PLoS ONE (Jan 2015)

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

  • Ole A Andreassen,
  • Rahul S Desikan,
  • Yunpeng Wang,
  • Wesley K Thompson,
  • Andrew J Schork,
  • Verena Zuber,
  • Nadezhda T Doncheva,
  • Eva Ellinghaus,
  • Mario Albrecht,
  • Morten Mattingsdal,
  • Andre Franke,
  • Benedicte A Lie,
  • Ian G Mills,
  • Pål Aukrust,
  • Linda K McEvoy,
  • Srdjan Djurovic,
  • Tom H Karlsen,
  • Anders M Dale

DOI
https://doi.org/10.1371/journal.pone.0123057
Journal volume & issue
Vol. 10, no. 4
p. e0123057

Abstract

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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~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.