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SLEGEN

As evidence mounted toward the connection between lupus and an individual’s genetic makeup, the Alliance for Lupus Research (ALR) made a commitment:  to assemble some of the best and brightest minds in lupus research to identify and understand the genes that predispose someone to the disease.  In 2005, the International Consortium on the Genetics of Systemic Lupus Erythematosus (SLEGEN) was formed.  The consortium is comprised of 18 prominent lupus genetics researchers and their groups, who are committed to isolating these genes and determining how variations in them influence the disease.

In just a few years, SLEGEN has accomplished more than thought possible with discoveries that are changing the way we think about the disease. In January 2008, less than three years after the formation of SLEGEN, the group published landmark data identifying 13 genes linked to women with lupus.  Since then, and because of the breakthroughs made by SLEGEN, scientists have identified many more genes that are likely associated with the disease.  These findings were so compelling that additional studies were initiated to take a closer look at these genes and possibly discover more. 

Earlier this year, the ALR provided an additional $500,000 in funding for SLEGEN to continue its research utilizing advanced chip technology, called the Immunochip, to close in on the more than 30 probable genes.  This research includes completing genome-wide studies for multiple ethnicities including African American, Hispanic, Native American and Asian descent.  These studies will likely result in a greater understanding of how genetic variance impacts age of disease onset and lupus-related complications common with the disease.  In other words, scientists theorize that certain genetic variants may tell us which conditions, such as kidney disease and cardiovascular issues, a patient is more likely to experience.  Furthermore, the research will allow scientists to assess the correlation of lupus genetics to that of other autoimmune diseases.  

“The ALR has played the critical, pivotal role in the creation of the SLEGEN consortium and sending the message that bringing people together can actually solve the challenge of lupus.” -- Robert F. Kimberly, MD, Senior Associate Dean for Research and Director of the University of Alabama, Birmingham Arthritis and Musculoskeletal Center

SLEGEN AT A GLANCE

  • The Alliance for Lupus Research (ALR) founded the international research consortium in 2005.
  • The ALR supported the initial three-year study with $2.25 million in funding.
  • After scanning the entire genome and 317,000 single nucleotide polymorphisms (SNPs), scientists found 13 genes linked to lupus. Study results were published in the January 20, 2008 issue of Nature Genetics.  Since then, more than 30 genes have now been linked to the disease.
  • In January of 2011, the ALR provided an additional $500,000 in funding to more closely scrutinize genetic variations in multiple ethnicities utilizing advanced chip technologies and allowing scientists to learn more about the 13 identified genes.
  • Studies are designed to assess how genetics will impact if and when an individual will develop lupus, and the complications that may occur.
  • Findings will continue to spur more studies, leading to new treatment strategies.
  • SLEGEN scientists have secured additional funding from other agencies, including National Institutes of Health (NIH), that have helped further their groundbreaking research.

SLEGEN serves as an immense knowledge bank full of an unprecedented amount of data, enabling a more swift and accurate identification of genetic variations that increase one’s risk of developing lupus.  Because of this strength in numbers, SLEGEN has helped to accelerate lupus genetic research, moving us even closer to effective treatments and a cure for this debilitating disease. To date, over 60 different researchers and research groups from around the world have participated in the SLEGEN consortium or used the SLEGEN consortium data and analysis resources to further their studies.  This is, perhaps, one of the most profound aspects of SLEGEN -- bringing together researchers from around the world, generating an unparalleled level of focus and commitment to a disease that has been elusive to scientists for decades. 

“The breadth of SLEGEN gives us unprecedented sample size and statistical power.  We have maximized the lupus community and are at the point of making some real breakthroughs.”  -- Carl Langefeld, PhD, SLEGEN Co-Director, Director of the Center for Public Health Genomics and co-Director of the Biomedical Informatics Program at Wake Forest University

In January 2008, SLEGEN published data in Nature Genetics that identified 13 genes linked to women with lupus. Researchers studied the DNA of more than 6,700 women including individuals with lupus, their family members and control subjects. Researchers sifted through a massive database and scanned the entire human genome for more than 317,000 single nucleotide polymorphisms (SNPs), or small genetic variations that may occur within a person’s DNA, to pinpoint those associated with lupus.  SLEGEN was among the first to utilize an advanced chip technology that allowed for this rapid scanning and gene identification.

