Increased prevalence of EPAS1 variant in cattle with high-altitude pulmonary hypertension

Newman, John H.; Holt, Timothy N.; Cogan, Joy D.; Womack, Bethany; Phillips, John A.; Li, Chun; Kendall, Zachary; Stenmark, Kurt R.; Thomas, M. G.; Brown, Robert D.; Riddle, Suzette; West, James; Hamid, Rizwan

doi:10.1038/ncomms7863

Cited by 71 publications

(80 citation statements)

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“…Comparison between cattle that developed PH at altitude and those that did not revealed variants in EPAS1 that likely confer gain of function and were associated with HPH susceptibility. 113 Taken together, the genomic studies in both humans and cattle at high altitude independently identified variants in the HIF signaling pathway that confer protection or susceptibility to high-altitude PH.…”

Section: Mechanisms Of Hph: Lessons From High-altitude Genomicsmentioning

confidence: 99%

Pulmonary Vascular and Ventricular Dysfunction in the Susceptible Patient (2015 Grover Conference Series)

2016

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Pulmonary blood vessel structure and tone are maintained by a complex interplay between endogenous vasoactive factors and oxygen-sensing intermediaries. Under physiological conditions, these signaling networks function as an adaptive interface between the pulmonary circulation and environmental or acquired perturbations to preserve oxygenation and maintain systemic delivery of oxygen-rich hemoglobin. Chronic exposure to hypoxia, however, triggers a range of pathogenetic mechanisms that include hypoxia-inducible factor 1α (HIF-1α)-dependent upregulation of the vasoconstrictor peptide endothelin 1 in pulmonary endothelial cells. In pulmonary arterial smooth muscle cells, chronic hypoxia induces HIF-1α-mediated upregulation of canonical transient receptor potential proteins, as well as increased Rho kinase-Ca 2+ signaling and pulmonary arteriole synthesis of the profibrotic hormone aldosterone. Collectively, these mechanisms contribute to a contractile or hypertrophic pulmonary vascular phenotype. Genetically inherited disorders in hemoglobin structure are also an important etiology of abnormal pulmonary vasoreactivity. In sickle cell anemia, for example, consumption of the vasodilator and antimitogenic molecule nitric oxide by cell-free hemoglobin is an important mechanism underpinning pulmonary hypertension. Contemporary genomic and transcriptomic analytic methods have also allowed for the discovery of novel risk factors relevant to sickle cell disease, including GALNT13 gene variants. In this report, we review cutting-edge observations characterizing these and other pathobiological mechanisms that contribute to pulmonary vascular and right ventricular vulnerability.Keywords: hypoxia, pulmonary hypertension, genetics. In the autumn of 2015 at the Lost Valley Ranch in Sedalia, Colorado, the 34th Grover Conference, on pulmonary circulation in the "omics" era, convened for a 4-day symposium to discuss contemporary scientific concepts in the genetics, genomics, proteomics, and epigenetics of pulmonary vascular diseases. This biannual meeting, sponsored by the American Thoracic Society and co-led this year by Drs. C. Gregory Elliot, Wendy K. Chung, D. Hunter Best, and Eric D. Austin, commemorates the perpetual and transformative scientific contributions of Dr. Robert Grover 1 to the fields of high-altitude medicine and pulmonary vascular disease. This review is part of an ongoing Pulmonary Circulation thematic series that aims to provide a synopsis of key concepts presented at this year's Grover Conference.Here, we summarize the discussions that constituted a section of the conference emphasizing novel genetic and molecular mechanisms underpinning "pulmonary vascular and ventricular dysfunction in the susceptible patient." To accomplish this, three concepts are reviewed in detail: the functional relevance of chronic hypoxia (CH), discovered through genomic analyses; novel molecular mechanisms and phenotypic signatures of pulmonary vascular disease in sickle cell disease; and hormonal regulation of vascular f...

