SHANGHAI, China—Family genetic linkage studies, candidate gene analysis, and whole genome scans have helped researchers identify several gene polymorphisms associated with a high risk for systemic lupus erythematosus (SLE). This work will help researchers put these genes into context, Marta E. AlarcÏŒn-Riquelme, MD, PhD, will report at the 8th International Congress on SLE.1

"The step towards understanding how these genes, in combination with environmental factors, lead to the disease will be a much more difficult one."—Marta E. AlarcÏŒn-Riquelme, MD, PhD.
"In the coming years we will have identified the genes for SLE. The step towards understanding how these genes, in combination with environmental factors, lead to the disease will be a much more difficult one," says Dr. AlarcÏŒn-Riquelme, with the department of genetics and pathology at Uppsala University, in Sweden.

Dr. AlarcÏŒn-Riquelme's group has been using microsatellite markers to find regions of genetic linkage in families where at least two individuals have SLE. This study led to the discovery that PDCD1 is a susceptibility gene for SLE. PDCD1 encodes the PD-1 protein, which has two ligands, either of which inhibits T-cell activation. "Thus PD-1 is expressed during T- or B-cell activation and is thought then to control peripheral tolerance in a way similar to CTLA-4," Dr. AlarcÏŒn-Riquelme says.

Other researchers have been using candidate gene analysis, which identified the IRF5 gene from the type I interferon system as SLE-associated. Thus far, four suspect polymorphisms have been identified: rs2004640, rs2280714, rs20954213, and an insertion-deletion in the sixth exon of the IRF5 gene.

"In addition, new single nucleotide polymorphisms [SNPs] have been found that break the risk haplotype of IRF5, leading to a more precise haplotype with 15% frequency in Europeans. At present we are studying the frequency of the haplotype in other populations, including the Mexican and Chinese," Dr. AlarcÏŒn-Riquelme adds.

Whole genome scans with SNPs have confirmed the association between SLE and the major histocompatibility complex region in Swedes, but Dr. AlarcÏŒn-Riquelme warns that this study approach is more hypothetical than definitive. "The high rate of false positives in these types of studies leads to the need for replication of the genetic signals in order to select further work with a gene without ambiguity. We are at present replicating such signals in sets of individuals from other European populations," she concludes.

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Reference

1. AlarcÏŒn-Riquelme ME. The genetics of SLE: an update. Presented at: 8th International Congress on SLE; May 24, 2007; Shanghai, China.