Advances in lupus genetics and epigenetics.

Abstract

Genome-wide association studies have identified more than 50 robust loci associated with systemic lupus erythematosus (SLE) susceptibility, and follow-up studies help reveal candidate causative genetic variants and their biological relevance contributing to the development of SLE. Epigenetic modulation is emerging as an important mechanism for understanding how the implicated genes interact with environmental factors. We review recent progress toward identifying causative variants of SLE-associated loci and epigenetic impact on lupus, especially genetic-epigenetic interactions that modulate expression levels of SLE susceptibility genes. A few SLE-risk loci have been refined to localize likely causative variants responsible for the observed genome-wide association study signals. Few of such variants disrupt coding sequences resulting in gain or loss of function for the encoded protein, whereas most fall in noncoding regions with potential to regulate gene expression through alterations in transcriptional activity, splicing, mRNA stability and epigenetic modifications. Multiple key pathways related to the SLE pathogenesis have been indicated by the identified genetic risk factors, including type I interferon signaling pathway that can also be regulated by epigenetic changes occurred in SLE. These findings provide novel insights into the disease pathogenesis and promise better diagnostic accuracy and new therapeutic targets for patient management.