Precision medicine study of lupus links regulatory DNA to autoimmunity

Researchers used next-generation DNA sequencing technology to identify more than 1,000 gene variants that affect susceptibility to systemic lupus erythematosus (SLE); of these variants, extensive differences occurred in a region that regulates the production of Human Leukocyte Antigen (HLA) class II molecules, which are known to play a critical role in activating the immune system, according to a study published online March 17, 2016 in eLife.

The vast majority of these variants were found in stretches of DNA that regulate the expression of nearby genes rather than in DNA that encodes the structures of proteins, the researchers discovered.

“Our findings support the potential of precision medicine to provide clinically relevant information about genetic susceptibility that may ultimately improve diagnosis and treatment,” said co-senior author of the study Edward Wakeland, PhD, Chair of Immunology and Genetics at University of Texas Southwestern Medical Center in Dallas, TX.

Previous genome-wide association analyses (GWAS) have identified more than 50 SLE risk loci to date, indicating that susceptibility is polygenic. But the effects that these disease genes contribute to the disease process have not been clearly delineated.

In this multicenter study, scientists performed targeted, deep sequencing of 28 risk loci for SLE using the DNA samples of 1,349 whites of European ancestry (773 with SLE disease and 576 without) from sample collections at UT Southwestern, the University of Southern California, UCLA, Oklahoma Medical Research Foundation, and the Université Catholique de Louvain in Belgium.

They then determined the precise DNA sequences at SLE-associated genetic regions scattered throughout the genome. They found that SLE risk is associated with specific haplotypes, and that some haplotypes increased the risk for SLE while others provided protection from SLE.

“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. Wakeland said.

After identifying the sets of DNA variants that increased SLE susceptibility in whites, the researchers used multiple public databases (including the international 1000 Genomes Project) to determine whether these haplotypes were also found in South American, South Asian, African, and East Asian populations.

They discovered that the variants and haplotypes were distributed across subpopulations worldwide. Their findings indicate that many common haplotypes in the immune system are shared at different frequencies throughout the global population, which suggests that these variations in the immune system have ancient origins that persist in populations for long periods, Dr. Wakeland said.

The researchers determined that slight changes to the regulatory DNA sequences result in an overabundance of HLA polymorphisms, which lead to a hyperactive immune system that is strongly associated with SLE.

“The most intriguing result of our sequence analyses is the discovery of a strong association between SLE susceptibility and HLA-D polymorphisms that regulate HLA class II gene expression,” the authors wrote. “The HLA-D region is consistently a potent susceptibility locus in autoimmunity.”

The scientists plan to continue this deep sequencing research by obtaining more DNA samples and expanding their analysis to additional SLE risk genes. Their eventual goal is to obtain a dataset that could be used to predict an individual’s unique risk of SLE as well as that individual’s likelihood of benefiting from specific treatments.

“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,” Dr. Wakeland said.

Future studies may investigate whether these findings relate to other autoimmune disorders as well.