Abundant Genetic Overlap between Blood Lipids and Immune-Mediated Diseases Indicates Shared Molecular Genetic Mechanisms

被引：35

作者：

Andreassen, Ole A. ^{[1
,2
]}

Desikan, Rahul S. ^{[3
,4
]}

Wang, Yunpeng ^{[1
,2
,3
]}

Thompson, Wesley K.

Schork, Andrew J. ^{[3
,5
,6
]}

Zuber, Verena ^{[1
,2
,7
,8
]}

Doncheva, Nadezhda T. ^{[9
]}

Ellinghaus, Eva ^{[10
]}

Albrecht, Mario ^{[9
,11
,12
,13
]}

Mattingsdal, Morten ^{[1
,2
,14
]}

Franke, Andre ^{[10
]}

Lie, Benedicte A. ^{[13
]}

Mills, Ian ^{[7
,8
,16
,17
]}

Aukrust, Pal ^{[15
,19
]}

McEvoy, Linda K. ^{[3
]}

Djurovic, Srdjan ^{[1
,2
,15
]}

Karlsen, Tom H. ^{[18
,20
,21
]}

Dale, Anders M. ^{[4
,22
,23
]}

机构：

[1] Univ Oslo, Inst Clin Med, KG Jebsen Ctr Psychosis Res, NORMENT, N-0407 Oslo, Norway

[2] Oslo Univ Hosp, Div Mental Hlth & Addict, N-0407 Oslo, Norway

[3] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA

[4] Univ Calif San Diego, Multimodal Imaging Lab, La Jolla, CA 92093 USA

[5] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92093 USA

[6] Univ Calif San Diego, Cognit Sci Grad Program, La Jolla, CA 92093 USA

[7] Univ Calif San Diego, Ctr Human Dev, La Jolla, CA 92093 USA

[8] Univ Oslo, Nord EMBL Partnership, Ctr Mol Med Norway, N-0407 Oslo, Norway

[9] Oslo Univ Hosp, N-0407 Oslo, Norway

[10] Max Planck Inst Informat, D-66123 Saarbrucken, Germany

[11] Univ Kiel, Inst Clin Mol Biol, D-24118 Kiel, Germany

[12] Univ Med Greifswald, Inst Biometr & Med Informat, Dept Bioinformat, D-17475 Greifswald, Germany

[13] Graz Univ Technol, Inst Knowledge Discovery, A-8010 Graz, Austria

[14] BioTechMed Graz, A-8010 Graz, Austria

[15] Sorlandet Hosp, N-3000 Kristiansand, Norway

[16] Univ Oslo, Dept Med Genet, N-0407 Oslo, Norway

[17] Oslo Univ Hosp, Inst Canc Res, Dept Canc Prevent, N-0407 Oslo, Norway

[18] Oslo Univ Hosp, Dept Urol, N-0407 Oslo, Norway

[19] Oslo Univ Hosp, Rikshosp, KG Jebsen Inflammat Res Ctr, Internal Med Res Inst,Div Canc Med Surg & Transpl, N-0407 Oslo, Norway

[20] Oslo Univ Hosp, Sect Clin Immunol & Infect Dis, N-0407 Oslo, Norway

[21] Univ Bergen, Inst Med, Div Gastroenterol, N-5000 Bergen, Norway

[22] Oslo Univ Hosp, Rikshosp, Norwegian PSC Res Ctr, Dept Transplantat Med,Div Canc Med Surg & Transpl, N-0407 Oslo, Norway

[23] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA

来源：

PLOS ONE | 2015年 / 10卷 / 04期

关键词：

GENOME-WIDE ASSOCIATION; COMMON VARIANTS; RHEUMATOID-ARTHRITIS; CROHN DISEASE; PUBLIC-HEALTH; IDENTIFIES; 7; RISK LOCUS; ATHEROSCLEROSIS; INFLAMMATION; METABOLISM;

D O I：

10.1371/journal.pone.0123057

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 from GWAS (n similar to 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 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 lipid-lowering and anti-inflammatory agents.

引用

页数：17

共 63 条

[21] The pathogenesis of atherosclerosis in autoimmune rheumatic diseases: Roles of inflammation and dyslipidemia [J].

Hahn, Bevra H. ;

Grossman, Jennifer ;

Chen, Weiling ;

McMahon, Maureen .

JOURNAL OF AUTOIMMUNITY, 2007, 28 (2-3) :69-75

[22] Genome-wide association analysis reveals 12q13.3-q14.1 as new risk locus for sarcoidosis [J].

Hofmann, Sylvia ;

Fischer, Annegret ;

Nothnagel, Michael ;

Jacobs, Gunnar ;

Schmid, Benjamin ;

Wittig, Michael ;

Franke, Andre ;

Gaede, Karoline I. ;

Schuermann, Manfred ;

Petrek, Martin ;

Mrazek, Frantisek ;

Pabst, Stefan ;

Grohe, Christian ;

Grunewald, Johan ;

Ronninger, Marcus ;

Eklund, Anders ;

Rosenstiel, Philip ;

Hoehne, Kerstin ;

Zissel, Gernot ;

Mueller-Quernheim, Joachim ;

Schreiber, Stefan .