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Section: Mechanisms Of Hph: Lessons From High-altitude Genomicsmentioning

confidence: 99%

Pulmonary Vascular and Ventricular Dysfunction in the Susceptible Patient (2015 Grover Conference Series)

2016

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“…Our initial filtering strategy did not show a single genetic variant, although we (15,18,19,43). In this context, given the possibility that multiple genes are required to develop some disease phenotypes, we hypothesize that IPAH may develop due to either (1) multiple GVs in certain key pathways, or (2) multiple affected key pathways within an individual patient.…”

Section: Discussionmentioning

confidence: 99%

Critical Genomic Networks and Vasoreactive Variants in Idiopathic Pulmonary Arterial Hypertension

Hemnes

Zhao²,

West

et al. 2016

Am J Respir Crit Care Med

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Rationale: Idiopathic pulmonary arterial hypertension (IPAH) is usually without an identified genetic cause, despite clinical and molecular similarity to bone morphogenetic protein receptor type 2 mutation-associated heritable pulmonary arterial hypertension (PAH). There is phenotypic heterogeneity in IPAH, with a minority of patients showing long-term improvement with calcium channel-blocker therapy. Objectives: We sought to identify gene variants (GVs) underlying IPAH and determine whether GVs differ in vasodilator-responsive IPAH (VR-PAH) versus vasodilator-nonresponsive IPAH (VN-PAH).Methods: We performed whole-exome sequencing (WES) on 36 patients with IPAH: 17 with VR-PAH and 19 with VN-PAH. Wnt pathway differences were explored in human lung fibroblasts.Measurements and Main Results: We identified 1,369 genes with 1,580 variants unique to IPAH. We used a gene ontology approach to analyze variants and identified overrepresentation of several pathways, including cytoskeletal function and ion binding. By mapping WES data to prior genome-wide association study data, Wnt pathway genes were highlighted. Using the connectivity map to define genetic differences between VR-PAH and VN-PAH, we found enrichment in vascular smooth muscle cell contraction pathways and greater genetic variation in VR-PAH versus VN-PAH. Using human lung fibroblasts, we found increased stimulated Wnt activity in IPAH versus controls.Conclusions: A pathway-based analysis of WES data in IPAH demonstrated multiple rare GVs that converge on key biological pathways, such as cytoskeletal function and Wnt signaling pathway. Vascular smooth muscle contraction-related genes were enriched in VR-PAH, suggesting a potentially different genetic predisposition for VR-PAH. This pathway-based approach may be applied to next-generation sequencing data in other diseases to uncover the contribution of unexpected or multiple GVs to a phenotype.

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“…These genes have previously been identified in Tibetan people, and have been shown to help humans adapt to high altitude conditions [24][25][26][27] , hypoxia, and myocardial infarction [28] . Previous studies of these genes in local domestic livestock were performed either solely within cattle [29] or Yak. In total, 44 SNVs were found in the CDS region of these four genes, including 16 non-synonymous SNVs.…”

Section: Resultsmentioning

confidence: 99%

“…In humans, a SNV in EPAS1 has been detected between Tibetan (high-altitude) and Han (low-altitude) populations, and is associated with erythrocyte abundance, and thus supports the role of EPAS1 in the adaptation to hypoxia necessary for adaptation to high altitudes [24] . Newman et al [29] found a high degree of association in the oxygen degradation domain of EPAS1 between an EPAS1 (HIF-2α) double variant in Angus cattle with high-altitude pulmonary hypertension (HAPH) and demonstrated that the variant appears to be prevalent only in lowland cattle. In Yak, three novel SNPs have also been identified in EPAS1, and have been genotyped in three breeds.…”

Section: Discussionmentioning

confidence: 99%

Dzo Sığırlarında Tüm Genom Sekanslaması: Yüksek Rakıma Adaptasyon, Sterilite İle Süt ve Et Üretimine Etkisi

