Double trouble

Variations in a single gene simultaneously increase the risk of two autoimmune conditions

Japanese researchers have identified two single nucleotide polymorphisms (SNPs), each of which significantly increases susceptibility to the autoimmune diseases rheumatoid arthritis (RA) and systemic lupus erythmatosus (SLE). They occur in a gene for a protein that regulates immune system cells. While the SNPs have so far only been detected in East Asians, understanding their role in promoting the onset of both autoimmune diseases could lead to better treatments for all, the researchers say.

RA is a painful condition where the body’s immune system attacks and degrades joints. The disease affects up to one person in a hundred, and both genetic and environmental factors can increase susceptibility to it. Other researchers have uncovered several genes with variants that increase the risk of RA. Some, presumably for compounds involved in the autoimmune process at a generic level, simultaneously increase the risk of other autoimmune conditions, such as SLE.

The current study, recently published in Nature Genetics (1), was led by researchers from RIKEN’s Center for Genomic Medicine in Yokohama. It focuses on a region of the long arm of human chromosome 1 which contains genes of the signaling lymphocyte activation molecule (SLAM) family. Proteins of the SLAM family are involved in regulating cells of the immune system, so there is a potential link with autoimmune conditions. The chromosome region had already been linked with increased risk of RA and SLE in previous studies.

In two independent Japanese populations—one of 830 arthritis sufferers and 658 controls, the other of 1,112 arthritis sufferers and 940 controls—the researchers identified five SNPs closely associated with RA in the SLAM family gene, CD244. The researchers showed that these SNPs also increase susceptibility to SLE.

All the SNPs occurred in the gene’s introns—segments of the DNA sequence that are chopped out before the final protein is synthesized. It has recently been suggested that introns may well play a role in regulating gene activity. So the researchers assayed the SNPs for their impact on the rate of transcription of CD244, and determined that two of five led to significant increases in gene activity.

As CD244 is known to encode a protein which activates or inhibits the natural killer cells of the immune system, the researchers say they are not surprised that its SNPs are associated with susceptibility to autoimmune diseases. “But we don’t yet know the precise molecular mechanisms involved,” says project leader, Kazuhiko Yamamoto.

Reference

1. Suzuki, A., Yamada, R., Kochi, Y., Sawada, T., Okada, Y., Matsuda, K., Kamatani, Y., Mori, M., Shimane, K., Hirabayashi, Y., et al. Functional SNPs in CD244 increase the risk of rheumatoid arthritis in a Japanese population. Nature Genetics 40, 1224–1229 (2008).

The corresponding author for this highlight is based at the RIKEN Laboratory for Autoimmune Diseases