A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological datasets 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 (GWAS) 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 (SNPs). We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 1012–4. We devised an in-silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci (cis-eQTL)6, and pathway analyses7–9 – as well as novel methods based on genetic overlap with human primary immunodeficiency (PID), hematological cancer somatic mutations and knock-out 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.
bone morphogenetic protein type II receptor; cell cycle; Id; pulmonary arterial smooth muscle cell; pulmonary hypertension PULMONARY ARTERIAL HYPERTENSION (PAH) is a severe clinical condition associated with a poor prognosis and high mortality. Occlusive remodeling of the distal pulmonary vasculature is the major pathological finding in PAH. Proliferation of myofibroblasts and smooth muscle cells in the pulmonary arterial wall increases pulmonary vascular resistance and elevates pulmonary arterial pressure, ultimately leading to right ventricular failure and eventually death (20,26,29). A greater understanding of the molecular mechanisms involved in pulmonary vascular remodeling will facilitate new approaches for therapy.Bone morphogenetic protein type II receptor (BMPR-II) mutations are responsible for the majority (Ͼ70%)of cases of heritable PAH and have been reported in 15-40% of apparently sporadic idiopathic cases (6, 15, 34). Loss of BMPR-II or dysfunction of BMP signaling are now recognized in several preclinical models of PAH, including those induced by hypoxia, monocrotaline, and high flow (10, 16). BMPs are pleiotropic cytokines involved in a wide range of vascular cell function including proliferation, migration, differentiation, and apoptosis, but how BMPR-II mutations cause these abnormalities remains uncertain.The inhibitor of DNA binding family of proteins (Id proteins) are major downstream mediators of BMP signaling (19). Id proteins are basic helix-loop-helix transcription factors that lack a DNA binding domain. These proteins bind to the ubiquitously expressed E protein family members with high affinity and inhibit their binding to target DNA (5, 11). This special function of Id proteins confers a central role in the regulation of gene expression and hence cell differentiation and proliferation (24,31). Until now, four members of the Id family, Id1-4, have been identified in mammalian cells. They are encoded by separate genes and demonstrate individual expression patterns and protein structure, which may contribute to their different functions. For example, Id2 is largely expressed in immune cells (8,40), and only Id1 lacks the consensus CDK2 phosphorylation site at its NH 2 terminus (5). Our recent study revealed that Id1 and Id2 are induced by BMPs in pulmonary artery smooth muscle cells (PASMCs) through a canonical Smad-dependent pathway (37) and that BMPR-II mutation reduced the BMP-stimulated induction of Id1 and Id2 in these cells. We further showed that Id1 and Id2 are involved in the inhibition of PASMC proliferation by BMP4. We have also shown that agents enhancing BMP/ Smad/Id signaling in PASMCs can restore the growth-suppressive effects of BMPs in BMPR-II mutant cells (38,39).In the present study, we undertook a systematic analysis of the regulation of Id1-4 in PASMCs via a range of growth factors, cytokines, and BMPs. Having identified Id1 and Id3 as major targets of BMP signaling in these cells, we show that the induction of both Id1 and Id3 is dependent on intact BMPR-II and that...
Objective. To investigate differences in genetic risk factors for rheumatoid arthritis (RA) in Han Chinese as compared with Europeans.Methods. A genome-wide association study was conducted in China with 952 patients and 943 controls, and 32 variants were followed up in 2,132 patients and 2,553 controls. A transpopulation meta-analysis with results from a large European RA study was also performed to compare the genetic architecture across the 2 ethnic remote populations.Results. Three non-major histocompatibility complex (non-MHC) loci were identified at the genomewide significance level, the effect sizes of which were larger in anti-citrullinated protein antibody (ACPA)-positive patients than in ACPA-negative patients. These
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