that automated clustering algorithms have to accurately detect and assign genotype calls. Combining intensity data from large numbers of samples may increase the ability to accurately call the genotypes of rare variants. Approximately 62,000 ethnically diverse samples from eleven Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium cohorts were genotyped with the Illumina HumanExome BeadChip across seven genotyping centers. The raw data files for the samples were assembled into a single project for joint calling. To assess the quality of the joint calling, concordance of genotypes in a subset of individuals having both exome chip and exome sequence data was analyzed. After exclusion of low performing SNPs on the exome chip and non-overlap of SNPs derived from sequence data, genotypes of 185,119 variants (11,356 were monomorphic) were compared in 530 individuals that had whole exome sequence data. A total of 98,113,070 pairs of genotypes were tested and 99.77% were concordant, 0.14% had missing data, and 0.09% were discordant. We report that joint calling allows the ability to accurately genotype rare variation using array technology when large sample sizes are available and best practices are followed. The cluster file from this experiment is available at www.chargeconsortium.com/main/exomechip.
Search for the Standard Model Higgs Boson at LEP
Andre G. Holzner
Physics , 2002, DOI: 10.1016/S0920-5632(02)02021-2
Abstract: One of the missions of the LEP program was the search for the Standard Model Higgs Boson. The skillful operation of the machine in the year 2000, the final year of operation, has allowed the four collaborations ALEPH, DELPHI, L3 and OPAL to collect 536/pb of data at center-of-mass energies of 206 GeV or higher. This data is used to probe the existence of the Higgs boson up to a mass of around 115 GeV. Tantalizing candidates have been observed in excess over the Standard Model predictions, but without enough statistical power to claim a discovery. A Higgs boson lighter than 114.4 GeV is hence excluded at 95% confidence level.
Searches for Charged Higgs Bosons at LEP
Andre G. Holzner
Physics , 2001,
Abstract: The four LEP experiments Aleph, Delphi, L3 and Opal updated their searches for pair production of charged Higgs bosons using more than 210/pb luminosity collected per experiment in the year 2000. Combining it with previously collected data, a significant deviation from background (equivalent to 4.4 sigma) is found by the L3 collaboration for low values of the branching ratio H+/- -> tau nu around masses of about 68 GeV. This excess is however not seen by the other LEP collaborations and thus a lower limit on the charged Higgs mass is set at 78.5 GeV at 95% confidence level. All results reported here are still preliminary.
Searches for Exotic Higgs Bosons at LEP
Andre G. Holzner
Physics , 2004,
Abstract: In the Standard Model (SM), the weak gauge bosons and fermions acquire mass through the Higgs mechanism. A lower limit on the SM Higgs mass of 114.4 GeV was obtained from the direct search at LEP. Although a single Higgs doublet is sufficient to explain the non-zero particle masses while keeping the theory SU(2) gauge invariant, several extensions to this minimal model were proposed, to which this limit does not apply. Most of the models discussed here introduce one additional Higgs doublet and are therefore called Two Higgs doublet models (2HDM). Several signatures predicted by such models have been searched for at LEP using data collected at center-of-mass energies up to 209 GeV. All limits quoted in this report are at 95% confidence level.