The initial data has allowed researchers to move into new phases of study to more clearly delineate genetic variations across multiple ethnicities and between other autoimmune diseases.  The team has spent the last three years looking closely at African-American and Hispanic populations and genetic variations responsible for lupus in these groups. 

The ALR is continuing its commitment to lupus genetic research and SLEGEN through funding of its Functional Genomics and Molecular Pathways (FGMP) in SLE Grant.  Since the FGMP’s inception, the ALR has awarded over $4 million in innovative and crucial research studies.  Building on this genetics-focused approach, an additional $500,000 in funding for studies that utilize a highly specialized Immunochip that hones in on the identified genes has been awarded.  These studies engage in a higher level of specificity with the goal of understanding which genetic variants influence specific aspects of the disease. The team is conducting genome-wide studies in more than 10,000 individuals from multiple ethnicities including African American, Hispanic, Native American and Asian descent.  These studies will likely result in a greater understanding of how genetic variance impacts age of disease onset and lupus-related complications common with the disease.  Furthermore, the research will allow scientists to assess the correlation of lupus genetics to that of other autoimmune diseases.  These genes are thought to have some commonalities that may tell us more about autoimmune diseases and what genetic variations influence each disease, bringing us closer to finding effective treatments.

“The formation of SLEGEN and its success has helped secure additional support and funding from organizations such as the NIH.  This would not have been possible without the ongoing support from the ALR.” -- Tim Vyse, PhD, Professor of Rheumatology at the Imperial College, London and a collaborator, Human Lupus Genetics Study at Hammersmith Hospital.

The SLEGEN project has realized tremendous success since the ALR’s initial founding of the group in 2005 and is now taking the research to a whole new level. Utilizing the most advanced technology available, the ImmunoChip, SLEGEN scientists are more closely examining the genes that were identified in the most recent round of studies. This highly specialized and powerful tool is allowing researchers to engage in an even greater level of detail because the information contained on the ImmunoChip — based completely on findings from previous genetic studies — is extremely focused and specific. The new technology offers scientists the amazing ability to study hundreds of thousands of genetic variants – 250,000 to be exact -- in more than 10,000 participants.  

In this landmark study, SLEGEN Scientists are working to accomplish three goals:

  • Ethnicity and Lupus:  To learn how ethnicity affects one’s chance of developing lupus and severe complications by studying the genetic variants of African, Asian, and Hispanic Americans. It is well known that African Americans with lupus are much more likely to experience complications involving renal disease than are European Americans with lupus. Understanding why — in genetic terms — may help clinicians more closely predict when an individual might develop lupus, the complications he or she may experience and to what degree — leading to effective disease management and more precise treatments.
  • Autoimmune Disease Commonalities:  To study lupus together with 12 major autoimmune diseases — autoimmune thyroid disease, ankylosing spondylitis, Crohn’s disease, celiac disease, IgA deficiency, multiple sclerosis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes and ulcerative colitis — and help us understand how lupus is unique and how it is similar to other immune system diseases. These genes are thought to have some commonalities that may tell us more about autoimmune disease and what genetic variations influence each disease, bringing us closer to finding effective treatments. By looking at so many autoimmune diseases together, the study may provide a much deeper look into the alterations of the immune system that cause disease and help identify those common shared genetic risk factors.
  • Gene Variants & Biologic Pathways:  To acquire evidence of particular gene variants that are related to lupus and to biologic processes or pathways, like the processes involving Interferon Alpha and Toll-like Receptors — and to guide further research to evaluate if such processes are indeed potential clues for stopping the development of lupus.

