ARS | Publication request: Association of tumor necrosis factor-alpha(TNF-alpha)gene promoter polymorphisms with hyper-responsiveness to endotoxin (LPS)in calves.

Submitted to: Joint Abstracts of the American Dairy Science and Society of Animal Science
Publication Type: Abstract Only
Publication Acceptance Date: March 24, 2009
Publication Date: May 6, 2009
Citation: Kahl, S., Elsasser, T.H., Proszkowiec Wegla, M.K., Connor, E.E. Association of tumor necrosis factor-alpha(TNF-alpha)gene promoter polymorphisms with hyper-responsiveness to endotoxin (LPS)in calves. Joint Abstracts of the American Dairy Science and Society of Animal Science. 87(E-Suppl.2):13. Abstract M32.

Technical Abstract: Previously, we identified a subpopulation of beef calves that failed to develop normal immune tolerance as defined by the patterns and magnitude of changes in plasma TNF-alpha concentration after 2 repeated LPS challenges. In these hyper responding calves (HRC), impaired LPS tolerance was related to exacerbated metabolic and clinical signs and prolonged recovery time. Recently, we identified 2 linked SNP located in the promoter region of the TNF-alpha gene in Angus × Hereford calves and showed that G to A (-526) and C to T (-701) transitions were associated with increased TNF-alpha mRNA expression in white blood cells, increased plasma TNF-alpha concentration, and decreased tolerance to repeated LPS challenges. In the present investigation, we applied a logistic regression analysis (LRA) to retrospectively determine whether the G to A (-526) polymorphism may aid in identifying at-risk HRC. Altogether, across 5 separate trials over 8 yr, 96 Angus × Hereford calves were genotyped and challenged with 2 consecutive LPS injections 4 d apart (0.2 mcg E. coli 055:B5/kg BW, i.v.). Blood samples were obtained at 0, 1, 2, 3, and 4 h relative to each LPS injection. Plasma TNF-alpha was measured by RIA with TNF-alpha response calculated as area under the time × concentration curve (AUC). Within each experiment, HRC were identified using an algorithm to normalize AUC after each LPS challenge. In total, 18.7% of calves were recognized as HRC; genotype frequencies were 21.9%, 45.8%, and 32.3% for AA, AG, and GG, respectively. The LRA indicated an AA genotype was associated with a 10-fold higher risk for HRC vs. a GG genotype (odds ratio [OR], 10.3; 95% confidence interval [CI], 2.4 - 44.5; P < 0.001) and an 11-fold higher risk for HRC vs. AG (OR, 11.0; CI, 2.9 - 41.9; P < 0.001). No differences in OR for HRC were found between AG and GG genotypes. The results suggest that this TNF-alpha gene promoter polymorphism may be useful in identifying calves with a propensity to exhibit excessive or prolonged pathological responses to LPS-related infections.