Systemic lupus erythematosus (SLE) is a severe autoimmune disease characterized by persistent damage to multiple organs and tissues, including the skin, kidneys, cardiovascular system, and brain. Before symptom onset and throughout disease progression, SLE patients produce various types of autoantibodies. Although different immune cells are involved in disease development, the major pathological effects are likely dependent on B cells. The most well-known genetic associations with SLE are within the HLA locus, while multiple non-HLA genetic variants exhibit relatively low risk.

Both HLA and non-HLA associations suggest that genetic association profiles within subgroups of SLE differ and relate to autoantibody patterns.^{1 2} Although major genetic associations have been established for several years, understanding the specific mechanisms that increase SLE risk due to these variations and how they relate to specific clinical manifestations remains work in progress. Current research focuses on integrating clinical phenotypes with autoantibody patterns to define more specific disease subgroups.^{1 3} This subgrouping may suggest different treatments and explain variations in disease outcomes.

To date, more than 180 polymorphisms have been associated with SLE, and new discoveries are anticipated.⁴ These associations may have different effects in various human populations and ethnic groups due to genetic stratification and environmental differences. This ongoing research aims to build a robust foundation for integrating clinical and omics data in SLE studies, thereby enhancing our understanding of the disease’s pathogenesis and paving the way for more targeted therapeutic approaches.

References

1. Diaz-Gallo LM, Oke V, Lundström E, et al. Four systemic lupus erythematosus subgroups, defined by autoantibodies status, differ regarding HLA-DRB1 genotype associations and immunological and clinical manifestations. ACR Open Rheumatol. 2022;4(1):27–39. doi: 10.1002/acr2.11343.

2. Molineros JE, Looger LL, Kim K, et al. Amino acid signatures of HLA Class-I and II molecules are strongly associated with SLE susceptibility and autoantibody production in eastern Asians. PLoS Genet. 2019;15(4):e1008092. doi: 10.1371/journal.pgen.1008092.

3. Langefeld CD, Ainsworth HC, Cunninghame Graham DS, et al. Transancestral mapping and genetic load in systemic lupus erythematosus. Nat Commun. 2017;8:16021. doi: 10.1038/ncomms16021.

4. Ha E, Bae SC, Kim K. Recent advances in understanding the genetic basis of systemic lupus erythematosus. Semin Immunopathol. 2022;44(1):29–46. doi: 10.1007/s00281-021-00900-w.

Learning Objectives At the end of this presentation participants will be able to:

• Describe the major genetic associations with SLE: Explain the significance of HLA and non-HLA genetic variants and their impact on disease risk in SLE

• Discuss autoantibody patterns and genetic associations: Illustrate how autoantibody patterns and genetic associations help define specific subgroups within SLE, and how these subgroups relate to clinical outcomes and treatment strategies

• Explain challenges in SLE genetics research: Identify the main challenges in the study of SLE genetics and provide insight into ongoing research aimed at elucidating the specific mechanisms by which genetic variations increase the risk of SLE and their relation to clinical manifestations