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

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

doi:10.1371/journal.pone.0123057

Abstract

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.

Highlights

Plasma concentrations of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides (TG) are heritable risk factors for cardiovascular disease and important pharmacological targets for prevention strategies
Clinical and epidemiological data suggest an association between blood lipid levels and immune-mediated diseases, including Crohn’s disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), psoriasis (PSOR) and sarcoidosis (SARC)[1,2,3,4,5]
A different pattern of enrichment emerged for high density lipoproteins (HDL), where strong pleiotropic enrichment was observed with CD, UC and RA; weaker enrichment with T1D, and little enrichment with CeD, PSOR and SARC (Figure C in S1 File)

Summary

Introduction

Plasma concentrations of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides (TG) are heritable risk factors for cardiovascular disease and important pharmacological targets for prevention strategies. Clinical and epidemiological data suggest an association between blood lipid levels and immune-mediated diseases, including Crohn’s disease (CD), ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), psoriasis (PSOR) and sarcoidosis (SARC)[1,2,3,4,5]. Combining GWAS data from various phenotypes, it is feasible to determine the association of single nucleotide polymorphisms (SNPs) with more than one phenotype (genetic pleiotropy)[15]. This may enable identification of genetic factors responsible for shared disease mechanisms[15,16,17,18,19,20,21]

Methods

Results

Conclusion