Progress in ankylosing spondylitis (an extraintestinal manifestation of IBD)

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Genomics Yields Ankylosing Spondylitis Gene Variants

By Neil Osterweil, Senior Associate Editor, MedPage Today

Reviewed by Zalman S. Agus, MD; Emeritus Professor at the University

of Pennsylvania School of Medicine.

October 22, 2007

OXFORD, England, Oct. 22 -- Two gene variants strongly associated

with ankylosing spondylitis have emerged from a search of the DNA of

2,500 patients and others, an international team has found.

Action Points

Explain to patients that this study has found strong associations,

but not causality, between specific genetic variants and risk for the

disabling rheumatologic disorder ankylosing spondylitis. The

discovery, made possible by brute processing power, brings to three

the total number of genes associated with ankylosing spondylitis, and

possession of all three increases the risk for the condition to about

one-in-four, reported Lon R. Cardon, Ph.D., of the Wellcome Trust

Center for Human Genetics at the University of Oxford, and

colleagues. Their genome-wide scan of ankylosing spondylitis patients

and healthy controls also confirmed earlier findings of an

association between two other genes and autoimmune thyroid disease,

the investigators wrote online in Nature Genetics.

" We've long known that the HLA-B27 gene accounts for 40% of the

overall cause of ankylosing spondylitis, " said co-author D.

Reveille, M.D., of the University of Texas Medical School at

Houston. " Now we have found two new genes. Together with HLA-B27,

these genes account for roughly 70% of the overall cause. That means

we've almost nailed this disease. "

Dr. Reveille predicted that all of the genes associated with the

disabling rheumatic condition will be identified within the next

year, pointing the way to potential new therapies or preventive

measures.

One of the genes, IL23R, is also associated with Crohn's disease and

with psoriasis, two autoimmune conditions that are frequently co-

morbid with ankylosing spondylitis.

As part of a larger sweep of the human genome, the investigators

conducted a comprehensive scan looking for single-nucleotide

polymorphisms in various genes from patients with ankylosing

spondylitis, autoimmune thyroid disease, multiple sclerosis, and

breast cancer.

They found that the three autoimmune conditions, but not breast

cancer, were significantly associated (P10-20) with single-nucleotide

polymorphisms in the region of the genome associated with the major

histocompatibility complex.

" For each of the autoimmune diseases, the maximum signal was centered

around the known HLA-associated genes (for example, those encoding

HLA-B in ankylosing spondylitis, HLA-DRB1 in MS, and the major

histocompatibility class I and class II molecules in autoimmune

thyroid disease), " they wrote.

When the team genotyped patients with ankylosing spondylitis and

healthy controls, they found that two genes ARTS1, a tumor suppressor

gene, and IL23R, a gene encoding for the interleukin-23 regulator

(receptor).

" We already know that IL23R is involved in inflammation, but no one

had ever thought it was involved in ankylosing spondylitis, " said co-

author Brown, Ph.D., of Oxford. " A treatment for Crohn's

disease that inhibits the activity of this gene is already undergoing

human trials. This looks very promising as a potential treatment for

ankylosing spondylitis. "

Although how the interplay of genes may lead to ankylosing

spondylitis is not known, ARTS1 may alter the presentation of

antigens to the cell surface by HLA class-1 molecules, the authors

suggested. Additionally, because the protein cleaves cell surface

receptors of pro-inflammatory cytokines, " genetic variants that alter

the functioning of ARTS1 could therefore have pro-inflammatory

effects through this mechanism, " they wrote.

The authors also confirmed previous findings of associations between

two other genes, TSHR and FCRL3 with autoimmune thyroid disease. They

noted that the techniques they used may have caused them to miss

other associations between coding regions or specific chromosomal

locations and diseases.

The study was supported by the Arthritis Research Campaign (U.K.).

