Title Abundant genetic overlap between blood lipids and immune-mediated diseases indicates shared molecular genetic mechanisms Permalink

Epidemiological studies suggest a relationship between blood lipids and immune-mediated diseases, but the nature of these associations is not well understood. We used genome-wide association studies (GWAS) to investigate shared single nucleotide polymorphisms (SNPs) between blood lipids and immune-mediated diseases. We analyzed data fromGWAS (n~200,000 individuals), applying new False Discovery Rate (FDR) methods, to investigate genetic overlap between blood lipid levels [triglycerides (TG), low density lipoproteins (LDL), high density lipoproteins (HDL)] and a selection of archetypal immune-mediated diseases (Crohn’s disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, celiac disease, psoriasis and sarcoidosis). We found significant polygenic pleiotropy between the blood lipids PLOSONE | DOI:10.1371/journal.pone.0123057 April 8, 2015 1 / 17 OPEN ACCESS Citation: Andreassen OA, Desikan RS, Wang Y, Thompson WK, Schork AJ, Zuber V, et al. (2015) Abundant Genetic Overlap between Blood Lipids and Immune-Mediated Diseases Indicates Shared Molecular Genetic Mechanisms. PLoS ONE 10(4): e0123057. doi:10.1371/journal.pone.0123057 Received: October 30, 2014 Accepted: January 16, 2015 Published: April 8, 2015 Copyright: © 2015 Andreassen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: Data cannot be made publicly available because they were obtained from third parties. Summary statistics used in this study are available at: http://www.sph.umich.edu/csg/ abecasis/public/lipids2013/ and http://www. ibdgenetics.org/downloads.html. Data on Sarcoidosis (SARC) can be requested from Prof. Stefan Schreiber ( s.schreiber@mucosa.de), Department of General Internal Medicine and Popgen Biobank, University Hospital Schleswig-Holstein, Kiel, Germany. Data on Celiac Disease (CeD) can be requested from Prof. Lude Franke ( lude@cleverfranke.com) and David A van Heel ( d. vanheel@qmul.ac.uk), Blizard Institute of Cell and Molecular Science, Barts and The London School of and all the investigated immune-mediated diseases. We discovered several shared risk loci between the immune-mediated diseases and TG (n = 88), LDL (n = 87) and HDL (n = 52). Three-way analyses differentiated the pattern of pleiotropy among the immune-mediated diseases. The new pleiotropic loci increased the number of functional gene network nodes representing blood lipid loci by 40%. Pathway analyses implicated several novel shared mechanisms for immune pathogenesis and lipid biology, including glycosphingolipid synthesis (e.g. FUT2) and intestinal host-microbe interactions (e.g. ATG16L1). We demonstrate a shared genetic basis for blood lipids and immune-mediated diseases independent of environmental factors. Our findings provide novel mechanistic insights into dyslipidemia and immune-mediated diseases and may have implications for therapeutic trials involving lipidlowering and anti-inflammatory agents.

[1]  Francesco Bettella,et al.  Shared common variants in prostate cancer and blood lipids. , 2014, International journal of epidemiology.

[2]  Anders M. Dale,et al.  Identifying Common Genetic Variants in Blood Pressure Due to Polygenic Pleiotropy With Associated Phenotypes , 2014, Hypertension.

[3]  Y Wang,et al.  Genetic pleiotropy between multiple sclerosis and schizophrenia but not bipolar disorder: differential involvement of immune-related gene loci , 2014, Molecular Psychiatry.

[4]  Tanya M. Teslovich,et al.  Discovery and refinement of loci associated with lipid levels , 2013, Nature Genetics.

[5]  S. Hazen,et al.  Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. , 2013, The New England journal of medicine.

[6]  Judy H. Cho,et al.  Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis , 2013, Nature Genetics.

[7]  D. Rujescu,et al.  Improved Detection of Common Variants Associated with Schizophrenia and Bipolar Disorder Using Pleiotropy-Informed Conditional False Discovery Rate , 2013, PLoS genetics.

[8]  M. McCarthy,et al.  Improved detection of common variants associated with schizophrenia by leveraging pleiotropy with cardiovascular-disease risk factors. , 2013, American journal of human genetics.

[9]  C. Gieger,et al.  A novel sarcoidosis risk locus for Europeans on chromosome 11q13.1 , 2012 .

[10]  C. Mineo,et al.  Novel biological functions of high-density lipoprotein cholesterol. , 2012, Circulation research.

