Researchers uncover new genetic links to psoriasis

"Common diseases like psoriasis are incredibly complex at the genetic level," says lead investigator Anne Bowcock, Ph.D., professor of genetics at the School of Medicine. "Our research shows that small but common DNA differences are important in the development of psoriasis. Although each variation makes only a small contribution to the disease, patients usually have a number of different genetic variations that increases their risk of psoriasis and psoriatic arthritis."

The DNA variations uncovered by the researchers point to different biological pathways that underlie psoriasis and may eventually lead to new targeted drugs and treatments that hit specific pathways, Bowcock says.

An estimated 7 million Americans have psoriasis, an autoimmune disease that occurs when the body's immune cells mistakenly attack the skin. The condition is characterized by red, scaly patches that can be itchy, painful or both. Some 10 to 30 percent of patients with psoriasis develop psoriatic arthritis, a condition that is often excruciatingly painful and debilitating.

The Washington University researchers focused on points of common variation in the genome called single nucleotide polymorphisms, or SNPs. While most of the 3 billion nucleotides that comprise DNA are thought to be identical from one person to the next, some 10 million SNPs build variation into the genome and make each individual unique. Some of these SNPs play a crucial role in a person's predisposition to disease or good health.

Using an approach known as whole genome association, the investigators scanned more than 300,000 SNPs in the genomes of 223 psoriasis patients, including 91 who had psoriatic arthritis. They compared the DNA variations in people with psoriasis to those found in 519 healthy control patients, looking for specific differences that may be linked to the disease. They then replicated their findings in a larger set of patients -- 577 with psoriasis and 576 with psoriatic arthritis -- and more than 1,200 healthy controls.

Bowcock and her team found seven novel DNA variations linked to psoriasis. Four other variations associated with the disease that had been identified previously by other researchers also were confirmed by the current study.

Whole genome association studies have recently been used to identify common genetic variations that increase the risk of diseases such as breast cancer, heart disease and type 2 diabetes. They typically involve more than 1,000 patients with a particular disease to help ensure that the genetic variations identified in the study do not occur by chance. While the current study included fewer patients, nearly half of them had a sibling and, in some cases, a parent with psoriasis, which increases the odds of finding genetic variations that contribute to the disease.

The researchers found the strongest genetic risk for psoriasis lies in a region of the genome that contains the major histocompatibility complex, a collection of genes involved in distinguishing the body's own cells from foreign invaders. "Although this region has been known to play a major role in psoriasis, DNA variations in the MHC alone have been known to not be enough to trigger disease," Bowcock says. "Only 10 percent of patients with variations in the major histocompatibility complex developed psoriasis. This tells us that other genetic or environmental factors also contribute to the disease."

One MHC variation linked to psoriasis and psoriatic arthritis occurs in the gene HCP5, the scientists noted. That variation was recently reported to delay the onset of AIDS in people infected with HIV. This is particularly interesting, Bowcock says, because psoriasis can be triggered by infection with HIV or other viruses. It may be that in people with this SNP variant, viral infection triggers a larger immune response that slows the development of AIDS but also leads to excessive inflammation in the skin and bone joints in genetically susceptible individuals, leading to the onset of psoriasis and psoriatic arthritis.

Notably, DNA variations on chromosome 4 were strongly linked to psoriatic arthritis. These same variations were also associated with psoriasis and had been previously linked to type 1 diabetes, rheumatoid arthritis, Grave's disease (caused by an overproductive thyroid gland) and celiac disease (caused by the inability to digest gluten). "Doctors have noticed that some psoriasis patients have autoimmune diseases such as celiac disease, Grave's disease, and type 1 diabetes," Bowcock says. "But we didn't know whether this was a coincidence. Now we know there is a genetic component underlying all of these diseases."

The same region of chromosome 4 contains genes that code for the signaling molecules IL2 and IL21. This opens the door to investigating whether existing drugs that block either molecule may be effective in some psoriasis patients, especially those with psoriatic arthritis.

The researchers also uncovered significant DNA variations on chromosome 13 in a genetic region involved in modifying proteins, and on chromosome 15, in a region responsible for producing a protein that activates TNF alpha (tumor necrosis factor-alpha) in a specialized immune cell known as a dendritic cell. While TNF alpha normally helps fight infections, it is thought to be a major player in psoriasis and psoriatic arthritis. Several FDA-approved psoriasis medications work by binding to TNF-alpha, thereby preventing it from communicating with cells.

Bowcock is now involved in a larger genome-wide association study of psoriasis patients and says she expects it will uncover additional genetic variations that are associated with psoriasis.

Eventually, she predicts, such studies will lead to more effective, better-targeted therapies.

"The goal of this study and other genome-association studies is to get to personalized medicine, where you can diagnose a disease and ask what genetic risk factors this person has that points to altered pathways," she says. "Then, we can target those pathways for specific therapeutic interventions."

Source: Washington University

Study reveals 2 genes linked to disabling arthritis
An international team of researchers led by a Fred Hutchinson Cancer Research Center geneticist has discovered two genes linked to a disabling form of arthritis called ankylosing spondylitis, a painful and progressive disease in which some or all of the spine’s vertebrae fuse together. The researchers also validated the association of two genes implicated in Graves’ disease, an autoimmune condition that causes overactivity of the thyroid gland.
Could arthritis wonder drugs provide clues for all disease?
Drugs that have helped treat millions of rheumatoid arthritis sufferers may hold the key to many more medical conditions, including atherosclerosis – a leading cause of heart disease – says the researcher who jointly invented and developed them.
Discovery of a new signaling mechanism may lead to novel anti-inflammatory therapy
A team of researchers at the University of California, San Diego School of Medicine has uncovered a new signaling mechanism used to activate protein kinases that are critical for the body's inflammatory response. Their work will be published in the July 18 online edition of Science (Science Express).
New research reveals ultraviolet light therapy is as beneficial for darker skin as lighter skin
An analysis of more than 100 patients has confirmed for the first time that darker-skinned patients benefit as those with lighter skin when given light therapy for morphea and related diseases, UT Southwestern Medical Center researchers show.
Complexity of Crohn's disease revealed as 'gene' count tops 30
New research has trebled the number of genetic regions known to be implicated in Crohn's disease, a form of inflammatory bowel disease, to over thirty. The research, published today in the journal Nature Genetics, has identified a number of potential new targets for drug development as well as providing surprising new links between the condition and other common diseases including asthma.
NIAMS scientists find potential new way to block inflammation in autoimmune disease
Researchers from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the National Institutes of Health (NIH), have identified a promising new target for autoimmune disease treatment – a cell-surface receptor called DR3. Their research in mice, published on line in the journal Immunity, suggests that blocking this receptor could slow or stop the damaging inflammation characteristic of autoimmune diseases, potentially without leaving the body vulnerable to serious infections, as many current therapies do.
Scientist study bacterial communities inside us to better understand health and disease
The number of bacteria living within the body of the average healthy adult human are estimated to outnumber human cells 10 to 1. Changes in these microbial communities may be responsible for digestive disorders, skin diseases, gum disease and even obesity. Despite their vital imporance in human health and disease, these communities residing within us remain largely unstudied and a concerted research effort needs to be made to better understand them, say researchers today at the 108th General Meeting of the American Society for Microbiology in Boston.
Inflammation, depression and antidepressant response: Common mechanisms
Major depressive disorder is a common and complex condition that impacts about 15% of the population of the United States, yet very little is known about the mechanisms behind the psychiatric disorder. What is known is that there are clinical parallels between depressive symptoms and the symptoms of certain inflammatory disorders.

Researchers uncover new genetic links to psoriasis

Related stories:

News discussion: