Gene Interaction Suggests Novel Pathway for B-Cell Signaling in Systemic Lupus Erythematosus

Jacquelyn K. Beals, PhD

November 10, 2009

November 10, 2009 (Honolulu, Hawaii) — An international research team seeking genes that affect susceptibility to systemic lupus erythematosus (SLE) through interactions with BANK1 has identified 2 protein–protein interactions that might represent a previously unknown B-cell signaling pathway. The pathway might be regulated by type I interferon (IFN)-α and is likely to influence B-cell response to autoantigens in SLE.

The BANK1 gene encodes a B-cell scaffold protein with ankyrin repeats — repeating sequences of 33 amino acids that fold into structures involved in molecular recognition through protein–protein interactions. The association of a BANK1 variant with SLE was first demonstrated in 2008 in a Swedish genome-wide association study (GWAS). This association was validated in 3 independent European datasets and replicated in European-American and Chinese populations.

The goal of the new study, presented here at the American Society of Human Genetics (ASHG) 59th Annual Meeting by Angélica Maria A. Delgado-Vega, MD, MSc, Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Sweden, was to identify genes that influence SLE susceptibility through their genetic interaction with BANK1. Another goal was to determine if the interaction could explain larger risk factors.

The initial GWAS scan for genetic interactions included 256 SLE cases and 515 controls. Independent replication studies involved European-Americans (676 cases, 850 controls) and Europeans (1265 cases and 1506 controls). Statistical analyses of all possible interactions between genotype pairs determined that BANK1 interacted with 29 genes. Among these were BLK, coding for B-cell tyrosine kinase, and ITPR2, for inositol 1,4,5-triphosphate receptor 2.

"BANK1, as a scaffold protein, it's like a carrier of many other proteins," Dr. Delgado-Vega told Medscape Pathology & Lab Medicine. "So you can identify . . . the domains in which those proteins are interacting and that are very susceptible to modification. For example, the short isoform of BANK that is associated with disease completely lacks an exon [exon 2]. . . . And we have demonstrated that this short isoform . . . doesn't interact with BLK. It's the full-length isoform that interacts," she explained, adding: "It's very nice!"

Briefly, the study showed that ITPR2 interacts with BANK1, which interacts with BLK, which is associated with SLE susceptibility. The interactive effect was greater than expected, with an odds ratio of 3.20. Only 8% of control subjects, compared with 21% of SLE patients, were homozygous for risk variants in these 3 genes, with their significant interactive effect on SLE susceptibility (P < .0002). Replication in the independent European-American and European groups supported the genetic interactions (P = 2.1 × 10–6 and P = 4.11 × 10–9, respectively).

Asked about clinical applications, Dr. Delgado-Vega told Medscape Pathology & Lab Medicine that "it's a pathway that is specific for B-cells. That's very important because B-cells are very important for lupus. They are the ones that are producing the autoantibodies. If you can tag something that doesn't modify the whole immune system, but specifically goes to the problem [the B-cells], that's very good. So first you have a B-cell pathway," she said.

"We have also, for example, demonstrated that this regulation that BANK1 has on BLK is depending on interferon. . . . BLK is a kinase enzyme, and enzymes are also more susceptible to targeting," Dr. Delgado-Vega pointed out. Expression of the BANK1 protein keeps BLK from reaching the plasma membrane, so BLK accumulates in the cytoplasm. Both BANK1 and BLK expression (but not the expression of ITPR2) are affected by IFN-α.

The specificity of this pathway for SLE is also of interest. "It seems this B-cell [association] is quite specific to SLE. . . . There is a report showing that there is an association of BANK1 with arthritis, but the association is a lot weaker than with SLE," said Dr. Delgado-Vega.

"I don't agree with someone that was saying that the phenotypes in the autoimmune diseases were clearly defined, very separated. There is overlapping in the syndromes between autoimmune diseases," she said. "So that's hard to separate. . . . Also, I saw a [paper] showing that dogs with SLE — there were 3 major regions, and BANK1 was one of them!"

Medscape Pathology & Lab Medicine raised the topic with session comoderator Jonathan L. Haines, PhD, professor of human genetics, chief of the Division of Human Genomics, and director of the Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, Tennessee. "They've done a lot of work looking at all these different autoimmune diseases and what the overlaps are," said Dr. Haines.

"There is a set of genes that really do seem to predispose to autoimmunity more generally. Not to every single autoimmune disease, but to a number of them. And there are some that seem to be specific to the different autoimmune diseases. So it's a combination of those," Dr. Haines concluded.

Dr. Delgado-Vega has disclosed no relevant financial relationships. Dr. Haines reports receiving consulting fees and other remuneration from ArcticDx, and has held nonremunerative positions of influence (officer, board member, trustee, or public spokesperson) with ArcticDx and with Optherion, as well as being an inventor/patent owner.

American Society of Human Genetics (ASHG) 59th Annual Meeting: Abstract 272. Presented October 24, 2009.


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