Showing papers by "Niek de Vries published in 2014"
Broad Institute1, Harvard University2, Monash University3, Kyoto University4, Genentech5, Vanderbilt University6, New York University7, NewYork–Presbyterian Hospital8, Second Military Medical University9, University of Queensland10, University of Toronto11, University of Groningen12, University of Tartu13, Beijing Jiaotong University14, Icahn School of Medicine at Mount Sinai15, Radboud University Nijmegen16, Medisch Spectrum Twente17, Leiden University18, University of Paris19, French Institute of Health and Medical Research20, University of Alabama at Birmingham21, University of Amsterdam22, GlaxoSmithKline23, University of Cambridge24, Hanyang University25, Spanish National Research Council26, Complutense University of Madrid27, Umeå University28, Boston University29, Council on Education for Public Health30, McGill University31, University of Manchester32, National Health Service33, University of Pittsburgh34, University of California, San Francisco35, Karolinska Institutet36, North Shore-LIJ Health System37, University of Chicago38, University of Tokyo39
TL;DR: A genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries provides empirical evidence that the genetics of RA can provide important information for drug discovery, and sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis.
Abstract: A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1. Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2, 3, 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci6 and pathway analyses7, 8, 9—as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes—to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.
1,910 citations
Harvard University1, Broad Institute2, New York University3, Washington University in St. Louis4, Vanderbilt University5, Brigham and Women's Hospital6, Albany Medical College7, NewYork–Presbyterian Hospital8, Icahn School of Medicine at Mount Sinai9, Radboud University Nijmegen10, Leiden University Medical Center11, Leiden University12, University of Paris13, French Institute of Health and Medical Research14, Manchester Academic Health Science Centre15, Instituto de Medicina Molecular16, University of Amsterdam17, University of Pittsburgh18, University of Alabama at Birmingham19, Boston University20, Council on Education for Public Health21, McGill University22, Karolinska Institutet23, Lunenfeld-Tanenbaum Research Institute24, North Shore-LIJ Health System25, Cornell University26
TL;DR: It is demonstrated that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree and also in unrelated individuals from the general population (European ancestry).
Abstract: Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G>C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P = 0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF = 0.042] and rs116541814 [MAF = 0.021], combined P = 3.2×10−6). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P = 0.049 for C-alpha test and P = 0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted.
144 citations
TL;DR: The number of known interdonor-conserved TCRs is extended and it is suggested that many more exist and that these TCR patterns can be used to systematically evaluate human Ag exposure.
Abstract: During infection and autoimmune disease, activation and expansion of T cells take place. Consequently, the TCR repertoire contains information about ongoing and past diseases. Analysis and interpretation of the human TCR repertoire are hampered by its size and stochastic variation and by the diversity of Ags and Ag-presenting molecules encoded by the MHC, but are highly desirable and would greatly impact fundamental and clinical immunology. A subset of the TCR repertoire is formed by invariant T cells. Invariant T cells express interdonor-conserved TCRs and recognize a limited set of Ags, presented by nonpolymorphic Ag-presenting molecules. Discovery of the three known invariant T cell populations has been a tedious and slow process, identifying them one by one. Because conservation of the TCR α-chain of invariant T cells is much higher than the β-chain, and because the TCR α-chain V gene segment TRAV1-2 is used by two of the three known invariant TCRs, we employed next-generation sequencing of TCR α-chains that contain the TRAV1-2 gene segment to identify 16 invariant TCRs shared among many blood donors. Frequency analysis of individual clones indicates these T cells are expanded in many donors, implying an important role in human immunity. This approach extends the number of known interdonor-conserved TCRs and suggests that many more exist and that these TCR patterns can be used to systematically evaluate human Ag exposure.
28 citations
TL;DR: Long-term exposure to solvents and other organic agents might predispose to IgG4-RD, and analysis of the Amsterdam cohort and blinded extramural validation of the Oxford cohort of patients with IgG 4-RD disclosed a remarkable association with ‘blue-collar work'.
Abstract: IgG4-associated cholangitis (IAC) is the hepatobiliary manifestation of immunoglobulin G4-related disease (IgG4-RD), a systemic fibroinflammatory disorder with a wide variety of clinical presentations and organ manifestations. IgG4-RD predominantly affects the hepatobiliary tract (IAC) and pancreas (autoimmune pancreatitis) and mimics hepatobiliary, pancreatic and other malignancies. Patients typically are 60-80 years old and 80-85% are male. They often present with painless obstructive jaundice and organ swelling that can be mistaken for pancreatic or bile duct cancer, as well as primary or secondary sclerosing cholangitis. An accurate diagnostic marker is lacking and extensive surgery for presumed malignant hepatobiliary or pancreatic disease leads to the diagnosis of IgG4-RD in 1 of 3 patients. Early effective immunosuppressive treatment is often missed. The pathogenesis of IgG4-RD has been enigmatic. We recently identified dominant IgG4+ B-cell receptor clones in blood and tissue of patients with IAC, but not in healthy or disease controls, and hypothesized that specific B-cell responses are pivotal to the pathogenesis of IAC and IgG4-RD. Analysis of our Amsterdam cohort and blinded extramural validation of the Oxford cohort of patients with IgG4-RD disclosed a remarkable association with ‘blue-collar work'. Thus, long-term exposure to solvents and other organic agents might predispose to IgG4-RD.
10 citations