Genetic Loci Involved in Antibody Response to Mycobacterium avium ssp. paratuberculosis in Cattle

Abstract

Background Mycobacterium avium subsp. paratuberculosis (MAP) causes chronic enteritis in a wide range of animal species. In cattle, MAP causes a chronic disease called Johne's disease, or paratuberculosis, that is not treatable and the efficacy of vaccine control is controversial. The clinical phase of the disease is characterised by diarrhoea, weight loss, drop in milk production and eventually death. Susceptibility to MAP infection is heritable with heritability estimates ranging from 0.06 to 0.10. There have been several studies over the last few years that have identified genetic loci putatively associated with MAP susceptibility, however, with the availability of genome-wide high density SNP maker panels it is now possible to carry out association studies that have higher precision.Methodology/Principal FindingsThe objective of the current study was to localize genes having an impact on Johne's disease susceptibility using the latest bovine genome information and a high density SNP panel (Illumina BovineSNP50 BeadChip) to perform a case/control, genome-wide association analysis. Samples from MAP case and negative controls were selected from field samples collected in 2007 and 2008 in the province of Lombardy, Italy. Cases were defined as animals serologically positive for MAP by ELISA. In total 966 samples were genotyped: 483 MAP ELISA positive and 483 ELISA negative. Samples were selected randomly among those collected from 119 farms which had at least one positive animal.Conclusion/SignificanceThe analysis of the genotype data identified several chromosomal regions associated with disease status: a region on chromosome 12 with high significance (P<5×10−6), while regions on chromosome 9, 11, and 12 had moderate significance (P<5×10−5). These results provide evidence for genetic loci involved in the humoral response to MAP. Knowledge of genetic variations related to susceptibility will facilitate the incorporation of this information into breeding programmes for the improvement of health status.

Phenotype definition is a main point in genome-wide association studies for bovine Mycobacterium avium ssp. paratuberculosis infection status

“…None of these genes were found in previous published GWA studies (summarized in Supplementary Table S1). Also there is no functional candidate gene described in the literature within 1 Mbp region of the SNPs in the present study (Settles et al, 2009;Minozzi et al, 2010;Pant et al, 2010;Kirkpatrick et al, 2011;Minozzi et al, 2012;van Hulzen et al, 2012). This supports once more the conclusion that paratuberculosis is probably affected by a large number of genes.…”

“…On the other hand it could be an effect of the unclear definition of the animal phenotype, because GWA-studies based on phenotype definition by different test methods identify different genes (Minozzi et al, 2012). Most GWA studies used milk or blood ELISA for phenotyping (Minozzi et al, 2010;Pant et al, 2010;RuizLarranaga et al, 2010b;Kirkpatrick et al, 2011;Minozzi et al, 2012). ELISA may identify genes which are involved in the immune response to the agent, whereas bacterial culture of bacteria in feces or tissue will identify genetic loci, which are involved in the persistence of the MAP infection at different stages of the disease (Minozzi et al, 2012), the development of the granulomatous enteritis and the release of MAP into the feces.…”

“…In this study, regions on BTA 3 and 9 were identified with a high significance to MAP status tested by MAP culture in feces and tissue in US Holsteins. In different GWA studies several associations were found on different chromosomes (Minozzi et al, 2010;Pant et al, 2010;Kirkpatrick et al, 2011;Minozzi et al, 2012;van Hulzen et al, 2012), summarized in Supplementary Table S1. These studies provide in general evidence for the existence of genomic regions associated with MAP infection in dairy cows.…”

An alternative experimental case–control design for genetic association studies on bovine mastitis

“…For example, several GWAS on bovine paratuberculosis identified different chromosomal regions associated with infection with Mycobacterium avium. paratubercolosis (Gonda et al, 2007;Settles et al, 2009;Minozzi et al, 2010). Furthermore, these results extend and generalizes a previous validation of markers on BTA6 between 85.5 and 88.1 Mb, which were identified in GWAs on elite bulls and validated using logarithm transformed SCC measured in three lactations of cows from three German dairy farms similarly managed (Abdel-Shafy et al, 2014).…”

New phenotypes for new breeding goals in dairy cattle

“…An accurate phenotyping requires different tools and a longitudinal analysis over several years. In spite of the difficulty to generate large samples, the first estimates of genetic parameters (Gonda et al, 2006) have been published, as well as the first Quantitative Trait Loci detection results (Minozzi et al, 2010). According to these results and the knowledge in man and other species for similar diseases, it is likely that paratuberculosis has a large genetic determinism.…”