49 research outputs found
Labor LawâState Fair Employment Practices ActsâThe Power of the States to Act in the Field of Job Discrimination in the Face of Current and Proposed Federal Activity.âColorado Anti-Discrimination Comm\u27n v. Continental Airlines
Communications LawâCommunications Act of 1934âRight of a Party in Interest to a Trial-type Hearing upon a Challenge to a License Application.âInterstate Broadcasting Co. v. FCC
Recent Developments in Antitrust Law: Section 7 of the Clayton Act and the Demise of the Conglomerate Merger
Toll-Like Receptor 1 Locus Re-examined in a Genome-Wide Association Study Update on AntiâHelicobacter pylori IgG Titers
Funding Information: Funding The Rotterdam Study I-II was supported by the Netherlands Organization of Scientific Research (NWO; 175.010.2005.011, 911-03-012), Research Institute for Diseases in the Elderly (RIDE; 014-93-015), Genomics Initiative/NWO (project no. 050-060-810), Erasmus Medical Center Rotterdam, Erasmus University Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), Ministry of Education, Culture, and Science and Ministry for Health, Welfare, and Sports, European Commission, and the Municipality of Rotterdam. GenerationR was supported by Erasmus Medical Center Rotterdam, Erasmus University Rotterdam, ZonMw (907.00303, 916.10159), NWO, and the Ministry for Health, Welfare and Sports. The Study of Health in Pomerania (SHIP) and SHIP-TREND were supported by Deutsche Krebshilfe/Dr Mildred-Scheel-Stiftung (109102), Deutsche Forschungsgemeinschaft (DFG GRK840-D2/E3/E4, MA 4115/1-2/3), Federal Ministry of Education and Research (BMBF GANI-MED 03IS2061A and BMBF 0314107, 01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012), the European Union (EU-FP-7-EPCTM and EU-FP7-REGPOT-2010-1), AstraZeneca (unrestricted grant), the Federal Ministry of Education and Research, Siemens Healthcare, the Federal State of MecklenburgâWest Pomerania, and the University of Greifswald. The Framingham Heart Study was supported by National Institutes of Health grants N01-HC-25195, HHSN268201500001I, and 75N92019D00031 (to Boston University) and the Division of Intramural Research, National Heart, Lung, and Blood Institute (NHLBI). The Multi-Ethnic Study of Atherosclerosis (MESA) and the MESA SHARe projects were supported by the NHLBI (75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420. Funding for SHARe genotyping was provided by NHLBI grant N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, CA) and the Broad Institute of Harvard and MIT (Boston, MA) using the Affymetrix Genome-Wide Human SNP Array 6.0. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The Epidemiological Investigations on Chances of Preventing Recognizing Early and Optimally Treating Chronic Diseases in an Elderly Population were supported by the State Ministry of Science, Research and Arts, Baden-WĂŒrttemberg, Federal Ministry of Education and Research, and Federal Ministry of Family Affairs, Senior Citizens, Women and Youth. LATVIA was supported by the European Regional Development Fund (ERDF; 009/0220/1DP/1.1.1.2.0/09/APIA/VIAA/016), National Program for Research in Latvia, Ministry of Health (6-1396-2016), and Fundamental and Applied Research Projects Program in Latvia (project no. lzp-2018/1-0135). Funding Information: Conceptualization: Linda Broer, Manon C.W. Spaander, Fabian Frost, Stefan Weiss, Georg Homuth, Henry Völzke, Markus M. Lerch, Ben Schöttker, Hermann Brenner, Daniel Levy, Shih-Jen Hwang, Alexis C. Wood, Stephen S. Rich, Jerome I. Rotter, Kent D. Taylor, Russell P. Tracy, Edmond K. Kabagambe, Marcis Leja, Janis Klovins, Raitis Peculis, Dace Rudzite, Liene Nikitina-Zake, Girts Skenders, Vita Rovite, AndrĂ© Uitterlinden, Ernst J. Kuipers, Maikel P. Peppelenbosch, and additional members of Rotterdam Study I-II, GenerationR, Study of Health in Pomerania, Framingham Heart Study, Multi-Ethnic Study of Atherosclerosis, Epidemiological Investigations on Chances of Preventing Recognizing Early and Optimally Treating Chronic Diseases in an Elderly Population, and LATVIA cohorts not directly involved in this manuscript. Methodology: all authors. Investigation: all authors. Formal analysis of discovery: Linda Broer, Fabian Frost, Stefan Weiss, Georg Homuth, Henry Völzke, Markus M. Lerch, Daniel Levy, Shih-Jen Hwang, Alexis C. Wood, Stephen S. Rich, Jerome I. Rotter, Kent D. Taylor, Russell P. Tracy, and Edmond K. Kabagambe. Formal analysis of replication: Yan Zhang, Hannah Stocker, Hermann