The realistic hope is that the ImmunoChip study will reveal, in enormously expanded detail, the critical roles that genetic variance and ethnicities play in predisposing an individual to developing lupus, age of disease onset and lupus-related complications common with the disease. Preliminary results may be available as soon as mid-2012.

Dr. Robert Kimberly, a leading SLEGEN researcher and former ALR Scientific Advisory Board Member, says, “This is like shining a floodlight into the contributing genetic causes and biologic pathways of lupus. Our investigation is providing a deeper insight into the best potential targets for breakthroughs in diagnostics, prevention, treatment, and eventually a cure.”

 

What's Next?

SLEGEN scientists are hopeful that genetic research, particularly utilizing this level of collaboration and technology, will more quickly lead us to more effective treatment options and potentially a cure for this debilitating disease.  Results from ongoing studies conducted by the SLEGEN consortium will continue to provide insight in lupus-related conditions and possibly ways to help prevent or delay the onset of symptoms as well as alter the severity of the disease.

The scientists who worked tirelessly on SLEGEN represents some ofthe best and the brightest minds in genome research. Meet the people responsible for the success of this landmark study.

Co-Directors

Tim Vyse, PhD is a Professor of Rheumatology at the Imperial College, London and a collaborator in the Human Lupus Genetics Study at Hammersmith Hospital. Dr. Vyse also is the Principal Investigator of the Genetics of Human Lupus, which houses one of the largest family DNA collections from single-case SLE families in the world. The collection is used to identify genetic variants that contribute to lupus.

Carl Langefeld, PhD
Carl Langefeld, PhD Dr. Langefeld is a statistical geneticist whose research efforts have always focused on helping to find prevention and treatment solutions for diseases that are caused or exacerbated by family heritage. His work as the Director of the Center for Public Health Genomics and co-Director of the Biomedical Informatics Program at Wake Forest University has led to important discoveries that link genetics to a number of medical conditions, including lupus. He has developed a class of regression-based tests, which assist in isolating and cloning disease-predisposing genes.

Members

Marta Alarcon-Riquelme, MD, PhD, is a Medical Doctor from Universidad LaSalle and Universidad Nacional Autónoma de México. She completed her PhD in Immunology at Stockholm University and is currently a researcher of the Royal Swedish Academy of Sciences and Associate Professor at the Department of Genetics and Pathology, Uppsala University, Sweden.

Timothy Behrens, MD is the Senior Director of Immunology, Diagnostics and Biomarkers at Genentech South, San Francisco, California. He received his medical degree from the Medical College of Wisconsin, where he also completed his fellowship in Rheumatology/Immunology. Behrens joined Genentech in 2006 to build a group of scientists who can develop treatments for lupus and rheumatoid arthritis.

Lindsey Criswell, MD, is Professor in Residence of Medicine, Division of Rheumatology, and Associate Director of General Clinical Research at her alma mater, the University of California at San Francisco. After receiving her medical degree from the University of California, San Francisco, Dr. Criswell completed a postdoctoral fellowship in Rheumatology at the same institution. Her research focuses on the genetics and epidemiology of human autoimmune disease.

Jeffrey C. Edberg, PhD, is Assistant Professor of Clinical Immunology & Rheumatology at the University of Alabama at Birmingham. As a member of the leadership team of the UAB Pittman General Clinical Research Center, he has initiated and led efforts in Human Molecular Genetics. He is also involved in a number of NIH-funded studies exploring the genetic basis of human autoimmune diseases.

Stacey Gabriel, PhD, is Director of the Broad Institute of MIT and Harvard's Genetic Analysis Platform facility in Cambridge, Massachusetts. As principal investigator, Dr. Gabriel uses genome-wide association studies and new tools to measure environmental factors. These studies focus on determining if environmental exposures cause individuals to have increased risks in developing common diseases.