Susceptibility to Chronic Mucus Hypersecretion, a Genome Wide Association Study
Akkelies E. Dijkstra, Joanna Smolonska, Maarten van den Berge, Ciska Wijmenga, Pieter Zanen, Marjan A. Luinge, Mathieu Platteel, Jan-Willem Lammers, Magnus Dahlback, Kerrie Tosh, Pieter S. Hiemstra, Peter J. Sterk, Avi Spira, Jorgen Vestbo, Borge G. Nordestgaard, Marianne Benn, Sune F. Nielsen, Morten Dahl, W. Monique Verschuren, H. Susan J. Picavet, Henriette A. Smit, Michael Owsijewitsch, Hans U. Kauczor, Harry J. de Koning, Eva Nizankowska-Mogilnicka, Filip Mejza, Pawel Nastalek, Cleo C. van Diemen, Michael H. Cho, Edwin K. Silverman, James D. Crapo, Terri H. Beaty, David A. Lomas, Per Bakke, Amund Gulsvik, Yohan Bossé, M. A. Obeidat, Daan W. Loth, Lies Lahousse, Fernando Rivadeneira, Andre G. Uitterlinden, Andre Hofman, Bruno H. Stricker, Guy G. Brusselle, Cornelia M. van Duijn, Uilke Brouwer, Gerard H. Koppelman, Judith M. Vonk, Martijn C. Nawijn, Harry J. M. Groen, Wim Timens, H. Marike Boezen, Dirkje S. Postma, the LifeLines Cohort study
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0091621
Abstract: Background Chronic mucus hypersecretion (CMH) is associated with an increased frequency of respiratory infections, excess lung function decline, and increased hospitalisation and mortality rates in the general population. It is associated with smoking, but it is unknown why only a minority of smokers develops CMH. A plausible explanation for this phenomenon is a predisposing genetic constitution. Therefore, we performed a genome wide association (GWA) study of CMH in Caucasian populations. Methods GWA analysis was performed in the NELSON-study using the Illumina 610 array, followed by replication and meta-analysis in 11 additional cohorts. In total 2,704 subjects with, and 7,624 subjects without CMH were included, all current or former heavy smokers (≥20 pack-years). Additional studies were performed to test the functional relevance of the most significant single nucleotide polymorphism (SNP). Results A strong association with CMH, consistent across all cohorts, was observed with rs6577641 (p = 4.25×10?6, OR = 1.17), located in intron 9 of the special AT-rich sequence-binding protein 1 locus (SATB1) on chromosome 3. The risk allele (G) was associated with higher mRNA expression of SATB1 (4.3×10?9) in lung tissue. Presence of CMH was associated with increased SATB1 mRNA expression in bronchial biopsies from COPD patients. SATB1 expression was induced during differentiation of primary human bronchial epithelial cells in culture. Conclusions Our findings, that SNP rs6577641 is associated with CMH in multiple cohorts and is a cis-eQTL for SATB1, together with our additional observation that SATB1 expression increases during epithelial differentiation provide suggestive evidence that SATB1 is a gene that affects CMH.
The interleukin-6 –174 G/C promoter polymorphism and arterial stiffness; the Rotterdam Study
Mark PS Sie,Francesco US Mattace-Raso,André G Uitterlinden,Pascal P Arp
Vascular Health and Risk Management , 2008,
Abstract: Mark PS Sie1, Francesco US Mattace-Raso2, André G Uitterlinden2, Pascal P Arp2, Albert Hofman1, Huibert AP Pols2, Arnold PG Hoeks3, Robert S Reneman4, Roland Asmar5, Cornelia M van Duijn1, Jacqueline CM Witteman11Department of Epidemiology and Biostatistics, 2Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands; 3Department of Biophysics, 4Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands; 5Cardiovascular Institute, Paris, FranceAbstract: Arterial stiffness normally increases with age and has been established as a precursor of cardiovascular disease. Interleukin-6 is a pleiotropic inflammatory cytokine with an important role in the inflammatory cascade, such as up-regulation of C-reactive protein (CRP). The interleukin-6 –174-G/C promoter polymorphism appears to infl uence levels of inflammatory markers, which have been shown to be associated with arterial stiffness. We studied the association of this polymorphism with levels of interleukin-6 and CRP and with arterial stiffness. The study (n = 3849) was embedded in the Rotterdam Study, a prospective, population-based study. Analyses on the association between the –174-G/C polymorphism and pulse wave velocity, distensibility coefficient, and pulse pressure were performed using analyses of variance. Analyses on the levels of inflammatory markers and arterial stiffness were performed using linear regression analyses. Analyses were adjusted for age, sex, mean arterial pressure, heart rate, known cardiovascular risk factors, and atherosclerosis. We found pulse wave velocity to be 0.35 m/s higher for CC-homozygotes vs. wildtype GG-homozygotes (p = 0.018) with evidence for an allele-dose effect (p trend = 0.013), and a similar pattern for pulse pressure (p trend = 0.041). No apparent consistent association with the distensibility coefficient was found. CRP levels were associated with pulse wave velocity (p = 0.007). In conclusion, the interleukin-6 –174 G/C polymorphism is associated with increased arterial stiffness and pulse pressure.Keywords: IL-6, CRP, arterial stiffness, pulse wave velocity, distensibility coefficient, pulse pressure
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