[11]  Shane J. Neph,et al.  Systematic Localization of Common Disease-Associated Variation in Regulatory DNA , 2012, Science.

[12]  P. Rosenstiel,et al.  Genome-wide association analysis reveals 12q13.3–q14.1 as new risk locus for sarcoidosis , 2012, European Respiratory Journal.

[13]  Chris T. A. Evelo,et al.  Bioinformatics Applications Note Databases and Ontologies Go-elite: a Flexible Solution for Pathway and Ontology Over-representation , 2022 .

[14]  J. Nicholson,et al.  Host-Gut Microbiota Metabolic Interactions , 2012, Science.

[15]  D. Symmons,et al.  Cardiovascular comorbidities in patients with psoriatic arthritis: a systematic review , 2012, Annals of the rheumatic diseases.

[16]  L. Hudson,et al.  Lipid rafts are disrupted in mildly inflamed intestinal microenvironments without overt disruption of the epithelial barrier. , 2012, American journal of physiology. Gastrointestinal and liver physiology.

[17]  S. Taylor-Robinson,et al.  Serum Metabolic Profiling in Inflammatory Bowel Disease , 2012, Digestive Diseases and Sciences.

[18]  Christian Gieger,et al.  Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci. , 2012, American journal of human genetics.

[19]  A. Farooqi,et al.  Prevalence of dyslipidemias in autoimmune rheumatic diseases. , 2012, Journal of the College of Physicians and Surgeons--Pakistan : JCPSP.

[20]  Fredrik H. Karlsson,et al.  Symptomatic atherosclerosis is associated with an altered gut metagenome , 2012, Nature Communications.

[21]  Philip Rosenstiel,et al.  Colonic mucosa-associated microbiota is influenced by an interaction of Crohn disease and FUT2 (Secretor) genotype , 2011, Proceedings of the National Academy of Sciences.

[22]  C. Weber,et al.  Atherosclerosis: current pathogenesis and therapeutic options , 2011, Nature Medicine.

[23]  Rima Kaddurah-Daouk,et al.  Enteric Microbiome Metabolites Correlate with Response to Simvastatin Treatment , 2011, PloS one.

[24]  Kasper Lage,et al.  Pervasive Sharing of Genetic Effects in Autoimmune Disease , 2011, PLoS genetics.

[25]  G. Kitas,et al.  Rheumatoid arthritis susceptibility genes associate with lipid levels in patients with rheumatoid arthritis , 2011, Annals of the rheumatic diseases.

[26]  Brian J. Bennett,et al.  Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease , 2011, Nature.

[27]  P. Elliott,et al.  Meta-Analysis of Genome-Wide Association Studies in >80 000 Subjects Identifies Multiple Loci for C-Reactive Protein Levels , 2011, Circulation.

[28]  Tariq Ahmad,et al.  Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47 , 2011, Nature Genetics.

[29]  Y. Shoenfeld,et al.  Inflammatory and autoimmune mechanisms in the induction of atherosclerotic damage in systemic rheumatic diseases: Two faces of the same coin , 2011, Arthritis care & research.

[30]  Tariq Ahmad,et al.  Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci , 2010, Nature Genetics.

[31]  Dirk Repsilber,et al.  ExprEssence - Revealing the essence of differential experimental data in the context of an interaction/regulation net-work , 2010, BMC Systems Biology.

[32]  K. Mullen,et al.  Dyslipidemia and lipoprotein profiles in patients with inflammatory bowel disease. , 2010, Journal of clinical lipidology.

[33]  G. Chodick,et al.  Persistence with Statins and Onset of Rheumatoid Arthritis: A Population-Based Cohort Study , 2010, PLoS medicine.

[34]  Tanya M. Teslovich,et al.  Biological, Clinical, and Population Relevance of 95 Loci for Blood Lipids , 2010, Nature.

[35]  A. Pietrzak,et al.  Lipid Disturbances in Psoriasis: An Update , 2010, Mediators of inflammation.

[36]  Jing Cui,et al.  Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci , 2010, Nature Genetics.

[37]  Ming D. Li,et al.  Genome-wide meta-analyses identify multiple loci associated with smoking behavior , 2010, Nature Genetics.

[38]  P. Deloukas,et al.  Multiple common variants for celiac disease influencing immune gene expression , 2010, Nature Genetics.

[39]  D. Mehta,et al.  A common FADS2 promoter polymorphism increases promoter activity and facilitates binding of transcription factor ELK1 , 2010, Journal of Lipid Research.

