BOVINE RESPIRATORY DISEASE.

Transcription

1 BOVINE RESPIRATORY DISEASE

2 BOVINE RESPIRATORY DISEASE COMPLEX Common infectious disease of cattle worldwide Leading cause of death in dairy and beef cattle with losses of over 1 million cattle per year in the US alone (NASS 2006) Despite use of vaccines and antimicrobials, morbidity and mortality rates have remained virtually unchanged in cattle over the past several decades (Miles 2009; Gagea et al. 2006) BRDC accounted for 255,900 dairy calf deaths annually which represents 22.5% of mortalities in unweaned dairy heifers, 46.5% in weaned heifers, and 11.3% of cow deaths (NAHMS 2006) Losses associated with BRDC in dairy replacement animals outpace those for all other diseases (Patrick 2009)

3 BOVINE RESPIRATORY DISEASE COMPLEX A diagnosis of BRDC during the first six months of life resulted in reduced growth rates and decreased productivity of cows later in life (Sivula et al. 1996, Donovan et al. 1998) Cows affected by respiratory disease as a calf were twice as likely to die before calving, and calve at an older age than heifers that were not affected by BRDC prior to 90 days of age (Walter-Toews et al. 1986, Correa et al. 1988)

4 ECONOMICS BRDC remains the most economically important disease of beef cattle, responsible for losses of over $1 billion annually (Neibergs et al., 2014; Chirase & Greene 2001; Snowder et al. 2006; USDA 2001; Gagea et al. 2006) Actually, losses in dairy females alone approximate $800 million

5 CLINICAL SCORES/DIAGNOSTICS S. McGuirk s Diagnostic Criteria

6 RESEARCH OVERVIEW 2012 Objective 1. Identify genomic regions associated with BRD resistance/susceptibility in beef and dairy cattle. Population A 2000 Holstein calves Population B 1000 Holstein replacement heifers Population C 2000 Bos taurus feedlot cattle Population D 1000 Bos taurus purebred bulls

7 POPULATION A: DAIRY CALVES UC DAVIS, WSU Samples on 2800 calves collected and clinical scores obtained Diagnostics for Mycoplasma, P. Multocida, M. Haemolytica, H. Somni, bovine respiratory syncytial virus, bovine viral diarrhea virus, IBR completed DNA extracted, and genotyped for 778,000 SNPs New Mexico California

8 Neibergs WSU Taylor MU Seabury TAMU Seabury TAMU GENOME WIDE ASSOCIATION STUDY 4 analytical approaches (EMMAX, FvR, GBLUP, PLINK) 3 phenotypes (case/control, clinical scores, pathogen) 3 laboratories (Chris Seabury, Jerry Taylor, Holly Neibergs) Heritability estimates for BRDC susceptibility consistent at 19-21% for NM and CA as individual populations and 13% when combined

9 REGIONS CONCORDANT ACROSS ALL ANALYSES CALIFORNIA & NEW MEXICO COMBINED CASE CONTROL Regions associated with BRDC based on SNP rankings across four analyses. The number within the chromosomes represents the number of regions associated across analyses on that chromosome. 324 SNPs and 116 regions were concordant (1 to 20 SNPs/region) across all analyses

10 DIAGNOSTICS NM & CA COMBINED Pathogen Completion of sample collection and BRDC diagnostics on 2800 preweaned dairy calves (WSU & UC Davis diagnostic labs) Prevalence CA % Cases (% Controls) N=2031 Prevalence NM % Cases (% Controls) N=767 Odds Ratio 95% Confidence Interval Significance Arcanobacterium pyogenes 10.6 (4.3) 0.3 (0) Histophilus somni 1.7 (0.4) 3.2 (0.5) Manheimia haemolytica 25.4 (11.1) 4.5 (3.5) <0.001 Pasteurella multocida 36.6 (23.7) 61 (54.8) < Mycoplasma spp (57.1) 57.3 (48.7) Bovine corona virus 9.2 (7.4) 43.5 (30.4) Bovine respiratory syncytial virus 19.4 (7.4) 4.8 (2.4) <0.0001

11 ECONOMICS BRDC costs for preweaned dairy calves was $20.43 per animal raised (not treated) in the 80,000 calf facility in California (JS Neibergs, unpublished)