Brenner, Marcis Leja, Janis Klovins, and Raitis Peculis. Formal analysis of meta-analysis: Linda Broer. Project administration: Suk Yee Lam and Gwenny M. Fuhler. Resources: Fabian Frost, Stefan Weiss, Georg Homuth, Henry Völzke, Markus M. Lerch, Hermann Brenner, Daniel Levy, Shih-Jen Hwang, Alexis C. Wood, Stephen S. Rich, Jerome I. Rotter, Kent D. Taylor, Russell P. Tracy, Edmond K. Kabagambe, Marcis Leja, Janis Klovins, Dace Rudzite, Liene Nikitina-Zake, Girts Skenders, Vita Rovite, Ernst J. Kuipers, and Maikel P. Peppelenbosch. Supervision: Manon C.W. Spaander, Fabian Frost, Stefan Weiss, Georg Homuth, Henry Völzke, Markus M. Lerch, Hermann Brenner, Daniel Levy, Shih-Jen Hwang, Alexis C. Wood, Stephen S. Rich, Jerome I. Rotter, Kent D. Taylor, Russell P. Tracy, Edmond K. Kabagambe, Marcis Leja, Janis Klovins, Gwenny M. Fuhler, Maikel P. Peppelenbosch, and AndrĂ© Uitterlinden. Visualization: Suk Yee Lam, Michiel C. Mommersteeg, Bingting Yu, Linda Broer, and Gwenny M. Fuhler. Writingâoriginal draft: Suk Yee Lam, Michiel C. Mommersteeg, and Gwenny M. Fuhler. Writingâreviewing and editing: all authors. Publisher Copyright: © 2022 The Author(s)Background & Aims: A genome-wide significant association between antiâHelicobacter pylori (H pylori) IgG titers and Toll-like receptor (TLR1/6/10) locus on 4p14 was demonstrated for individuals of European ancestry, but not uniformly replicated. We re-investigated this association in an updated genome-wide association study (GWAS) meta-analysis for populations with low gastric cancer incidence, address potential causes of cohort heterogeneity, and explore functional implications of genetic variation at the TLR1/6/10 locus. Methods: The dichotomous GWAS (25% individuals exhibiting highest antiâH pylori IgG titers vs remaining 75%) included discovery and replication sampls of, respectively, n = 15,685 and n = 9676, all of European ancestry. Longitudinal analysis of serologic data was performed on H pyloriâeradicated subjects (n = 132) and patients under surveillance for premalignant gastric lesions (n = 107). TLR1/6/10 surface expression, TLR1 mRNA, and cytokine levels were measured in leukocyte subsets of healthy subjects (n = 26) genotyped for TLR1/6/10 variants. Results: The association of the TLR1/6/10 locus with antiâH pylori IgG titers (rs12233670; ÎČ = â0.267 ± SE 0.034; P = 4.42 Ă 10â15) presented with high heterogeneity and failed replication. AntiâH pylori IgG titers declined within 2â4 years after eradication treatment (P = 0.004), and decreased over time in patients with premalignant gastric lesions (P < 0.001). Variation at the TLR1/6/10 locus affected TLR1-mediated cytokine production and TLR1 surface expression on monocytes (P = 0.016) and neutrophils (P = 0.030), but not mRNA levels. Conclusions: The association between antiâH pylori IgG titers and TLR1/6/10 locus was not replicated across cohorts, possibly owing to dependency of antiâH pylori IgG titers on therapy, clearance, and antibody decay. H pyloriâmediated immune cell activation is partly mediated via TLR1 signaling, which in turn is affected by genetic variation.publishersversionPeer reviewe
Extensive recombination events and horizontal gene transfer shaped the Legionella pneumophila genomes
<p>Abstract</p> <p>Background</p> <p><it>Legionella pneumophila </it>is an intracellular pathogen of environmental protozoa. When humans inhale contaminated aerosols this bacterium may cause a severe pneumonia called Legionnaires' disease. Despite the abundance of dozens of <it>Legionella </it>species in aquatic reservoirs, the vast majority of human disease is caused by a single serogroup (Sg) of a single species, namely <it>L. pneumophila </it>Sg1. To get further insights into genome dynamics and evolution of Sg1 strains, we sequenced strains Lorraine and HL 0604 1035 (Sg1) and compared them to the available sequences of Sg1 strains Paris, Lens, Corby and Philadelphia, resulting in a comprehensive multigenome analysis.</p> <p>Results</p> <p>We show that <it>L. pneumophila </it>Sg1 has a highly conserved and syntenic core genome that comprises the many eukaryotic like proteins and a conserved repertoire of over 200 Dot/Icm type IV secreted substrates. However, recombination events and horizontal gene transfer are frequent. In particular the analyses of the distribution of nucleotide polymorphisms suggests that large chromosomal fragments of over 200 kbs are exchanged between <it>L. pneumophila </it>strains and contribute to the genome dynamics in the natural population. The many secretion systems present might be implicated in exchange of these fragments by conjugal transfer. Plasmids also play a role in genome diversification and are exchanged among strains and circulate between different <it>Legionella </it>species.</p> <p>Conclusion</p> <p>Horizontal gene transfer among bacteria and from eukaryotes to <it>L. pneumophila </it>as well as recombination between strains allows different clones to evolve into predominant disease clones and others to replace them subsequently within relatively short periods of time.</p
