NATURE REVIEWS | RHEUMATOLOGY ADVANCE ONLINE PUBLICATION | 1 Division of Rheumatology, Beth Israel Deaconess Medical Centre, Harvard Medical School, 330 Brookline Avenue, Dana 517‑C, Boston, MA 02215, USA (J. C. Crispín, C. M. Hedrich, G. C. Tsokos). Correspondence to: J. C. Crispín jcrispin@ bidmc.harvard.edu Gene-function studies in systemic lupus erythematosus José C. Crispín, Christian M. Hedrich and George C. Tsokos Abstract | The aetiology of systemic lupus erythematosus (SLE) is complex and is known to involve both genetic and environmental factors. In a small number of patients, single‑gene defects can lead to the development of SLE. Such genes include those encoding early components of the complement cascade and the 3'–5' DNA exonuclease TREX1. In addition, genome‑wide association studies have identified single‑nucleotide polymorphisms that confer some susceptibility to SLE. In this Review, we discuss selected examples of genes whose products have distinctly altered function in SLE and contribute to the pathogenic process. Specifically, we focus on the genes encoding integrin αM (ITGAM), IgG Fc receptors, sialic acid O‑acetyl esterase (SIAE), the catalytic subunit of protein phosphatase PP2A (PPP2CA) and signalling lymphocytic activation molecule (SLAM) family members. Moreover, we highlight the changes in epigenetic signatures that occur in SLE. Such epigenetic modifications, which are abundantly present and might alter gene expression in the presence or absence of susceptibility variants, should be carefully considered when deconstructing the contribution of individual genes to the complex pathogenesis of SLE. Crispín, J. C. et al. Nat. Rev. Rheumatol. advance online publication 4 June 2013; doi:10.1038/nrrheum.2013.78 Introduction Early and recent genetic studies have established that autoimmunity is associated with heritable traits and that predisposition to autoimmunity is, at least in part, genetically determined. 1 Accordingly, autoimmune disorders commonly cluster among first-degree rela- tives. 2 However, the fact that the clinical concord- ance among monozygotic twins is <50% in systemic lupus erythematosus (SLE) 3 indicates that additional factors make a substantial contribution towards the development of this disease. The immune system is comprised of an extensive array of cellular and molecular elements that must discern between self and nonself molecules and mount responses tailored to fit a huge variety of antigens. Individual genetic variation appears to affect various phases of the immune response, ranging from foreign or self antigen recognition to the final effector phases. However, the mechanisms by which heritable traits determine pro- tection or susceptibility to autoimmunity are currently poorly understood. Furthermore, the immune system is extremely plastic and continuously reshapes itself in an attempt to increase its affinity for antigens by changing its rep- ertoire and modifying its receptors. This plasticity is accomplished by complex regulatory changes in gene expression that include ‘silencing’ or ‘opening’ of genetic loci and even the mutation of germline DNA (as in the case of immunoglobulin somatic hypermutation). This fundamental aspect of the immune system must be considered in conceptual models intended to link heredi- tary factors to disease pathogenesis. Genetic variation represents only the starting point, and its influence is gradually and differentially modified by several layers of nonhereditary factors. Genome-wide association studies (GWAS) have iden- tified a fairly large number of genes associated with SLE. 4–6 A substantial effort is underway to determine how SLE-associated variants contribute to the risk of SLE development, and the current working models have been described in detail elsewhere. 7,8 In this Review, we discuss pathways through which selected genes contribute to the initiation and propagation of the autoimmune response and the development of organ damage in patients with SLE. We have chosen to focus on a small number of genes that encode proteins whose expression levels and/or functions are abnormal in patients with SLE but that have not been extensively reviewed elsewhere. Some of these genes have not been detected by GWAS; this might be because of technical limitations or, more impor- tantly, because genetic variation is not what links them to SLE but rather the fact that their expression is con- trolled by other SLE-associated factors, such as particular epigenetic changes or cellular events (for example, those associated with chronic immune activation). SNPs and copy number variations Approximately 35 genes have been associated with SLE through GWAS. 9 These associations are established when a given genetic marker (usually a single-nucleotide poly- morphism [SNP]) is found more frequently in patients with SLE than in matched healthy controls. In rare cases, Competing interests The authors declare no competing interests. REVIEWS © 2013 Macmillan Publishers Limited. All rights reserved