12 ECONOMICS OF BRDC Additional costs of $2.05 to $2.22 (1990 dollars) were incurred in weaned calves and $4.31 for mature cows in Michigan herds and $9.08 in Ohio herds (Kaneene & Hurd 1990, Sischo et al. 1990) Converting 1990 dollars into 2013 dollars based on the growth in U.S. GDP, the cost of BRDC per female ranged from $46.53 to $64.93 across her lifetime. With a current inventory of over 9 million dairy cows and 4.3 million replacement heifers, the U.S. will have spent between $618 and $863 million for the prevention and treatment of BRDC in the current female dairy population

13 POPULATION C BOS TAURUS FEEDLOT CATTLE WSU, TAMU, UC DAVIS Sample collection completed on 1000 feedlot animals Diagnostics, clinical scores, DNA extraction completed Carcass data collected Genotyping completed JBS Five Rivers Feedlot, Kersey, CO

14 ECONOMICS In 2013, 9,131,500 heifers and 16,003,400 steers were harvested from US feedlots with >1000 head of cattle 4,071,854 feedlot cattle were estimated to be affected with BRDC with a 16.2% prevalence rate When feeder purchase costs are included, the cost of BRDC was $ per affected animal or $1,034,128,760 in 2013 (Neibergs et al. 2014)

15 RESEARCH OBJECTIVE 2 Objective 2. Identify the interaction of the cattle genome with the pathogens responsible for BRD POPULATION E CHALLENGE CALVES

16 CHALLENGE STUDY UC DAVIS, MISSOURI 300 kg Angus calves challenged with Mycoplasma bovis, P. Multocida, M. Haemolytica, bovine viral diarrhea virus, and bovine respiratory syncytial virus Identify genes expressed with given pathogens via RNA-seq of bronchia-alveolar lymph nodes Characterize immunological responses

17 CHALLENGE STUDY SUMMARY Challenge studies have provided gene expression differences between: Controls and BRSV challenged 3515 genes, n = 6 Controls and IBR challenged 3900 genes, n = 6 Controls and BVDV challenged 2688 genes, n = 6 Controls and M. hemolytica challenged 2346 genes, n = 6 Controls and P. multocida challenged 707 genes, n = 2 Controls and M. bovis challenged 227 genes, n = 4

18 CHALLENGE STUDY Data from challenge studies have been used to determine genes that are differentially expressed with a single pathogen challenge using RNA-seq GWAS data identified loci associated with disease and the genes associated were also differentially expressed between cases and controls Combination of GWAS and RNA-seq data will be used to identify pathways to disease

19 GENE SET ENRICHMENT ANALYSIS WITH SNPS (GSEA) 1376 BRDC cases and 1380 controls from California and New Mexico Holstein calves were used GWAS was conducted with the GRAMMAR mixed-models method (Auluchenko et al. 2007) GWAS was followed by Gene Set Enrichment Analysis (GSEA) of SNP data (Wang et al. 2007) utilizing Bos taurus pathways from GO, KEGG, Panther, Reactome, and Metacyc SNPs were mapped to genes that were either closest to them, that were within 20 kb or that were within a haplotype block as defined by Haploview

20 GENE SET ENRICHMENT ANALYSIS Tests association of gene sets with disease Allows discovery of genes that individually have modest effects Ranks all genes based on test statistic of a proxy SNP H 0 : genes in a pathway are randomly distributed throughout the list H a : genes in a pathway are primarily found at the top of the list Running-sum statistic is increased when a gene in the gene set is encountered; otherwise it is decreased

21 GSEA GENE SET ENRICHMENT ANALYSIS WITH SNPS Test statistic was approximated after 10,000 permutations 4 Gene sets were associated (FDR<0.25): GO: regulation of myeloid cell differentiation, bta pyruvate metabolism, GO: regulation of myeloid leukocyte differentiation, bta glycolysis/gluconeogenesis Pathways include 249 unique genes; 89 of which contributed to an increase in the GSEA test statistic and represent putative functional candidate genes involved in BRD susceptibility

22 GSEA SIGNIFICANT PATHWAYS COMBINED CALIFORNIA AND NEW MEXICO

23 GSEA PATHWAYS IN CALIFORNIA OR NEW MEXICO ONLY California only New Mexico only

24 APPLICATIONS Results of these studies can be used for genomic selection to improve the cattle population in a cost effective, sustainable manner