[40]  Tao Chen,et al.  Cellular Production of n-3 PUFAs and Reduction of n-6–to–n-3 Ratios in the Pancreatic β-Cells and Islets Enhance Insulin Secretion and Confer Protection Against Cytokine-Induced Cell Death , 2009, Diabetes.

[41]  Mario Albrecht,et al.  FunSimMat update: new features for exploring functional similarity , 2009, Nucleic Acids Res..

[42]  B. Vergès.  Lipid disorders in type 1 diabetes. , 2009, Diabetes & metabolism.

[43]  O. Olivieri,et al.  A ‘Desaturase Hypothesis’ for Atherosclerosis: Janus-Faced Enzymes in ω–6 and ω–3 Polyunsaturated Fatty Acid Metabolism , 2009, Lifestyle Genomics.

[44]  S. Hauguel-de Mouzon,et al.  Differential regulation of genes for fetoplacental lipid pathways in pregnancy with gestational and type 1 diabetes mellitus. , 2009, American journal of obstetrics and gynecology.

[45]  Olli Simell,et al.  Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes , 2008, The Journal of experimental medicine.

[46]  Ian M. Donaldson,et al.  iRefIndex: A consolidated protein interaction database with provenance , 2008, BMC Bioinformatics.

[47]  J. D. da Silva,et al.  Anti-tumour necrosis factor agents and lipid profile: a class effect? , 2008, Annals of the rheumatic diseases.

[48]  N. Cook,et al.  Loci related to metabolic-syndrome pathways including LEPR,HNF1A, IL6R, and GCKR associate with plasma C-reactive protein: the Women's Genome Health Study. , 2008, American journal of human genetics.

[49]  B. Hahn,et al.  The pathogenesis of atherosclerosis in autoimmune rheumatic diseases: roles of inflammation and dyslipidemia. , 2007, Journal of autoimmunity.

[50]  J. Galmiche,et al.  Altered lipid, apolipoprotein, and lipoprotein profiles in inflammatory bowel disease: consequences on the cholesterol efflux capacity of serum using Fu5AH cell system. , 2006, Metabolism: clinical and experimental.

[51]  Thomas Lengauer,et al.  A new measure for functional similarity of gene products based on Gene Ontology , 2006, BMC Bioinformatics.

[52]  J W R Twisk,et al.  Lipids and inflammation: serial measurements of the lipid profile of blood donors who later developed rheumatoid arthritis , 2006, Annals of the rheumatic diseases.

[53]  Sarah Lewis,et al.  Genetic epidemiology and public health: hope, hype, and future prospects , 2005, The Lancet.

[54]  Jesper Andersson,et al.  Valid conjunction inference with the minimum statistic , 2005, NeuroImage.

[55]  P. Shannon,et al.  Cytoscape: a software environment for integrated models of biomolecular interaction networks. , 2003, Genome research.

[56]  Sidney C. Smith,et al.  MARKERS OF INFLAMMATION AND CARDIOVASCULAR DISEASE: APPLICATION TO CLINICAL AND PUBLIC HEALTH PRACTICE: A STATEMENT FOR HEALTHCARE PROFESSIONALS FROM THE CENTERS FOR DISEASE CONTROL AND PREVENTION AND THE AMERICAN HEART ASSOCIATION , 2003 .

[57]  C. Clish,et al.  Novel Functional Sets of Lipid-Derived Mediators with Antiinflammatory Actions Generated from Omega-3 Fatty Acids via Cyclooxygenase 2–Nonsteroidal Antiinflammatory Drugs and Transcellular Processing , 2000, The Journal of experimental medicine.

[58]  O. Andreassen,et al.  Boosting the power of schizophrenia genetics by leveraging new statistical tools. , 2014, Schizophrenia bulletin.

[59]  G. Norata,et al.  Emerging role of high density lipoproteins as a player in the immune system. , 2012, Atherosclerosis.

[60]  D. Clayton,et al.  Genome-wide association study and meta-analysis finds over 40 loci affect risk of type 1 diabetes , 2009, Nature Genetics.

[61]  Andrew Onderdonk,et al.  Effect of antibiotics as cholesterol-lowering agents. , 2005, Metabolism: clinical and experimental.

[62]  M. J. Castiñeiras,et al.  Low levels of high density lipoprotein cholesterol in patients with active sarcoidosis. , 1998, Atherosclerosis.