Journal Article

Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus

Bentham, James, Chen, Lingyan, Vyse, Timothy J, Pinder, Christopher L, Knight, Julian C, Tombleson, Philip, Morris, David L, Martín, Javier, Rioux, John D, Behrens, Timothy W, Replogle, Joseph, Fairfax, Benjamin P, Alarcón-Riquelme, Marta E, Syvänen, Ann-Christine, Rönnblom, Lars, Graham, Robert R, Cunninghame Graham, Deborah S, Wither, Joan E

2015

Overview

Timothy Vyse and colleagues report the results of a large-scale association study of systemic lupus erythematosus (SLE). They identify ten new susceptibility loci and implicate aberrant regulation of innate and adaptive immunity genes in disease pathogenesis. Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis -acting eQTL effects in a range of ex vivo immune cells. We found an over-representation ( n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/205/2138 / 692/699/249/1313/1613 / Adaptive Immunity - genetics / Agriculture / Animal Genetics and Genomics / Autoimmune diseases / Biomedicine / Cancer Research / Case-Control Studies / Confidence intervals / Development and progression / Gene expression / Gene Expression Regulation / Gene Function / Genetic aspects / Genetic Association Studies / Genetic Loci / Genetic Markers - genetics / Genetic Predisposition to Disease / Genetic research / Genetic susceptibility / Genomes / Genotype / Health care networks / Hospitals / Human Genetics / Humans / Identification and classification / Immune response / Immunity, Innate - genetics / letter / Lupus / Lupus Erythematosus, Systemic - genetics / Lupus Erythematosus, Systemic - immunology / Lupus Erythematosus, Systemic - pathology / Medical research / Meta-analysis / Meta-Analysis as Topic / Polymorphism, Single Nucleotide - genetics / Quality control / Regulation / Risk Factors / Statistical analysis / Studies / Systemic lupus erythematosus