Evidence for gene-gene epistatic interactions between susceptibility genes for Mycobacterium avium subsp. paratuberculosis infection in cattle

Johne's disease is a chronic granulomatous inflammatory disease caused by Mycobacterium avium subsp. paratuberculosis (MAP), with a particularly negative impact on the economy of the dairy industry. In recent years, several whole genome and candidate gene association studies have been published reporting MAP susceptibility genes, but the putative interaction between them remains unknown. Here, twenty-four single nucleotide polymorphisms in the bovine SLC11A1, NOD2, SP110, TLR2, TLR4, and CD209 genes, previously related with paratuberculosis disease, have been analyzed. Several significant (P<0.05) pair-wise genetic interactions were detected: CD209-TLR4, CD209-TLR2, TLR4-TLR2, SP110-SLC11A1, SP110-TLR2, and SP110-NOD2. The statistical interaction described here between bovine CD209 and TLR4 genes may be indicative of the biological interaction between their protein products upon infection by mycobacteria, as has been reported to occur in humans. Overall, this is the first evidence of epistasis among bovine innate immunity genes affecting susceptibility to MAP infection, corroborating, in turn, their implication in the disease.