National Health and Medical Research Council, National Institute of

Arthritis and Musculoskeletal and Skin Diseases, University of Texas

at Houston, Cedars-Sinai, The lind Center for Arthritis

Research at The University of California San Francisco, United States

Army Medical Research and Material Command, The Institute of Cancer

Research and Cancer Research UK, Wellcome Trust, Medical Research

Council (U.K.), and the Multiple Sclerosis Society of Great Britain

and Northern Ireland.

Author conflicts of interest were not listed.

Primary source: Nature Genetics

Source reference: Cardon L et al. " Association scan of 14,500

nonsynonymous SNPs in four diseases identifies autoimmunity

variants, " Nature Genetics 2007; doi:10.1038/ng.2007.17.

Find this article at:

http://www.medpagetoday.com/Rheumatology/GeneralRheumatology/tb/7055

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Major genetic breakthrough for ankylosing spondylitis brings

treatment hope

http://www.sanger.ac.uk/Info/Press/2007/071021.shtml

Press Releases: 21st October 2007

Research funded by the Wellcome Trust and the Arthritis Research

Campaign has identified two genes implicated in the disease

ankylosing spondylitis, a common disease primarily causing back pain

and progressive stiffness. The research, published online today in

Nature Genetics, suggests that a treatment currently being trialled

for Crohn's disease may also be applied to this disease.

Ankylosing spondylitis affects as many as 1 in 200 men and 1 in 500

women in the UK, typically striking people in their late teens and

twenties. Whilst it mainly affects the spine, it can also affect

other joints, tendons and ligaments. More rarely, it can affect other

areas, such as the eyes, lungs, bowel and heart1. High-profile

sufferers of the condition include former England cricket captain

Mike Atherton.

Now, using a technique known as genome-wide association scanning,

researchers led by Professors Lon Cardon, Brown and

Wordsworth, from the Wellcome Trust Centre for Human Genetics at the

University of Oxford, and Dr Panos Deloukas from the Wellcome Trust

Sanger Institute, Cambridge, have analysed DNA samples from 1,000

patients with ankylosing spondylitis and a further 1,500 people

unaffected by the disease in search of genetic mutations which, if

present, increase a person's risk of developing the disease. The

findings from this study were then confirmed by a team at University

of Texas (Houston) led by Professor Reveille.

" Ankylosing spondylitis is a painful and often very disabling

disease, " says Professor Brown. " Yet, our understanding of the causes

of the disease, and hence our ability to treat it effectively, is

relatively poor. "

The researchers have identified two genes, ARTS1 and IL23R, which

increase the risk of developing the disease. Together with the

genetic variant HLA-B27, this takes the number of genes definitely

known to be involved in the disease to three. A person carrying all

three variants would be expected to have a one in four chance of

developing the disease.

" The two genes discovered to be associated with ankylosing

spondylitis provide striking insights into the mechanisms of the

disease " ... Dr Mark Walport

The IL23R gene plays a role in the immune response to infection,

providing instructions for making a receptor present on the surface

of several types of immune system cells. The receptor is involved in

triggering certain chemical signals inside the cell that promote

inflammation and help coordinate the immune system's response to

infection. It is already recognised as playing a role in a number of

autoimmune diseases, such as Crohn's disease (a type of inflammatory

bowel disease) and psoriasis (a skin disease). Ankylosing

spondylitis, Crohn's disease and psoriasis are known to often occur

together, and this genetic finding goes a long way to explain why.

Professor Brown believes that the unexpected involvement of IL23R in

ankylosing spondylitis provides a major step towards being able to

treat the disease. " We already know that IL23R is involved in

inflammation, but no one had ever thought it was involved in

ankylosing spondylitis, " says Professor Brown. " A treatment for

Crohn's disease that inhibits the activity of this gene is already

undergoing human trials. This looks very promising as a potential

treatment for ankylosing spondylitis. "

Scientists have known that there is a genetic component to ankylosing

spondylitis for 37 years, since the discovery of the gene HLA-B27.

However, how this gene led to disease is not known. Professor Brown

believes that the gene ARTS1 may hold the answer.

