Spotlight on Research 2010

May 2010 (historical)

NIAMS Scientists Identify New Genetic Loci for Ankylosing Spondylitis

Scientists from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and others supported by NIAMS have identified four places, or loci, on the human genome that are associated with ankylosing spondylitis (AS), a form of arthritis that causes inflammation and pain in the spine. The research, the first genome-wide association study for AS, showed two genes and two non-gene regions newly associated with increased risk for the disease. Interestingly, the loci are not located near other AS-susceptibility genes within the major histocompatibility complex (MHC), a section of the genome containing a high number of immune-related genes. The study appeared in the February issue of the journal Nature Genetics.

AS affects men three times more frequently than women and symptoms generally appear between the ages of 20 and 40. It is characterized by inflammatory arthritis, pain, and stiffness in the spine and pelvic joints. Some people with AS have arthritis in other joints and may have inflammation in the eye and other organs, such as the heart, lungs or kidneys. As the disease progresses, overgrowth of bone in the spine can result in fusion of vertebrae, occasionally resulting in the appearance of "bamboo spine" on imaging films and a characteristic curvature of the spine that causes a person with AS to stoop.

In the 1970s, scientists identified a gene, called human leukocyte antigen (HLA)-B27, that has a high association with AS. Approximately 80 percent of people with AS have the HLA-B27 gene marker. However, only one to five percent of people who have HLA-B27 develop AS. This means that there must be other factors contributing to the disease. Many scientists believe that other genes or genetic factors influence the development and progression of the disease. In addition to HLA-B27, which is found within the MHC section of the genome, scientists have found AS associations with other genes within the MHC, including the gene for tumor necrosis factor alpha (TNFα), and with several regions outside of the MHC, including areas within the IL23R gene at chromosome 1p23 and the ERAP1 gene (previously known as ARTS-1) at chromosome 5p15.

Since the completion of the Human Genome Project in 2003, scientists have been able to do large genetic studies that provide insight into gene-based diseases. One of the tools used to investigate these diseases is the genome-wide association study (GWAS), which looks for genetic variations across the whole human genome. By looking at all of the genes in a large number of people with a disease and then comparing them to the genes in people without the disease, scientists can pick out places in the genome where these two groups differ. The assumption is that these differences point out genes that might have something to do with the disease.

The current study was performed by the Australo-Anglo-American Spondyloarthritis Consortium (TASC), which included researchers from the United Kingdom, Australia, and North America. The TASC scientists looked at the genomes of more than 2,000 AS patients from North America, United Kingdom, and Australia and compared them to the genomes of more than 5,000 healthy people from North America and United Kingdom. Both groups of people were of European descent. The investigators limited their search to people of European descent in order to decrease the amount of genetic variability in the two groups. In other words, the more similar the people are, the more likely it is that any differences seen among them are directly linked to the disease.

Also, many AS patients are of European descent. In this first analysis, the researchers found a number of places in the genome where the two groups differed. In order to validate these findings, they did a second analysis in a new cohort of people from Britain, consisting of 898 patients with AS and 1,518 people without AS. The researchers concentrated their investigation on genome regions that demonstrated a high probability of association with AS in the first analysis.

As expected, they found a strong association with the MHC. They also confirmed an association with two genes already shown to be linked to AS — IL23R and ERAP1. In addition to these established findings, the researchers identified two new regions on chromosomes 2p15 and 21q22 and two new genes — ANTXR2 and IL1R2 — associated with AS. The identification of four new genetic loci associated with AS will contribute to the understanding of the genetic underpinnings of the disease. Further GWAS research with more subjects may be useful and may identify more genes associated with the disease.

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Servicesí National Institutes of Health (NIH), is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at 301-495-4484 or 877-22-NIAMS (free call) or visit the NIAMS Web site at


Australo-Anglo-American Spondyloarthritis Consortium (TASC), Reveille JD, Sims AM, Danoy P, Evans DM, Leo P, Pointon JJ, Jin R, Zhou X, Bradbury LA, Appleton LH, Davis JC, Diekman L, Doan T, Dowling A, Duan R, Duncan EL, Farrar C, Hadler J, Harvey D, Karaderi T, Mogg R, Pomeroy E, Pryce K, Taylor J, Savage L, Deloukas P, Kumanduri V, Peltonen L, Ring SM, Whittaker P, Glazov E, Thomas GP, Maksymowych WP, Inman RD, Ward MM, Stone MA, Weisman MH, Wordsworth BP, Brown MA.Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet. 2010 Feb;42(2):123-7.