Novel insight into the genetic basis of high-altitude pulmonary hypertension in Kyrgyz highlanders

Iranmehr, Arya; Stobdan, Tsering; Zhou, Dan; Poulsen, Orit; Aldashev, Almaz; Telenti, Amalio; Wong, Emily H. M.; Kirkness, Ewen F.; Venter, J. Craig; Bafna, Vineet; Haddad, Gabriel G.

doi:10.1038/s41431-018-0270-8

Cited by 13 publications

(16 citation statements)

References 50 publications

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“…Finally, the signature near NBEAL1 is bordered in sheep by BMPR2, for which mutations have been associated with high Altitude Pulmonary Hypertension (APH) in Kyrgyz Highlanders 73 and in cattle 74 . Moreover, this gene was found to be associated with desert and plateau conditions in Chinese sheep 9 .…”

Section: Discussionmentioning

confidence: 99%

Local adaptations of Mediterranean sheep and goats through an integrative approach

Serranito

Cavalazzi

Vidal

et al. 2021

Sci Rep

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Small ruminants are suited to a wide variety of habitats and thus represent promising study models for identifying genes underlying adaptations. Here, we considered local Mediterranean breeds of goats (n = 17) and sheep (n = 25) from Italy, France and Spain. Based on historical archives, we selected the breeds potentially most linked to a territory and defined their original cradle (i.e., the geographical area in which the breed has emerged), including transhumant pastoral areas. We then used the programs PCAdapt and LFMM to identify signatures of artificial and environmental selection. Considering cradles instead of current GPS coordinates resulted in a greater number of signatures identified by the LFMM analysis. The results, combined with a systematic literature review, revealed a set of genes with potentially key adaptive roles in relation to the gradient of aridity and altitude. Some of these genes have been previously implicated in lipid metabolism (SUCLG2, BMP2), hypoxia stress/lung function (BMPR2), seasonal patterns (SOX2, DPH6) or neuronal function (TRPC4, TRPC6). Selection signatures involving the PCDH9 and KLH1 genes, as well as NBEA/NBEAL1, were identified in both species and thus could play an important adaptive role.

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Section: Discussionmentioning

confidence: 99%

Local adaptations of Mediterranean sheep and goats through an integrative approach

Serranito

Cavalazzi

Vidal

et al. 2021

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Finally, the signature near NBEA is bordered in sheep, by BMPR2, for which mutations have been associated with high Altitude Pulmonary Hypertension (APH), in Kyrgyz Highlanders (Iranmehr et al, 2019) and also in cattle (Newman et al, 2011). Moreover, this gene was found associated with desert and plateau conditions in Chinese sheep (Yang et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Local adaptations of Mediterranean sheep and goats through an integrative approach

Serranito

Cavalazzi

Vidal

et al. 2021

Preprint

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In a context of climate change, identifying the genes underlying adaptations to extreme environments is essential. Small ruminants are adapted to a wide variety of habitats and thus, are promising study models. Here, we considered 17 goat and 25 sheep local Mediterranean breeds, in Italy, France and Spain. We proposed, and empirically tested a new methodology to highlight selection signatures in relation to the environments. Based on historical archives, we selected the breeds potentially most linked to a territory and defined their original geographical cradle, including transhumant pastoral areas. For both species, the cradles were arranged along latitudinal gradient of aridity and altitude. Then we used the programs PCAdapt and LFMM. Considering cradles, instead of current GPS coordinates, markedly improved the sensitivity of the LFMM analyses. All the results combined with a systematic literature review, revealed a set of genes with potentially key adaptive roles. Some of these genes, have been found implicated in lipid metabolism (SUCLG2, BMP2), hypoxia/heat stress (UBE2R2/UBAP2), lung function (BMPR2), seasonal patterns (SOX2, DPH6) or neuronal function (TRPC4, TRPC6). For the intergenic region between PCDH9 and KLH1, as well as NBEA, identified in both species, the adaptive role could be strong. We found for RXFP2, associated with sheep horn development, and MSRB3 and SLC26A4, both associated with hearing of sheep, a strong association with the environment gradient. We conclude that our new methodology, which considers breeds in their historical, environmental and anthropological context, provides novel and essential information on local breeds and their unique adaptations.

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“…These individuals carried a more active gene variant of the enzyme soluble guanylate cyclase, which is essential for NO-mediated vasodilation. A recent study compared whole genome sequences of Kyrgyz highlanders susceptible to high-altitude pulmonary hypertension to those resistant to the disease (36). Three candidate genes, MTMR4, TMOD3, and VCAM1, which were implicated in the BMPR2 signaling pathway, tissue repair, and endothelial cell function, were highlighted as possible protective genes.…”

Section: High-altitude Pulmonary Hypertensionmentioning

confidence: 99%

“…In contrast to PAH and HAPE, no mutations in high-altitude pulmonary hypertension subjects have been identified despite a strong overlap of disease symptoms with PAH. Instead, possible protective genomic regions have been suggested, which might be interesting candidate genes to be investigated in PAH patients (36,68). In high-altitude pulmonary hypertension a few rare familial cases have been described with affected siblings or sibling offspring pairs (41).…”

Section: Future Research Directionsmentioning

confidence: 99%

Genetics of pulmonary hypertension and high-altitude pulmonary edema

Eichstaedt

Benjamin

Grünig

2020

Journal of Applied Physiology

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Heritable pulmonary arterial hypertension (PAH) is an autosomal dominantly inherited disease caused by mutations in the bone morphogenetic protein receptor 2 ( BMPR2) gene and/or genes of its signaling pathway in ~85% of patients. A genetic predisposition to high-altitude pulmonary edema (HAPE) has long been suspected because of familial HAPE cases, but very few possibly disease-causing mutations have been identified to date. This minireview provides an overview of genetic analyses investigating common polymorphisms in HAPE-susceptible patients and the directed identification of disease-causing mutations in PAH patients. Increased pulmonary artery pressure is highlighted as an overlapping clinical feature of the two diseases. Moreover, studies showing increased pulmonary artery pressures in HAPE-susceptible patients during exercise or hypoxia as well as in healthy BMPR2 mutation carriers are illustrated. Finally, high-altitude pulmonary hypertension is introduced and future research perspectives outlined.

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Novel insight into the genetic basis of high-altitude pulmonary hypertension in Kyrgyz highlanders

Cited by 13 publications

References 50 publications

Local adaptations of Mediterranean sheep and goats through an integrative approach

Local adaptations of Mediterranean sheep and goats through an integrative approach

Local adaptations of Mediterranean sheep and goats through an integrative approach

Genetics of pulmonary hypertension and high-altitude pulmonary edema

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