Zhong¹,

Ma²,

Chai³

et al. 2018

Kafkas Univ Vet Fak Derg

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Xin J: Whole genome sequencing of the Dzo: Genetic implications for high altitude adaptation, sterility, and milk and meat production. Kafkas Univ Vet Fak Derg, 24 (6): 835-844, 2018. DOI: 10.9775/kvfd.2018 AbstractThe Dzo, a hybrid between the domestic Yak and cattle found on the Qinghai-Tibetan plateau are commercially important owing to increased meat and milk production, as well as their adaptation to extremely high-altitude environments. To better understand the genomic architecture and adaptive capabilities of this unique domesticated hybrid, we performed whole genome resequencing and compared the genomic architecture and variation of the Dzo to its progenitors: the cattle and Yak. In total, 33.17 M single nucleotide variations (SNVs) were detected between the Dzo and cattle reference genomes. Even though the Dzo is known to be sterile, no genetic signatures associated with sterility were found on the Dzo Y chromosome. On the contrary, our results suggest that the autosomal DMC1 locus (Chromosome 5. 110729098. C>CT) plays a role in the sterility of Dzo, which warrants further exploration of its functions. We integrated the whole genome resequencing data of cattle and Yak to obtain candidate genes with a high degree of variation that might be associated with altitudinal adaptation. We found that the EPAS1 gene, which encodes hypoxia-inducible factor 2α, exhibited significant variation (Chromosome 11.28664187 C>T) between Yak and cattle, and may play a key role in the genetic basis of altitudinal adaptation. In addition, in analyzing differences between the Dzo, Yak, and cattle genomes, we uncovered several additional genomic signatures relevant to high altitude adaptation and meat and milk production. These findings underscore the need for further studies to improve ruminant stock for sustainable agriculture on the Qinghai-Tibet plateau.. Keywords: Dzo: Genome sequencing, Dzo, Altitude adaptation, Sterility, Milk and meat production Dzo Sığırlarında Tüm Genom Sekanslaması: Yüksek Rakıma Adaptasyon, Sterilite İle Süt ve Et Verimine Etkisi ÖzEvcil Yak ile Qinghai-Tibet platosunda bulunan sığırın bir hibriti olan Dzo artmış et ve süt üretimi ile birlikte aynı zamanda oldukça yüksek rakımlı bölgelere adaptasyonu nedeni ile ticari olarak önem arz etmektedir. Bu özgün evcil hibritin genomik yapısını ve uyum kapasitelerini daha iyi anlamak amacıyla tüm genom sekanslaması yapılarak genomik yapısı ve varyasyonlar Dzonun progenitörleri olan sığır ve Yak ile karşılaştırıldı. Dzo ile sığır referans genomları arasında toplam 33.17 M tek nükleotid varyasyonu belirlendi. Dzo steril olarak bilinmesine rağmen Dzo Y kromozomunda sterilite ile ilgili hiç bir genetik işarete rastlanmadı. Aksine, elde edilen bulgular otozomal DMC1 lokusunun (Kromozom 5. 110729098. C>CT) Dzonun sterilitesinde rol oynadığına işaret etmekte ve bu nedenle de daha ileri araştırılmaların yapılması gerekmektedir. Yüksek rakıma adaptasyon ile ilişkili yüksek oranda varyasyona sahip genlerin araştırılması amacıyla sığır ve Yakın tüm genom sekanslama ve...

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Increased prevalence of EPAS1 variant in cattle with high-altitude pulmonary hypertension

Cited by 71 publications

References 24 publications

Pulmonary Vascular and Ventricular Dysfunction in the Susceptible Patient (2015 Grover Conference Series)

Pulmonary Vascular and Ventricular Dysfunction in the Susceptible Patient (2015 Grover Conference Series)

Critical Genomic Networks and Vasoreactive Variants in Idiopathic Pulmonary Arterial Hypertension

Dzo Sığırlarında Tüm Genom Sekanslaması: Yüksek Rakıma Adaptasyon, Sterilite İle Süt ve Et Üretimine Etkisi

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