Genetics play a significant role in the pathogenesis of systemic lupus erythematosus (SLE), as the risk among twins and siblings is substantially higher than in the general population. The genetics of SLE are complex: patients who present before puberty are more likely to have a monogenic etiology, whereas older adolescents and adult-onset SLE are more likely to have a polygenic form of disease. In addition, the marked phenotypic heterogeneity of SLE is shaped by epigenetic modifiers and environmental factors.
Monogenic SLE has been linked to novel or ultra-rare high-impact pathogenic variants in a number of genes regulating the type I interferon (IFN) pathway, nucleic acid sensing pathways, and complement signaling. Thus, despite the presence of diverse autoantibodies, monogenic lupus is primarily associated with defects in genes involved in innate immune function. Genetic testing is recommended in early-onset cases; however, the diagnostic yield generally does not exceed 20%, depending on the population studied. A molecular diagnosis is important for selection of targeted therapies.
In the polygenic model of SLE, multiple common single-nucleotide polymorphisms (SNPs), each with small effect sizes, contribute to disease susceptibility. More than 100 risk SNPs have been identified through genome-wide association studies (GWAS) across diverse adult populations. These variants are most frequently located in noncoding regions but often map to genes involved in key pathogenic pathways. Polygenic risk scores (PRS) are used to quantify the cumulative burden of common variants. Higher PRS values have generally been associated with earlier disease onset and more severe phenotypes. Recent studies suggest that younger patients may also carry a greater burden of rare and common risk variants, as reflected by higher PRS.
Together, these findings point to a complex interplay between novel, rare, and common genetic variants in SLE. To date, the relationship between these variant classes has not been systematically evaluated and warrants further investigation.
