Gene hunters have discovered a new variant of a gene on chromosome 9 that is associated with increased risk of anticyclic citrullinated peptide (CCP)-positive rheumatoid arthritis (RA) and a new variant of the STAT4 gene locus on chromosome 2q that dramatically increases the risk for both RA and systemic lupus erythematosus (SLE).^1,2  Peter K. Gregersen, MD, head of the Feinstein Institute's Robert S. Boas Center for Genomics & Human Genetics, in Manhasset, New York, led the research groups that conducted both studies.

"There has been a huge amount of optimism about what genetics can bring, but everyone working on complex diseases underestimated the size of the problem, which is why it has taken a decade to identify genes related to these problems," Dr. Gregersen said during a teleconference. He predicted that in addition to the five genes known to be associated with RA an additional three to five high-risk genes will be discovered in the near future. "We are talking about gene variants that are fairly common in the population, present in 5% or more of the population," he said.

TRAF1-C5 increases RA risk by 30%

The genomewide study involved genotyping 317,503 single-nucleotide polymorphisms (SNPs) in a combined case-control study of 1522 case subjects with RA and 1850 matched controls. All patients were seropositive for autoantibodies against CCP. Lead author Robert M. Plenge, MD, PhD, with the Broad Institute of Harvard and the Massachusetts Institute of Technology (MIT), both in Cambridge, reports that

• the 100-kb region on chromosome 9 is associated with a 30% increase in risk of anti-CCP-positive RA
• the region contains the locus for TRAF1 (which encodes TNF receptor-associated factor 1)
• the region also contains the locus for C5 (which encodes TNF receptor-associated factor 1)
• the region also contains the locus for C5 (which encodes complement component 5)

In an accompanying editorial, Kazuhiko Yamamoto, MD, PhD, and Ryo Yamada, MD, PhD, write, "The scale of genomewide association studies continues to grow, and the number of markers used in such studies will soon approximate or exceed a million. It is not unrealistic to expect that the entire genome of all samples will be sequenced in the not-to-distant future."³ They predict that "we will have a catalogue of genes with variants for susceptibility to rheumatoid arthritis with various degrees of risk within several years."

STAT4 links RA and lupus risks

Meanwhile, lead author Elaine F. Remmers, PhD, from National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), in Bethesda, Maryland, reports that homozygosity for the STAT4 variant is associated with a more than doubled risk for lupus and with a 60% increased risk for RA.

This study involved testing SNPs in 13 candidate genes within the chromosome 2q region (which had already been identified as associated with RA) in 1620 patients with established RA and 2635 controls. Those identified in this first-level screening were then tested in an independent case-control series of 1529 patients with early RA and 881 controls.

Dr. Remmers writes, "We have shown that a variant allele of STAT4 confers an increased risk for both rheumatoid arthritis and systemic lupus erythematosus. This finding provides support for the evolving concept that common risk genes underlie multiple autoimmune disorders and suggests the involvement of common pathways of pathogenesis among these different diseases."

Stephen I. Katz, MD, PhD, director of NIAMS, commented, "This work required the collection and genotyping of thousands of RA and lupus cases and controls, a task that would have been difficult to accomplish without the strong partnerships we forged."

The research team included scientists from MIT; Brigham and Women's Hospital, in Boston; Biogen Idec; Genentech, Inc; NIAMS; the Broad Institute of Harvard; and the Genome Institute of Singapore. Other research institutions included Hanyang University College of Medicine in Seoul, South Korea; the Karolinska Institute in Stockholm, Sweden; the University of California at Davis, the University of California at San Francisco; and the University of Texas M. D. Anderson Cancer Center, in Houston.

References

1. 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. doi 10.1056/NEJMoa073491. [Epub ahead of print]
2. 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;977-986.
3. Yamamoto K, Yamada R. Lessons from a genomewide association study of rheumatoid arthritis (editorial). N Engl J Med. 2007;357. doi 10.1056/NEJMe078174. [Epub ahead of print]