EUROPEAN RESPIRATORY JOURNAL, 2013, 41 (04) :888-900

[23] Cardiovascular comorbidities in patients with psoriatic arthritis: a systematic review (vol 72, pg 211, 2013) [J].

Jamnitski, A. ;

Symmons, D. ;

Peters, M. J. L. .

ANNALS OF THE RHEUMATIC DISEASES, 2013, 72 (03) :467-467

[24] Effect of antibiotics as cholesterol-lowering agents [J].

Jenkins, DJA ;

Kendall, CWC ;

Hamidi, M ;

Vidgen, E ;

Faulkner, D ;

Parker, T ;

Irani, N ;

Wolever, TMS ;

Fong, I ;

Kopplin, P ;

Connelly, PW ;

Onderdonk, A ;

Rao, AV .

METABOLISM-CLINICAL AND EXPERIMENTAL, 2005, 54 (01) :103-112

[25] Enteric Microbiome Metabolites Correlate with Response to Simvastatin Treatment [J].

Kaddurah-Daouk, Rima ;

Baillie, Rebecca A. ;

Zhu, Hongjie ;

Zeng, Zhao-Bang ;

Wiest, Michelle M. ;

Uyen Thao Nguyen ;

Wojnoonski, Katie ;

Watkins, Steven M. ;

Trupp, Miles ;

Krauss, Ronald M. .

PLOS ONE, 2011, 6 (10)

[26] KEGG: Kyoto Encyclopedia of Genes and Genomes [J].

Kanehisa, M ;

Goto, S .

NUCLEIC ACIDS RESEARCH, 2000, 28 (01) :27-30

[27] Symptomatic atherosclerosis is associated with an altered gut metagenome [J].

Karlsson, Fredrik H. ;

Fak, Frida ;

Nookaew, Intawat ;

Tremaroli, Valentina ;

Fagerberg, Bjorn ;

Petranovic, Dina ;

Backhed, Fredrik ;

Nielsen, Jens .

NATURE COMMUNICATIONS, 2012, 3

[28] A common FADS2 promoter polymorphism increases promoter activity and facilitates binding of transcription factor ELK1 [J].

Lattka, E. ;

Eggers, S. ;

Moeller, G. ;

Heim, K. ;

Weber, M. ;

Mehta, D. ;

Prokisch, H. ;

Illig, T. ;

Adamski, J. .

JOURNAL OF LIPID RESEARCH, 2010, 51 (01) :182-191

[29] Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis [J].

Liu, Jimmy Z. ;

Hov, Johannes Roksund ;

Folseraas, Trine ;

Ellinghaus, Eva ;

Rushbrook, Simon M. ;

Doncheva, Nadezhda T. ;

Andreassen, Ole A. ;

Weersma, Rinse K. ;

Weismueller, Tobias J. ;

Eksteen, Bertus ;

Invernizzi, Pietro ;

Hirschfield, Gideon M. ;

Gotthardt, Daniel Nils ;

Pares, Albert ;

Ellinghaus, David ;

Shah, Tejas ;

Juran, Brian D. ;

Milkiewicz, Piotr ;

Rust, Christian ;

Schramm, Christoph ;

Mueller, Tobias ;

Srivastava, Brijesh ;

Dalekos, Georgios ;

Noethen, Markus M. ;

Herms, Stefan ;

Winkelmann, Juliane ;

Mitrovic, Mitja ;

Braun, Felix ;

Ponsioen, Cyriel Y. ;

Croucher, Peter J. P. ;

Sterneck, Martina ;

Teufel, Andreas ;

Mason, Andrew L. ;

Saarela, Janna ;

Leppa, Virpi ;

Dorfman, Ruslan ;

Alvaro, Domenico ;

Floreani, Annarosa ;

Onengut-Gumuscu, Suna ;

Rich, Stephen S. ;

Thompson, Wesley K. ;

Schork, Andrew J. ;

Naess, Sigrid ;

Thomsen, Ingo ;

Mayr, Gabriele ;

Koenig, Inke R. ;

Hveem, Kristian ;

Cleynen, Isabelle ;

Gutierrez-Achury, Javier ;

Ricano-Ponce, Isis .

NATURE GENETICS, 2013, 45 (06) :670-+

[30] A 'Desaturase Hypothesis' for Atherosclerosis: Janus-Faced Enzymes in ω-6 and ω-3 Polyunsaturated Fatty Acid Metabolism [J].

Martinelli, Nicola ;

Consoli, Letizia ;

Olivieri, Oliviero .

JOURNAL OF NUTRIGENETICS AND NUTRIGENOMICS, 2009, 2 (03) :129-139

← 1 2 3 4 5 6 7 →