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DNA sequencing technology unlocks the genetics of lupus

Demonstrating the potential of precision medicine, an international study based at UT Southwestern Medical Center used next-generation DNA sequencing technology to identify more than 1,000 gene variants that affect susceptibility to systemic lupus erythematosus (SLE).

Precision medicine is an emerging field that aims to deliver highly personalized health care by understanding how individual differences in genetics, environment, and lifestyle impact health and disease.

SLE, commonly called lupus, is a serious, potentially fatal autoimmune disease that the National Institutes of Health reports affects nine times more women than men, and is more likely to strike young African-American, Hispanic, Asian, and Native American women. The disease typically begins between the ages of 15 and 44.

Dr. Prithvi Raj (left) and Dr. Edward Wakeland examine DNA sequencing data
Dr. Prithvi Raj (left) and Dr. Edward Wakeland examine DNA sequencing data used in a study that identified more than 1,000 gene variants that affect susceptibility to lupus.

“SLE starts when the immune system attacks multiple organ systems in the body, which can result in a complex array of symptoms that are difficult to manage clinically and can lead to organ damage,” said Dr. Edward Wakeland, Professor of Immunology at UT Southwestern and co-senior author of the study published last year in eLife. “Our findings support the potential of precision medicine to provide clinically relevant information about genetic susceptibility that may ultimately improve diagnosis and treatment.”

Dr. Wakeland, an expert in next-generation sequencing applications, leads a new DNA-sequencing initiative to take this technology to the next level to advance patient treatment in areas such as cancer and autoimmune disease. (See related story on page 56.) For years, Dr. Wakeland’s laboratory has served as the Medical Center’s Genomics and Microarray Core Facility.

The eLife study also may have implications for other systemic autoimmune diseases, a category of diseases that affects multiple body systems and includes Type 1 diabetes, rheumatoid arthritis, and multiple sclerosis, he said. Dr. Prithvi Raj, Instructor of Immunology, was a lead author of the study.

A DNA sequencing study pinpointed more than 1,000 genetic mutations associated with lupus.
A DNA sequencing study pinpointed more than 1,000 genetic mutations associated with lupus.

Dr. Wakeland and colleagues sequenced millions of DNA base pairs from more than 1,700 people, which allowed precise identification of the genetic variations contributing to SLE, he said. Specifically, the researchers identified 1,206 DNA variations located in 16 different regions of the human genome associated with increased susceptibility to SLE. They then showed that almost all of them (1,199) modify the level of expression of specific molecules that regulate immune responses, he said.

In addition, the two-year study identified many of the specific regulatory variations that were changed in SLE patients and demonstrated that accurately identifying such so-called causal variants increased the accuracy of the genetic association of individual SLE risk genes with susceptibility to 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,” added Dr. Wakeland, who holds the Edwin L. Cox Distinguished Chair in Immunology and Genetics.

The scientists began their comprehensive sequence analysis using the DNA samples of 1,349 American Europeans (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 clusters of DNA variations, commonly called haplotypes, and that some haplotypes increased the risk for SLE while others provided protection from SLE.

After identifying the sets of DNA variants that increased SLE susceptibility in Caucasians, they used multiple public databases, including the international 1000 Genomes Project (2,504 genomic samples from the global human population) to determine whether these haplotypes also were 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, suggesting that these variations in the immune system have ancient origins and persist in populations for long periods, Dr. Wakeland said.

Dr. Wakeland and colleagues plan to continue the research by obtaining more DNA samples and expanding their analysis to additional SLE risk genes with the goal of obtaining a data set that can be used to predict an individual’s unique risk of SLE, as well as the 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.

Wakeland leads UTSW sequencing initiative

(Left to right) Dr. Edward Wakeland, assisted by computational biologist Carlos Arana and Dr. Prithvi Raj, leads a new DNA sequencing initiative at UT Southwestern.
(Left to right) Dr. Edward Wakeland, assisted by computational biologist Carlos Arana and Dr. Prithvi Raj, leads a new DNA sequencing initiative at UT Southwestern.

A DNA sequencing initiative to address important clinical challenges launched last year, led by Dr. Edward Wakeland, whose laboratory has long served as the institution’s Genomics and Microarray Core Facility.

Working collaboratively with the Department of Pathology, the new clinical sequencing facility at the BioCenter on the East Campus provides both gene panel and whole-exome sequencing for cancer and other diagnoses, and plans to expand to the analysis of a variety of infectious and genetic diseases for the clinical care of patients at UT Southwestern.

“This clinical sequencing core facility will generate laboratory data to be used for the evaluation of patient samples, including tumors and infectious diseases. These sequencing technologies are essential laboratory components in the rapidly developing field of precision medicine and we plan to make this technology a standard element of patient care at UT Southwestern,” said Dr. Wakeland, Professor of Immunology and holder of the Edwin L. Cox Distinguished Chair in Immunology and Genetics.