PMID- 22530101
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20120823
LR  - 20240318
IS  - 2045-8940 (Electronic)
IS  - 2045-8932 (Print)
IS  - 2045-8932 (Linking)
VI  - 1
IP  - 4
DP  - 2011 Oct-Dec
TI  - High-altitude pulmonary hypertension in cattle (brisket disease): Candidate genes 
      and gene expression profiling of peripheral blood mononuclear cells.
PG  - 462-9
LID - 10.4103/2045-8932.93545 [doi]
AB  - High-altitude pulmonary hypertension (HAPH) is a consequence of chronic alveolar 
      hypoxia, leading to hypoxic vasoconstriction and remodeling of the pulmonary 
      circulation. Brisket disease in cattle is a naturally occurring animal model of 
      hypoxic pulmonary hypertension. Genetically susceptible cattle develop severe 
      pulmonary hypertension and right heart failure at altitudes >7,000 ft. No 
      information currently exists regarding the identity of the pathways and gene(s) 
      responsible for HAPH or influencing severity. We hypothesized that initial 
      insights into the pathogenesis of the disease could be discovered by a strategy 
      of (1) sequencing of functional candidates revealed by single nucleotide 
      polymorphism (SNP) analysis and (2) gene expression profiling of affected cattle 
      compared with altitude-matched normal controls, with gene set enrichment analysis 
      (GSEA) and Ingenuity pathway analysis (IPA). We isolated blood from a single herd 
      of Black Angus cattle of both genders, aged 12-18 months, by jugular vein 
      puncture. Mean pulmonary arterial pressures were 85.6+/-13 mmHg STD in the 10 
      affected and 35.3+/-1.2 mmHg STD in the 10 resistant cattle, P<0.001. From 
      peripheral blood mononuclear cells, DNA was hybridized to an Affymetrix 10K Gene 
      Chip SNP, and RNA was used to probe an Affymetrix Bovine genome array. SNP loci 
      were remapped using the Btau 4.0 bovine genome assembly. mRNA data was analyzed 
      by the Partek software package to identify sets of genes with an expression that 
      was statistically different between the two groups. GSEA and IPA were conducted 
      on the refined expression data to identify key cellular pathways and to generate 
      networks and conduct functional analyses of the pathways and networks. Ten SNPs 
      were identified by allelelic association and four candidate genes were sequenced 
      in the cohort. Neither endothelial nitric oxide synthetase, NADH dehydrogenase, 
      TG-interacting factor-2 nor BMPR2 were different among affected and resistant 
      cattle. A 60-gene mRNA signature was identified that differentiated affected from 
      unaffected cattle. Forty-six genes were overexpressed in the affected and 14 
      genes were downregulated in the affected cattle by at least 20%. GSEA and 
      Ingenuity analysis identified respiratory diseases, inflammatory diseases and 
      pathways as the top diseases and disorders (P<5.14x10(-14)), cell development and 
      cell signaling as the top cellular functions (P<1.20x10(-08)), and IL6, TREM, 
      PPAR, NFkB cell signaling (P<8.69x10(-09)) as the top canonical pathways 
      associated with this gene signature. This study provides insights into 
      differences in RNA expression in HAPH at a molecular level, and eliminates four 
      functional gene candidates. Further studies are needed to validate and refine 
      these preliminary findings and to determine the role of transcribed genes in the 
      development of HAPH.
FAU - Newman, John H
AU  - Newman JH
AD  - Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, 
      USA.
FAU - Holt, Timothy N
AU  - Holt TN
FAU - Hedges, Lora K
AU  - Hedges LK
FAU - Womack, Bethany
AU  - Womack B
FAU - Memon, Shafia S
AU  - Memon SS
FAU - Willers, Elisabeth D
AU  - Willers ED
FAU - Wheeler, Lisa
AU  - Wheeler L
FAU - Phillips, John A 3rd
AU  - Phillips JA 3rd
FAU - Hamid, Rizwan
AU  - Hamid R
LA  - eng
GR  - R01 HL102020/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PL  - United States
TA  - Pulm Circ
JT  - Pulmonary circulation
JID - 101557243
PMC - PMC3329076
OTO - NOTNLM
OT  - brisket disease
OT  - hypoxia
OT  - microarray analysis
COIS- Conflict of Interest: None declared.
EDAT- 2012/04/25 06:00
MHDA- 2012/04/25 06:01
PMCR- 2011/10/01
CRDT- 2012/04/25 06:00
PHST- 2012/04/25 06:00 [entrez]
PHST- 2012/04/25 06:00 [pubmed]
PHST- 2012/04/25 06:01 [medline]
PHST- 2011/10/01 00:00 [pmc-release]
AID - PC-1-462 [pii]
AID - 10.4103/2045-8932.93545 [doi]
PST - ppublish
SO  - Pulm Circ. 2011 Oct-Dec;1(4):462-9. doi: 10.4103/2045-8932.93545.