Our previous work has resulted in the discovery of two novel susceptibility genes in lupus, methyl-CpG-binding protein 2 (MECP2) and interleukin-21 (IL21), both of which have since been replicated repeatedly by other groups, and also extended to other autoimmune diseases. Using our DNA methylome analysis approach in T cells with cells expressing either the lupus-risk or lupus-protective haplotype in MECP2, coupled with an in vivo approach using a human MECP2 transgenic mouse and Mecp2 knockout mice, we characterized the functional consequences of the lupus risk haplotype in MECP2 upon lupus susceptibility. Our discovery of MECP2 as a genetic risk locus for lupus and that MECP2 risk haplotype alters MECP2 expression and the DNA methylome in T cells provided the first evidence for genetic-epigenetic interaction in the pathogenesis of this disease. Other work from our lab demonstrated an inverse relationship between genetic risk for lupus and age of disease onset, suggesting that a higher genetic risk can explain both the earlier disease onset and increased disease severity in children with lupus. Our other work in lupus provided the first evidence for sex-gene interaction in the disease, with the finding that men require a higher genetic risk to develop lupus compared to women, and that these differences in genetic risk primarily stem from susceptibility loci in the HLA region and IRF5. These data provided an explanation for why lupus is less common in men. In subsequent collaborative work we have demonstrated that men require a higher genetic risk and/or lower T cell DNA methylation to develop a lupus flare of equal severity to women.
Our group provided evidence for gene-gene interaction in lupus risk, and published the largest lupus genetics study to date in African-Americans. In another recent publication, we performed the first systematic work to identify and predict specific clinical disease features in lupus based on genotypes. As described in a recent News and Views in Nature Reviews Rheumatology written about this paper: “These findings present important new insights into the role of genetics in end-organ involvement during disease development, and provide direction for a variety of new experimental strategies with the aim of elucidating genotype–phenotype relationships in patients with SLE”.