Patrick Gaffney, MD, Patrick Gaffney, MD, is a faculty member of the Oklahoma Medical Research Foundation's Arthritis & Immunology Research Program. He received his medical degree in Oncology from the University of Minnesota. Dr. Gaffney's research interests focus on genomic analysis of head and neck cancer and oral pre-malignant lesions, hereditary colorectal cancer, and studies of genes that cause lupus.

Peter Gregersen, MD, is Investigator Head of the Robert S. Boas Center for Genomics and Human Genetics and the Director of the Eileen Ludwig Greenland Center for Rheumatoid Arthritis at North Shore Jewish Research Institute in Manhasset, New York. He and his colleagues has directed the world's largest effort to identify the genes underlying rheumatoid arthritis and other autoimmune diseases.

“ALR is different...there are not many agencies that are focusing aggressively on bringing treatments from the laboratory to the bedside in a short time.”
-Robert Wood Johnson IV, Chairman, Board of Directors

Chaim Jacob, MD, PhD, is Associate Professor of Molecular Microbiology and Immunology at the Keck School of Medicine, University of Southern California, Los Angeles. His research efforts focus on the role of cytokines and cytokine receptors in the genetic tendency of certain diseases. In addition, his studies in molecular genetic linkage have helped to identify genes that predispose individuals to autoimmune conditions.

Ken Kaufman, PhD, is a Research Assistant Member of the Arthritis and Immunology Research Program at the Oklahoma Medical Research Foundation and serves as Associate Professor at the University of Oklahoma Health Sciences Center. Kaufman is also Scientific Director of the Genotyping of DNA Sequencing Center for the U.S. Department of Veterans Affairs Medical Center, Oklahoma. His research focuses on the molecular mechanisms in lupus pathogenesis.

Robert F. Kimberly, MD, is Senior Associate Dean for Research and Director of the University of Alabama, Birmingham Arthritis and Musculoskeletal Center. A rheumatologist and immunologist, Dr. Kimberly has expertise in autoimmune disease, including systemic lupus erythematosus, systemic vasculitis and rheumatoid arthritis. He establishes collaborative research groups in both clinical and translational studies.

Daniel Mirel, PhD, is a member of the Project Management team at the Broad Institute of MIT and Harvard's Genetic Analysis Platform facility. He serves as project manager for the facility's contribution to the Genes, Environment and Health Initiative, a NIH-supported research project aimed at conducting genome-scale analyses to pinpoint common genetic variants that underlie disease.

Kathy Moser, PhD, is a faculty member of the Oklahoma Medical Research Foundation's Arthritis & Immunology Research Program, Tulsa. Dr. Moser oversees a clinic that focuses on Sjögren's syndrome, a chronic disease in which white blood cells attack the body's moisture-producing glands. With a PhD in Microbiology/Immunology, she also conducts lupus research.

John Rioux, PhD, is an Associate Professor of Medicine at the Université de Montréal and at the Montreal Heart Institute, where he works as a researcher and director of the Laboratory in Genetics and Genomic Medicine of Inflammation. He is also a visiting scientist at the Broad Institute of MIT and Harvard. Dr. Rioux holds the Canada Research Chair in Genetics and Genomic Medicine of Inflammation.

Kimberly Taylor, PhD, is a Principal Statistician for the Department of Medicine/Rheumatology at the University of California, San Francisco. The department's research division is involved in defining the basic biochemical mechanisms that regulate normal immune responses and the genetic and environmental causes of autoimmune diseases.

Betty Tsao, PhD, is a Professor of Medicine and Adjunct Assistant Professor of Rheumatology and Arthritis at the University of California, Los Angeles. She is also a member of the Jonsson Comprehensive Cancer Center Tumor Immunology Program. Dr. Tsao was the first person to link a specific human chromosome region to increased risk of developing lupus.

Raphael Zidovetzki, PhD, is a Professor of Cell Biology and Neuroscience at the University of Southern California, Riverside. In addition to his contributions to the SLEGEN project, Dr. Zibovetzki has also contributed to other research studies related to particular genes that contribute to tumor growth and HIV production.


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