Risk of Psoriasis for Same Genetic Diseases

Risk of Psoriasis for Same Genetic Diseases

Psoriasis, an autoimmune disease, causes the skin to become thicker because the growth of skin cells is out of control. In psoriasis, immune cells, which usually protect against infection, instead trigger the release of cytokines, which causes inflammation and the overproduction of skin cells. Other autoimmune diseases with similar side effects include lupus, which can lead to skin lesions, and dandruff.

All diseases are complex, the result of different genes and environmental risk factors acting together in concert. But if NALP1 turns out to be one of the major genes involved in numerous autoimmune diseases, and if we can interrupt its negative effects, we may have the chance to treat many different chronic autoimmune disorders like vitiligo, lupus and psoriasis and perhaps eventually eliminate them altogether.

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.

While the exact cause of psoriasis is unknown, the disease is considered a chronic immune disorder in which certain immune cells become overactive and release proteins called cytokines and chemokines. Tumor necrosis factor (TNF) is a cytokine involved in the body's normal immune response to infection. In patients with psoriasis, TNF is overproduced, which causes inflammation that also drives the formation of often painful and potentially disfiguring skin plaques.

Due to genetic factors, certain people are more likely to develop psoriasis, but a "trigger" is usually associated with onset and recurrence. These triggers may include emotional stress, some types of infection, or reaction to certain drugs.

Researchers hunt for genetic clues to a range of diseases including psoriasis, schizophrenia, Crohn's disease, rheumatoid arthritis, Alzheimer's disease, hyperactivity attention deficit disorder and coronary heart disease. A mutation in a person's genetic code produces a susceptibility to a disease. The hope is that once those genetic triggers have been identified, drug treatments can be developed to target them.

The gene's causative role in psoriasis was demonstrated in a University of Michigan Medical School study of 2,723 people from 678 families in which at least one family member had the disease. Unlike diseases caused by a mutation in just one gene, psoriasis is what scientists call a multi-factorial disease. This means that people must inherit several disease-related genes, plus be exposed to one or more environmental triggers, in order to get psoriasis.

In a paper to be published in the Journal of Investigative Dermatology, Dr. Helen S. Young and colleagues at the University of Manchester, in Manchester, UK, provide the first evidence that there are alterations in a gene involving the development of the vascular system that may contribute to psoriasis susceptibility. It has been previously observed that aspects of the vascular system, or blood vessel network in the skin, are altered in psoriasis. An essential regulator of vascular development produced by skin cells, called VEGF or Vascular Endothelial Growth Factor, is found in high levels in psoriatic skin lesions. VEGF acts as a modifier gene in psoriasis and that therapeutic blockade of the VEGF/VEGF receptor system might represent a novel, pharmacogenomic approach for the future treatment of psoriasis.

An international team of researchers led by a Fred Hutchinson Cancer Research Center geneticist also has linked IL23R with inflammatory-bowel disease (Crohn's disease) and psoriasis. "Clinically these diseases tend to occur together -- people with inflammatory-bowel disease also tend to have a higher probability of having ankylosing spondylitis and psoriasis. The IL23R gene provides a genetic link that sheds new light on their co-occurrence," said Cardon, a member of the Hutchinson Center's Human Biology Division.

Now, dermatologists are finding that psoriasis, especially severe psoriasis, is linked with a number of serious medical conditions – including cardiovascular disease, depression and cancer; published online in Mar. 25, 2008 in the Journal of the American Academy of Dermatology, dermatologist Alexa B. Kimball, MD, MPH, FAAD, associate professor of dermatology at Harvard Medical School in Boston. They found that people with more severe cases of psoriasis appear to have an increased incidence of psoriatic arthritis, cardiovascular disease, hypertension, diabetes, cancer, depression, obesity and even other immune-related conditions such as Crohn’s disease

As well as these physical effects, it can also have a significant, life-ruining impact on a patient's quality of life.1 In a National Psoriasis Foundation (US) survey, people with psoriasis reported that living with the disease might be worse than many other chronic conditions such as coronary heart disease or chronic obstructive pulmonary disease (COPD); the only condition that they deemed worse was depression.

Most recent theory:

Recently In the first comprehensive study of the genetic basis of psoriasis, researchers at Washington University School of Medicine in St. Louis have discovered seven new sites of common DNA variation that increase the risk of the troublesome skin condition. They also found that variations in one genetic region link psoriasis and a related joint disorder, psoriatic arthritis, to four autoimmune diseases: type 1 diabetes, Grave's disease, celiac disease and rheumatoid arthritis.

"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.

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."













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