Precision medicine targets Lupus

Precision medicine is developing as a new field to deliver highly personalized health care. In order to succeed, it must understand how individual genes, environment and lifestyle impact diseases that can affect a patient.

For example, the University of Texas Southwestern Medical Center (USA) hopes to identify more than 1,000 gene variations that define susceptibility to Systemic Lupus Erythematosus (SLE). SLE is also called Lupus and is a serious, potentially fatal, autoimmune disease.

The National Institutes of Health reports Lupus affects nine times more women than men, and is more likely to strike young women of color: African-American, Hispanic, Asian, and Native American women, often at ages 15 thru 44.

"SLE starts when the immune system attacks multiple organ systems, which can result in a complex array of symptoms difficult to manage clinically. It can lead to organ damage," says Dr. Edward Wakeland, Chair of Immunology at the University of Texas Southwestern Medical Center, co-senior author of the study published in the journal eLife.

Systemic autoimmune diseases are a category that affect multiple body systems and includes Type 1 diabetes, rheumatoid arthritis, and multiple sclerosis.

Dr. Wakeland and colleagues sequenced millions of DNA base pairs from more than 1,700 people, to precisely identify the genetic variations contributing to SLE. Researchers identified 1,206 DNA variations located in 16 different regions of the genome often associated with increased susceptibility to SLE. They found almost all of the variations (1,199) affect specific molecules regulating immune responses.

"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 genes causing SLE," adds Dr. Wakeland, holder of the Edwin L. Cox Distinguished Chair in Immunology and Genetics.

The analysis was done using DNA samples from 1,349 European Americans (773 with SLE and 576 without) in gene collections at the University of Texas Southwestern, the University of Southern California, UCLA, Oklahoma Medical Research Foundation, and the Université Catholique de Louvain in Belgium.

Scientists found SLE risk associated with specific clusters of DNA variations called haplotypes. Some haplotypes increased the risk for SLE while others provided protection against SLE.

After identifying which sets of haplotypes increased SLE susceptibility in Caucasians, they went on to analyze other public databases — including the international 1000 Genomes Project (2,504 genomic global human samples). The goal was to determine whether these haplotypes exist in South American, South Asian, African, and East Asian populations as well, and found many common immune system haplotypes are shared throughout the global population. This suggests these immune variations have ancient origins.

Wakeland and colleagues plan to continue obtaining more DNA samples in order to find if there are any more additional SLE risk genes. Their new goal being to predict an individual's risk for SLE.

Abstract
Targeted sequencing of sixteen SLE risk loci among 1349 Caucasian cases and controls produced a comprehensive dataset of the variations causing susceptibility to Systemic Lupus Erythematosus (SLE). Two independent disease association signals in the HLA-D region identified two regulatory regions containing 3562 polymorphisms that modified thirty-seven transcription factor binding sites. These extensive functional variations are a new and potent facet of HLA polymorphism. Variations modifying the consensus binding motifs of IRF4 and CTCF in the XL9 regulatory complex modified the transcription of HLA-DRB1, HLA-DQA1 and HLA-DQB1 in a chromosome-specific manner, resulting in a 2.5-fold increase in the surface expression of HLA-DR and DQ molecules on dendritic cells with SLE risk genotypes, which increases to >4-fold after stimulation. Similar analyses of fifteen other SLE risk loci identified 1206 functional variants tightly linked with disease-associated SNPs and demonstrated that common disease alleles contain multiple causal variants modulating multiple immune system genes.

Co-lead authors of the eLife study from UT Southwestern were Dr. Prithvi Raj, Instructor of Immunology, and Dr. Ekta Rai, a former postdoctoral fellow in the Wakeland lab. Other contributing UTSW authors, all from Immunology, included Dr. Ran Song, postdoctoral researcher; Dr. Shaheen Khan, Instructor; Benjamin Wakeland, database analyst; Kasthuribai Viswanathan and Carlos Arana, computational biologists; Chaoying Liang, laboratory manager; Bo Zhang, senior research associate; Ferdicia Carr-Johnson; former lab manager; and Dr. Igor Dozmorov, Dr. Chandrashekhar Pasare, and Dr. Quan-Zhen Li, Associate Professors. Dr. Pasare holds the J. Wayne Streilein, M.D. Professorship in Immunology and is a Louise W. Kahn Scholar in Biomedical Research.

Additional UTSW co-authors include Dr. Christine Garcia, Associate Professor of Internal Medicine and in the Eugene McDermott Center for Human Growth and Development; Dr. Carol Wise, Professor of Orthopaedic Surgery and in the McDermott Center; and Dr. David Karp, Chief of Rheumatic Diseases and Professor of Internal Medicine. Dr. Garcia holds the Kern and Marnie Wildenthal President's Research Council Professorship in Medical Science, while Dr. Karp holds the Fredye Factor Chair in Rheumatoid Arthritis Research, and the Harold C. Simmons Chair in Arthritis Research.

Co-senior author was Dr. Patrick Gaffney of the Oklahoma Medical Research Foundation. Others contributors were from Yale School of Medicine, Oklahoma Medical Research Foundation; Université Catholique de Louvain; Penn State College of Medicine; Cincinnati Children's Hospital Medical Center and Cincinnati VA Medical Center; University of Southern California; and UCLA.

This study was supported by the National Institutes of Health, the Alliance for Lupus Research, and the Walter M. and Helen D. Bader Center for Research on Arthritis and Autoimmune Diseases.

About UT Southwestern Medical Center
UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty includes many distinguished members, including six who have been awarded Nobel Prizes since 1985. The faculty of almost 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in about 80 specialties to more than 100,000 hospitalized patients and oversee approximately 2.2 million outpatient visits a year.

Return to top of page

Mar 28, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Image Credit: Latina Moms and Family Living