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首页> 外文期刊>Pulmonary Circulation >High-Altitude Pulmonary Hypertension in Cattle (Brisket Disease): Candidate Genes and Gene Expression Profiling of Peripheral Blood Mononuclear Cells:
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High-Altitude Pulmonary Hypertension in Cattle (Brisket Disease): Candidate Genes and Gene Expression Profiling of Peripheral Blood Mononuclear Cells:

机译：牛（牛ris病）高海拔肺动脉高压：外周血单个核细胞的候选基因和基因表达谱：

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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, P0.001. 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 (P5.14×10?14), cell development and cell signaling as the top cellular functions (P1.20×10?08), and IL6, TREM, PPAR, NFkB cell signaling (P8.69×10?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.
机译：高原肺动脉高压（HAPH）是慢性肺泡缺氧的结果，导致缺氧性血管收缩和肺循环重塑。牛的s病是缺氧性肺动脉高压的自然动物模型。具有遗传易感性的牛在海拔> 7,000英尺时会发展为严重的肺动脉高压和右心衰竭。目前尚无有关HAPH或影响严重程度的途径和基因的身份信息。我们假设可以通过以下策略发现对疾病发病机理的初步见解：（1）通过单核苷酸多态性（SNP）分析揭示的功能候选者测序和（2）与海拔高度匹配的正常人相比受影响的牛的基因表达谱对照，以及基因集富集分析（GSEA）和创造力途径分析（IPA）。我们通过颈静脉穿刺从一头雌性黑安格斯牛中分离出血液，年龄为12-18个月。 10头受影响牛的平均肺动脉压为85.6±13 mmHg STD，而10头耐药牛的平均肺动脉压为35.3±1.2 mmHg STD，P <0.001。将来自外周血单核细胞的DNA与Affymetrix 10K基因芯片SNP杂交，并使用RNA探测Affymetrix牛基因组阵列。使用Btau 4.0牛基因组装配重新映射SNP位点。通过Partek软件包对mRNA数据进行分析，以鉴定在两组之间具有统计学差异的表达基因组。对精制的表达数据进行了GSEA和IPA，以识别关键的细胞途径并生成网络并对该途径和网络进行功能分析。通过等位基因关联鉴定出十个SNP，并在队列中测序了四个候选基因。在受影响和耐药的牛中，内皮型一氧化氮合成酶，NADH脱氢酶，TG相互作用因子2和BMPR2都没有差异。鉴定出60个基因的mRNA签名，其与未受影响的牛区分开来。在受影响的牛中有46个基因过表达，而在受影响的牛中14个基因被下调了至少20％。 GSEA和Ingenuity分析确定呼吸系统疾病，炎性疾病和途径为最主要的疾病和障碍（P <5.14×10？14），细胞发育和细胞信号传导为最重要的细胞功能（P <1.20×10？08）和IL6 ，TREM，PPAR，NFkB细胞信号传导（P <8.69×10→09）是与此基因签名相关的最常见的经典途径。这项研究提供了分子水平上HAPH中RNA表达差异的见解，并消除了四个功能基因候选者。需要进一步的研究来验证和完善这些初步发现，并确定转录基因在HAPH发生中的作用。

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