Significant Breakthrough in Ankylosing Spondylitis Genome-wide Research

Science Daily report on recent and ground-breaking research announced in a letter to Nature Genetics by Drs. John D. Reveille and Matthew A. Brown et al that has identified two genes that are now believed to play a significant role in ankylosing spondylitis. AS is an inflammatory condition of the spine and joints, one that over the past 35 years has become extremely familiar to this blogger. Thus far, only the abstract of the authors’ letter to Nature is freely accessible, and it reads thus:

To identify susceptibility loci for ankylosing spondylitis, we undertook a genome-wide association study in 2,053 unrelated ankylosing spondylitis cases among people of European descent and 5,140 ethnically matched controls, with replication in an independent cohort of 898 ankylosing spondylitis cases and 1,518 controls.

Cases were genotyped with Illumina HumHap370 genotyping chips. In addition to strong association with the major histocompatibility complex (MHC; P < 10−800), we found association with SNPs in two gene deserts at 2p15 (rs10865331; combined P = 1.9 × 10−19) and 21q22 (rs2242944; P = 8.3 × 10−20), as well as in the genes ANTXR2 (rs4333130; P = 9.3 × 10−8) and IL1R2 (rs2310173; P = 4.8 × 10−7).

We also replicated previously reported associations at IL23R (rs11209026; P = 9.1 × 10−14) and ERAP1 (rs27434; P = 5.3 × 10−12). This study reports four genetic loci associated with ankylosing spondylitis risk and identifies a major role for the interleukin (IL)-23 and IL-1 cytokine pathways in disease susceptibility.

I’m not sure to what degree this technical data will be comprehensible to the lay AS patient, (and the revelation so by way of clarification, I’ll refer back to the Science Daily article, from which the following is excerpted:

The findings, a critical milestone in the understanding of AS, are published in the January issue of Nature Genetics, a journal that emphasizes research on the genetic basis for common and complex diseases. “This helps us better understand what is driving this disease and gives us direction for new treatments and diagnostic tests,” said John D. Reveille, M.D., the study’s principal investigator and professor and director of the Division of Rheumatology and Clinical Immunogenetics at The University of Texas Medical School at Houston.

Reveille, the university’s Linda and Ronny Finger Foundation Distinguished Chair in Neuroimmunologic Disorders, and Matthew A. Brown, M.D., professor of immunogenetics at Australia’s University of Queensland, led the research by the Triple “A” Spondylitis Consortium Genetic Study (i.e. the TASC or Australo-Anglo-American Spondylitis Consortium). Based on work from a genome-wide association scan, the team identified genes ANTXR2 and IL1R2 as well as two gene deserts, segments of DNA between genes on chromosomes 2 and 21 that are associated with ankylosing spondylitis. Importantly, the study also confirmed the Triple “A” Australo-Anglo-American Spondylitis Consortium’s previously reported associations of genes IL23R and ERAP1, formerly known as ARTS1.

The research doesn’t detail exactly what new treatments might one day become available, but there is comfort to be derived from the fact that research such as this will in the short term enable rheumatologists to more quickly identify AS in patients, thus affording those patients the opportunity of obtaining suitable anti-inflammatory medications sooner rather than later. This addresses a problem that has affected many, in that AS isn’t always easy to diagnose in its primary stages or at onset, with the consequence that there can often be a delay of several years  in prescribing effective medicines, although we’ve come a long way since the days when AS patients were routinely encased in plaster for weeks on end in a misguided bid to limit mobility and ease the pain.

