A team of researchers has identified new variations within the coding region of genes — which gives rise to proteins — that may be associated with a person’s susceptibility to systemic lupus erythematosus (SLE).
The study, “Exome-wide association study identifies four novel loci for systemic lupus erythematosus in Han Chinese population,” was published in the journal Annals of the Rheumatic Diseases.
Lupus is a chronic autoimmune disease that normally occurs in genetically predisposed individuals who have experienced certain environmental stimuli.
The genetic understanding of this disease has gained special attention with observational large-scale genomic studies, termed genome-wide association studies (GWAS).
Specifically, GWAS allow the discovery of certain regions in our DNA that are prone to small variations, known as single nucleotide polymorphisms (SNPs), that may be linked to the disease.
Previous studies have found that the majority of SNPs associated with lupus occurred in regions of the human genome devoid of any gene — which do not lead to the production of any protein. These regions are known as non-coding genomic regions. However, alone they cannot fully explain all the features associated with the disease, suggesting additional regions are involved.
With this new study, researchers propose that SNPs in regions that produce proteins (protein-coding regions) could lead to potential lupus target genes for additional functional experiments. They performed a large-scale search, or screen, for protein-coding variants in 10,103 SLE cases and 16,326 healthy controls in people of Han Chinese ancestry.
They were able to identify five novel susceptibility variants for lupus, three of which were located within four genes — called LCT, TPCN2, AHNAK2 and TNFRSF13B — “highlighting the role of coding variants in SLE,” researchers wrote.
“We suggest that the novel implicated genes might modulate immune response in SLE. To the best of our knowledge, this is the first large-scale exome array study for SLE,” they added.
For example, one of the genes identified, TNFRSF13B, provides instructions for a protein called TACI, which is located on the surface of B-cells and is a known target of Benlysta (belimumab), an approved human monoclonal antibody for lupus patients.
“The results suggest the novel finding of TNFRSF13B may provide a potential therapeutic target for SLE,” they wrote.
Additional experiments showed that one SNP had a regulatory effect on the TPCN2 gene, which is important for the normal response of another class of immune cells called T-cells. The newly identified SNP may inhibit TPCN2 levels, affecting the normal immune system response in lupus.
Overall, this report not only provides the first large-scale study for protein-coding variants in lupus, it can also help us understand the biological mechanisms associated with this disease.