Wingless-type MMTV integration site family member 2 (WNT2) gene is associated with resistance to MAP in faecal culture and antibody response in Holstein cattle

Mycobacterium avium subspecies paratuberculosis (MAP) is a pathogenic bacteria responsible of the lethal Johne's disease in cattle. So far, several GWA studies have been carried out to identify chromosomal regions highly associated with Johne's disease. The aim of this study was to investigate the genetic variability within a pool of 7 genes (LAMB1, DLD, WNT2, PRDM1,SOCS5, PTGER4 and IL10) indicated by former GWA/RNASeq studies as putatively associated with MAP infections and to achieve a confirmation study of association with paratuberculosis susceptibility in a population of 324 German Holstein cattle (162 cases: MAP-positive and 162 controls MAP-negative) using ELISA and faecal cultural tests. SNP validation and genotyping information are provided, quick methods for allelic discrimination were set up and transcription factor binding analyses were performed. The SNP rs43390642:G>T in the WNT2 promoter region is associated with paratuberculosis susceptibility (p=0.013), suggesting a protective role of the T allele (p=0.043, OR 0.50 [0.25-0.97]). The linkage disequilibrium with the DLD rs134692583:A>T might suggest a combined mechanism of action of these neighbor genes in the resistance to MAP infection, which is also supported by a significant effect showed by the haplotype DLDT/WNT2T (p=0.047). In silico analysis predicted rs43390642:G>T and rs134692583:A>T as essential parts of binding sites for the transcription factors GR and C/EBP?, GATA-1 respectively, hence suggesting a potential influence on WNT2 and DLD gene expression. This study confirms the region (UMD 3.1:50639460-51397892) on BTA 4 as involved in tolerance/resistance to Johne's disesase. In addition,this study clarifies the involvement of the investigated genes in MAP infection and it contributes to the understanding of genetic variability involved in Johne's disease susceptibility.