For the more technically adept patient, there is another paper, freely accessible and published in 2001 at PubMed, namely Whole-Genome Screening in Ankylosing Spondylitis: Evidence of Non-MHC Genetic-Susceptibility Loci, for which this is the abstract:

Ankylosing spondylitis (AS) is a common inflammatory arthritis predominantly affecting the axial skeleton. Susceptibility to the disease is thought to be oligogenic. To identify the genes involved, we have performed a genomewide scan in 185 families containing 255 affected sibling pairs. Two-point and multipoint nonparametric linkage analysis was performed. Regions were identified showing “suggestive” or stronger linkage with the disease on chromosomes 1p, 2q, 6p, 9q, 10q, 16q, and 19q. The MHC locus was identified as encoding the greatest component of susceptibility, with an overall LOD score of 15.6. The strongest non-MHC linkage lies on chromosome 16q (overall LOD score 4.7). These results strongly support the presence of non-MHC genetic-susceptibility factors in AS and point to their likely locations.

Here’s a final word from Science Daily, referring to the first paper mentioned above:

Laurie Savage, co-principal investigator and executive director of the Spondylitis Association of America (SAA) said, “These new breakthroughs are, indeed, good news for those whom we serve. It is very encouraging to know that the health impact and economic consequences of spondyloarthritis in the world eventually will be contained as a direct consequence of the dedication of Drs. Reveille, Brown and colleagues, and that of the many individuals affected by spondyloarthritis who have participated in these studies.”

The study was supported in part by two grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Other study contributors from the UT Health Science Center at Houston are research associates Laura Diekman and Rui Jin and Xiaodong Zhou, M.D., associate professor of medicine.

If the aspirations of the researchers are indeed realised, there are sure to be many thousands of suitably relieved people in the future, who will doubtless be most grateful for the efforts made by the teams and their volunteers.

Anthrax toxin receptor 2 (ANTXR2)

Interleukin 1 receptor, type II (IL1R2)

image from Ankylosing Spondylitis Association of Ireland


Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci by John Reveille and Matthew Brown et al, Nature Genetics Published online: 10 January 2010 | doi:10.1038/ng.513

Whole-Genome Screening in Ankylosing Spondylitis: Evidence of Non-MHC Genetic-Susceptibility Loci by S. H. Laval, A. Timms, S. Edwards, L. Bradbury, S. Brophy, A. Milicic, L. Rubin, K. A. Siminovitch, D. E. Weeks, A. Calin, B. P. Wordsworth and M. A. Brown, Am J Hum Genet. 2001 April; 68(4): 918–926. Published online 2001 February 27

9 thoughts on “Significant Breakthrough in Ankylosing Spondylitis Genome-wide Research

  1. I have spondylitis and psoriatic arthritis. Does any of your research indicate that Enbrel will be efficacious in helping to prevent the profression of spondylitis?

    Thank you for your kind consideration.
    Robynne Limoges

  2. Robynne – according to their own website, taking Enbrel can be quite harmful to the patient:

    “ENBREL is a medicine that affects your immune system. ENBREL can lower the ability of your immune system to fight infections. Serious infections have happened in patients taking ENBREL. These infections include tuberculosis (TB) and infections caused by viruses, fungi, or bacteria that have spread throughout the body. Some patients have died from these infections. Your doctor should test you for TB before you take ENBREL and monitor you closely for TB before, during, and after ENBREL treatment, even if you have tested negative for TB.

    There have been some cases of unusual cancers reported in children and teenage patients who started using TNF blockers before 18 years of age. Also, for children, teenagers, and adults taking TNF blockers, including ENBREL, the chances of getting lymphoma or other cancers may increase. Patients with RA and psoriasis may be more likely to get lymphoma. ”

    My comment would be that as with all cases of changing or starting a new medication, it’s always best to consult your medical practitioner first – and read up on published material where possible.

  3. I am patient of AS for the last 10 years and eager in knowing new drungs/research about this disease.

  4. sir iam a patient of as i am from india plz tell me about new study of treatment of as. thanx

  5. It sounds like Stelara which blocks il-23 could be effective against AS considering the above finding.

  6. Last year in 2011 i came to know i am patient of AS.having HLA20 +ve. can you please help me on same.

  7. i was diagnosed with AS in december 2011 an mri revealed a tumour attached to a rib in my back,after removal of the rib and tumour my AS went into total remission.My consultant is now carrying out a study and publishing a paper .I am hoping this will be of help to other sufferers.

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