Advances in lupus genetics and epigenetics

Abstract

Purpose of review Genome-wide association studies (GWAS) have identified more than 50 robust loci associated with 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 towards identifying causative variants of SLE-associated loci and epigenetic impact to lupus, especially genetic-epigenetic interactions that modulate expression levels of SLE susceptibility genes. Recent findings A few SLE-risk loci have been refined to localize likely causative variants responsible for the observed GWAS signals. Few of such variants disrupt coding sequences resulting in gain or loss of function for the encoded protein, while 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. Summary These findings provide novel insights of the disease pathogenesis, and promise better diagnostic accuracy and new therapeutic targets for patient management.

Increased expression of TLR2 in CD4+ T cells from SLE patients enhances immune reactivity and promotes IL‐17 expression through histone modifications

“…How T cells become hyperactive during SLE remains to be determined. However, both genetic background and environmental factors are believed to contribute to the development of SLE [3]. A number of epidemiological studies have suggested that onset and flares of SLE are associated with infection [4].…”

Epigenetics and Systemic Lupus Erythematosus: Unmet Needs

“…In particular, the disease is associated with inheritance of MHC class II and class III loci [1][2][3][4]. Two haplotypes of the MHC class II HLA-DRB1 (DRB1*1501 and DRB1*0301) display the strongest association with lupus.…”

“…End tissue damage is eventually supported by mechanisms that play an additional role at the local level ( Fig. 1) [1][2][3].…”

Aberrant Epigenetic Regulation in the Pathogenesis of Systemic Lupus Erythematosus and Its Implication in Precision Medicine

“…GWASs have identified more than 50 robust loci and genetic variations associated with SLE susceptibility [Han et al, 2009;Yang et al, 2010;Okada et al, 2012;Lee et al, 2014]. Only few of the variants (SNPs) lead to gain or loss of function of the encoded proteins, whereas the majority falls in noncoding regions [Deng and Tsao, 2014]. For example, IRF5, 7, and 8 are transcription factors required for activating transcription of IFN-α and IFN-inducible genes.…”

“…The research efforts accumulated in the last decades have been able to track the pathogenic origin of SLE to both genetic susceptibility and epigenetic variations arising from environmental factors [Sestak et al, 2007;Morel, 2010;Hedrich and Tsokos, 2011;Hughes and Sawalha, 2011;Deng and Tsao, 2014]. For example, environmental factors such as smoking, nutrition, viral infection, and the exposure to chemicals can trigger immunologic events to eventually result in SLE via epigenetic mechanisms [Costenbader et al, 2012].…”