Five Susceptibility Genes and Counting
Past Arthritis Foundation grant recipient, Peter K. Gregersen, MD, of the Feinstein Institute for Medical Research in Manhasset, NY, has spent years of his professional life analyzing the human genome to figure out what makes certain people susceptible to rheumatoid arthritis (RA). Published online today (September 5, 2007) in the New England Journal of Medicine, Dr. Gregersen and a huge international team of investigators announced two genes that impart an increased risk of developing RA. Combined with three previously recognized susceptibility genes, these two newly identified genes give us five in total that Dr. Gregersen says have been validated by the data and are “quite certainly” linked to RA.
Prior to these articles being published in the New England Journal, Dr. Gregersen updated his peers on the genetic analysis of RA at the Arthritis Foundation Research Conference held in April and again at the Federation of Clinical Immunology Services’ meetings in June. He explained how the research team has conducted genome-wide scans to identify genetic variants that are associated with RA. Daniel Kastner, MD, PhD, of the Genetics and Genomic Branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and one of the team of scientists involved in this project, explained that new technologies have enabled genome-wide scans, which represent an “encyclopedic, global approach to the problem of identifying RA risk factors.”
The Advent of Microarray Technology
The use of single-nucleotide polymorphism (SNP; pronounced “snip”) assays has allowed genetic evaluations to be done in a fraction of the time that it used to take when Gregersen first started his quest. These technological advances have made for a virtual explosion of scientists’ ability to link genetic variants with disease susceptibility. Associations that used to take two years to identify in the laboratory now take just two days. The speed is what excites Dr. Gregersen. “We have the tools to get at these genes rather quickly now,” he said. “The more patients and controls that we have, the more power we will have to pull out new genes and make associations.”
Genome: The genome of an organism is its whole hereditary information and is encoded in the DNA.
Allele: One of the variant forms of a gene at a particular locus, or location, on a chromosome.
SNP: A single nucleotide polymorphism, or SNP (pronounced “snip”), is a DNA sequence variation occurring when a single nucleotide – A, T, C, or G – in the genome differs between individuals. For example, two sequenced DNA fragments from different individuals, AAGCCTA to AAGCTTA, contain a difference in a single nucleotide. In this case we say that there are two alleles: C and T.
SNP microarray: DNA segments known as probes are robotically affixed to a “chip.” Thousands of these segments can be placed in known locations on a single microarray. In the past, scientists have only been able to conduct genetic analyses on a few genes at once. With the development of microarray technology, however, scientists can now examine thousands of genes at any given time.
Over the last decade, Dr. Gregersen and colleagues involved in the North American Rheumatoid Arthritis Consortium (NARAC) have amassed a genetic database of more than 1,000 people with RA as well as their siblings and other family members. By using this database and that of the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study group in Sweden, these researchers now have access to more than 3,000 genetic samples for their investigations. Between this work and that of the Wellcome Trust, great strides have been made in uncovering genetic risk factors involved in the development of RA.
The Susceptibility Genes
The first, and most robustly associated, gene to be identified as a susceptibility gene lies in HLA region, and is known as the “shared epitope.” In 2004, Dr. Gregersen’s team determined that a gene called PTPN22 is also clearly linked to RA, nearly doubling a person’s risk of developing the disease. The third gene identified is called PADI4; it has been identified as a major risk factor in people of Asian descent, but as less of a risk factor in those of European descent. Today, Dr. Gregersen and team have announced two other genes important in RA and systemic lupus erythematosus – STAT4 and TRAF1-C5. Although common genes, researchers found that having certain variations of the genes increased disease risk.
Having two copies of the risk variant of STAT4 was associated with a more than doubled risk for lupus and a 60 percent increased risk for developing RA compared with people who carried no copy of the risk variant. TRAF1-C5 are actually two genes that lie very close together on chromosome 9. Exactly which gene at this location is the susceptibility gene has not yet been determined. What is known, however, is that people with a particular variant at this chromosome location had a 35 percent increased risk of developing RA compared to those without that variant.
What the Future Holds
Dr. Gregersen admits that knowing which genes are modestly involved in a complex disease like rheumatoid arthritis is not very useful from a practical point of view, but he guarantees that it is very important for giving insight into the disease’s pathogenesis. He explains that once all susceptibility genes are identified – which he predicts will involve at least 10 genes, and possibly many more – individuals could be screened for the presence of these genetic variants. Those with several of the identified alleles can be identified as being at high risk for developing the disease, and prophylactic measures could be taken or specific treatment options can be selected. For example, he believes that one day, these genetic findings will help identify which patients will receive relief from anti-TNF therapy and which patients should focus on another therapy, perhaps B-cell depletion.
Another research team from Leiden University Medical Center, the Karolinska Institute, and Celera released their results regarding the TRAF1-C5 gene and its link to rheumatoid arthritis. Their paper was published the week of September 17 on PLoS Medicine, and open-access, peer-reviewed medical journal.
Plenge RM, Seielstad M, Padyukov L, et al. TRAF1-C5 as a risk locus for rheumatoid arthritis -- a genomewide study. N Engl J Med 2007;357. Read the journal article.
Remmers EF, plenge RM, Lee AT, et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 2007;357:977-86.
Read an Arthritis Today article about how your environment and genes interact to affect your arthritis.