Using next-generation DNA sequencing technology, researchers have targeted 16 specific regions of the human genome associated with increased susceptibility to systemic lupus erythematosus (SLE), identifying more than 1,000 DNA variations that regulate the expression of genes associated with immune responses and SLE pathology. The variations are linked to disease susceptibility.
The study, which also further highlighted the potential of precision medicine, is titled “Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity” and published in eLife.
Over the last decade, several genes have been associated with a higher likelihood of developing SLE, an autoimmune disease that affects multiple organs and systems. However, how the sequences of these genes differ between SLE patients and healthy individuals, and what precise changes lead to an increased disease risk remained open questions.
Researchers determined the precise genetic sequences of genome regions using DNA samples from over 700 SLE patients and 500 healthy controls. Results revealed that SLE risk is related to specific clusters of DNA variations, commonly called haplotypes. While some of these haplotypes provided protection against SLE, others increased the risk for the disease. The scientists identified 1,206 DNA variations associated with higher SLE susceptibility, and showed that almost all of them modified the expression levels of molecules that regulate the immune system. Moreover, identification of these DNA variants increased the accuracy of the predictive genetic association with an individual’s risk for SLE. While the study involved Americans of European descent, researchers investigated other sub-populations and found that the variants and haplotypes were distributed across South American, South Asian, African, and East Asian populations worldwide.
“Prior to our study, such a comprehensive sequence analysis had not been done and little was known about the exact genetic variations that modify the functions of the genes that cause SLE,” Dr. Edward Wakeland, chair of Immunology at UT Southwestern Medical Center and the study’s co-senior author, said in a news release. “It is feasible that this same type of genetic analysis will allow the clustering of SLE patients into specific groups, based on their genetic predispositions, which would improve clinical management and potentially allow the development of more targeted therapies.”
Researchers believe their findings support the potential of precision medicine to provide clinically relevant information at a personal level, leading to improvements in diagnosis and patient-targeted treatments.