A protein created by the HLA-B27 gene takes fragments of pathogens

and displays them on the outside of immune cells. These fragments

then trigger the immune system to fight against the pathogen. ARTS1

is involved in breaking up the pathogen into " bite-size chunks " that

can be displayed by HLA-B27.

" This strongly suggests that in ankylosing spondylitis, there are

problems with the information that the HLA-B27 protein receives,

thereby causing the disease, " says Professor Brown.

Scientists believe that ankylosing spondylitis may be triggered in

genetically-susceptible people by bacteria commonly found in the gut.

Why this should be the case is unclear, but it is hoped that the new

genetic discoveries will help answer this question.

" These findings are very exciting and show the value of exploring the

genetics of disease, " says Dr Mark Walport, Director of the Wellcome

Trust. " It usually takes many years between genetic discoveries and

new treatments for disease. In this case the two genes discovered to

be associated with ankylosing spondylitis provide striking insights

into the mechanisms of the disease and offer a possible new pathway

for treatment. "

The study is a collaboration between the Wellcome Trust Case Control

Consortium and the Australo-Anglo-American Spondylitis Consortium

funded by the National Institute of Arthritis and Musculoskeletal and

Skin Diseases.

" These genetic studies involve large patient samples and require

expertise over a wide range of scientific specialities " , says

Professor Cardon. " Bringing together these two consortia was the

final key that enabled these exciting discoveries. "

Recruitment and collection of samples of patients with ankylosing

spondylitis was assisted by the National Ankylosing Spondylitis

Society.

Notes to Editors

Statistics according to National Ankylosing Spondylitis Society.

http://www.nass.co.uk/

Wellcome Trust Case Control Consortium

Wellcome Trust Case Control Consortium. Association scan of 14,500

nonsynonymous SNPs in four diseases identifies autoimmunity variants;

Nature Genetics, published in advance online 21 October 2007

Funding For The Wellcome Trust Case Control Consortium

The Wellcome Trust Case Control Consortium was supported by: the

Medical Research Council, the British Heart Foundation, the Juvenile

Diabetes Research Foundation, Diabetes UK, the Arthritis Research

Campaign, the National Association for Colitis and Crohn's Disease

and MDF The Bipolar Organisation. http://www.wtccc.org.uk/

Arthritis Research Campaign

The Arthritis Research Campaign is the fourth largest medical

research charity in the UK, raising more than £30m in 2006/7 entirely

from public donations. It currently funds more than 350 research

projects into all types of arthritis and musculoskeletal conditions

in medical schools and hospitals around the UK, and also has an

extensive educational remit. http://www.arc.org.uk/

Websites

National Ankylosing Spondylitis Society - http://www.nass.co.uk/

Wellcome Trust Case Control Consortium - http://www.wtccc.org.uk/

Arthritis Research Campaign - http://www.arc.org.uk/

Wellcome Trust Centre for Human Genetics - http://www.well.ox.ac.uk/

Sequencing Information

The Wellcome Trust Sanger Institute, which receives the majority of

its funding from the Wellcome Trust, was founded in 1992 as the focus

for UK sequencing efforts. The Institute is responsible for the

completion of the sequence of approximately one-third of the human

genome as well as genomes of model organisms such as mouse and

zebrafish, and more than 90 pathogen genomes. In October 2005, new

funding was awarded by the Wellcome Trust to enable the Institute to

build on its world-class scientific achievements and exploit the

wealth of genome data now available to answer important questions

about health and disease. These programmes are built around a Faculty

of more than 30 senior researchers. The Wellcome Trust Sanger

Institute is based in Hinxton, Cambridge, UK.

Websites

http://www.sanger.ac.uk

The Wellcome Trust

The Wellcome Trust is the largest independent charity in the UK and

the second largest medical research charity in the world. It funds

innovative biomedical research, in the UK and internationally,

spending around £500 million each year to support the brightest

scientists with the best ideas. The Wellcome Trust supports public

debate about biomedical research and its impact on health and

wellbeing.

Websites

http://www.wellcome.ac.uk

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Dave R.