Assessment of gene-by-sex interaction effect on bone mineral density
To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field.Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; pâ<â1âĂâ10(-5) ) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effectâ=â0.02 and pâ=â3.0âĂâ10(-5) ; female effectâ=â-0.007 and pâ=â3.3âĂâ10(-2) ), and 11 suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (pâ<â5âĂâ10(-8) ) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found to influence BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP. © 2012 American Society for Bone and Mineral Research.Medtronic
NIH R01 AG18728
R01HL088119
R01AR046838
U01 HL084756
R01 AR43351
P01-HL45522
R01-MH-078111
R01-MH-083824
Nutrition and Obesity Research Center of Maryland P30DK072488
NIAMS/NIH F32AR059469
Instituto de Salud Carlos III-FIS (Spanish Health Ministry) PI 06/0034
PI08/0183
Canadian Institutes of Health Research (CIHR)
NHLBI HHSN268201200036C
N01-HC-85239
N01-HC-85079
N01-HC-85086
N01-HC-35129
N01 HC15103
N01 HC-55222
N01-HC-75150
N01-HC-45133
HL080295
HL087652
HL105756
NIA AG-023629
AG-15928
AG-20098
AG-027058
N01AG62101
N01AG62103
N01AG62106
1R01AG032098-01A1
National Center of Advancing Translational Technologies CTSI UL1TR000124
National Institute of Diabetes and Digestive and Kidney Diseases DK063491
EUROSPAN (European Special Populations Research Network)
European Commission FP6 STRP grant 018947
LSHG-CT-2006-01947
Netherlands Organisation for Scientific Research
Erasmus MC
Centre for Medical Systems Biology (CMSB)
Netherlands Brain Foundation (HersenStichting Nederland)
US National Institute for Arthritis, Musculoskeletal and Skin Diseases
National Institute on Aging R01 AR/AG41398
R01 AR050066
R21 AR056405
National Heart, Lung, and Blood Institute's Framingham Heart Study N01-HC-25195
Affymetrix, Inc. N02-HL-6-4278
Canadian Institutes of Health Research from Institute of Aging 165446
Institute of Genetics 179433
Institute of Musculoskeletal health 221765
Intramural Research Program of the NIH, National Institute on Aging
National Institutes of Health HHSN268200782096C
Hong Kong Research Grant Council HKU 768610M
Bone Health Fund of HKU Foundation
KC Wong Education Foundation
Small Project Funding 201007176237
Matching Grant
CRCG Grant
Osteoporosis and Endocrine Research Fund
Genomics Strategic Research Theme of The University of Hong Kong
Netherlands Organisation of Scientific Research NWO Investments 175.010.2005.011
911-03-012
Research Institute for Diseases in the Elderly 014-93-015
Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) 050-060-810
Erasmus Medical Center and Erasmus University, Rotterdam
Netherlands Organization for the Health Research and Development (ZonMw)
Research Institute for Diseases in the Elderly (RIDE)
Ministry of Education, Culture and Science
Ministry for Health, Welfare and Sports
European Commission (DG XII)
Municipality of Rotterdam
German Bundesministerium fur Forschung und Technology 01 AK 803 A-H
01 IG 07015
Whole-genome sequencing reveals host factors underlying critical COVID-19
Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2â4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genesâincluding reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)âin critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease
Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci.
Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity
New genetic loci link adipose and insulin biology to body fat distribution.
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (PÂ <Â 5Â ĂÂ 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms
Finishing the euchromatic sequence of the human genome
The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers âŒ99% of the euchromatic genome and is accurate to an error rate of âŒ1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead