Many studies have identified the clustering of multiple autoimmune disorders in certain families. A new study demonstrates that BANK1 is a susceptibility gene for rheumatoid arthritis (RA). Moreover, it appears that there is epistatic interaction between BANK1 and BLK that plays a role in RA pathogenesis.
Emmanuelle Genin, PhD, of the Institut National de Santé et de la Recherche Médicale in Paris, France, and colleagues published the results of their large meta-analysis in the April issue of PLoS ONE. The authors evaluated approximately 2,000 cases and 2,000 controls. While BLK is an established RA susceptibility gene, this is the first study to demonstrate that BANK1 contributes to RA susceptibility.
When the authors tested the SNPs individually, none of them were associated with the RA phenotype. The authors were able, however, to detect an epistatic interaction between BANK1 rs3733197 and BLK rs13277113.
“Occasionally, variations in two genes led to a phenotype that is unexpected in light of each variant’s individual effects. This phenomenon, which defines genetic interaction (or epistasis), can reveal functional relationships between genes and pathways,” wrote Philippe Dieudé, MD, PhD, head of the rheumatology department at the Hôpital Bichat Claude-Bernard of Paris, the corresponding author of the study, to The Rheumatologist.
The authors wrote in their conclusion: “Unexpectedly, the BANK1-BLK epistasis we identified involves the BLK rs 13277113 GG genotype found protective in SLE [systemic lupus erythematosus]. Such an inverse association could be surprising, but there are several examples of variants having opposite effects in distinct autoimmune diseases.”
BLK is involved in the regulation of B-cell activation and BANK1 encodes a B-cell adaptor protein. Moreover, recent studies have suggested that B-cell receptor stimulation enhances both BANK1 and BLK1 binding. B cells are known to play numerous critical roles in RA pathogenesis. In addition, B-cell depletion therapy has been successful in this patient population.
“Taking into account the growing evidence that epistasis contributes to risk for genetic complex diseases, our findings illustrate that accounting for gene–gene interactions might be necessary to identify genetic effects that could otherwise be missed.
Indeed, the univariate approach considering only a single genetic marker at a time, commonly used in genome-wide association studies, could overlook the complex interactions that often occur in biological systems,” wrote Dr. Dieudé.
Dr. Pullen is a medical writer based in the Chicago area.
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