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Circ Cardiovasc Genet. 2014 Dec;7(6):920-9. doi: 10.1161/CIRCGENETICS.114.000763. Epub 2014 Nov 4.

α1-A680T variant in GUCY1A3 as a candidate conferring protection from pulmonary hypertension among Kyrgyz highlanders.

Author information

1
From the Department of Medicine, Imperial College London, London, United Kingdom (M.R.W., J.W., C.J.R., S.R.); National Academy of Sciences of Kyrgyz Republic, Bishkek, Kyrgyz Republic (A.A.A.); Physiological Genomics and Medicine Group, MRC Clinical Sciences Centre, Hammersmith Hospital, London, United Kingdom (J.V., T.J.A.); NIHR BRC Clinical Genome Informatics Facility, Imperial College London, London, United Kingdom (D.K., S.G.B., M.M.); Cardiology Research, Bayer Pharma AG, Wuppertal, Germany (S.G., J.-P.S.); Department of Pharmacology, The School of Pharmacy, Martin-Luther-University, Halle, Germany (J.-P.S.); Department of Pulmonary Pharmacotherapy, University of Giessen and Marburg Lung Center, Giessen, Germany (B.K.); Department of Medicine, University of Cambridge, Cambridge, United Kingdom (N.W.M.); Department of Pharmacology, Toxicology, and Clinical Pharmacy, University of Braunschweig-Center of Pharmaceutical Engineering, Braunschweig, Germany (I.N., S.B.); and Department of Chemistry, The Scripps Research Institute, La Jolla, CA (N.B.S., M.A.M.). m.wilkins@imperial.ac.uk.
2
From the Department of Medicine, Imperial College London, London, United Kingdom (M.R.W., J.W., C.J.R., S.R.); National Academy of Sciences of Kyrgyz Republic, Bishkek, Kyrgyz Republic (A.A.A.); Physiological Genomics and Medicine Group, MRC Clinical Sciences Centre, Hammersmith Hospital, London, United Kingdom (J.V., T.J.A.); NIHR BRC Clinical Genome Informatics Facility, Imperial College London, London, United Kingdom (D.K., S.G.B., M.M.); Cardiology Research, Bayer Pharma AG, Wuppertal, Germany (S.G., J.-P.S.); Department of Pharmacology, The School of Pharmacy, Martin-Luther-University, Halle, Germany (J.-P.S.); Department of Pulmonary Pharmacotherapy, University of Giessen and Marburg Lung Center, Giessen, Germany (B.K.); Department of Medicine, University of Cambridge, Cambridge, United Kingdom (N.W.M.); Department of Pharmacology, Toxicology, and Clinical Pharmacy, University of Braunschweig-Center of Pharmaceutical Engineering, Braunschweig, Germany (I.N., S.B.); and Department of Chemistry, The Scripps Research Institute, La Jolla, CA (N.B.S., M.A.M.).

Erratum in

  • Circ Cardiovasc Genet. 2015 Feb;8(1):244. Surmeli, Nur Basek [corrected to Surmeli, Nur Basak].

Abstract

BACKGROUND:

Human variation in susceptibility to hypoxia-induced pulmonary hypertension is well recognized. High-altitude residents who do not develop pulmonary hypertension may host protective gene mutations.

METHODS AND RESULTS:

Exome sequencing was conducted on 24 unrelated Kyrgyz highlanders living 2400 to 3800 m above sea level, 12 (10 men; mean age, 54 years) with an elevated mean pulmonary artery pressure (mean±SD, 38.7±2.7 mm Hg) and 12 (11 men; mean age, 52 years) with a normal mean pulmonary artery pressure (19.2±0.6 mm Hg) to identify candidate genes that may influence the pulmonary vascular response to hypoxia. A total of 140 789 exomic variants were identified and 26 116 (18.5%) were classified as novel or rare. Thirty-three novel or rare potential pathogenic variants (frameshift, essential splice-site, and nonsynonymous) were found exclusively in either ≥3 subjects with high-altitude pulmonary hypertension or ≥3 highlanders with a normal mean pulmonary artery pressure. A novel missense mutation in GUCY1A3 in 3 subjects with a normal mean pulmonary artery pressure encodes an α1-A680T soluble guanylate cyclase (sGC) variant. Expression of the α1-A680T sGC variant in reporter cells resulted in higher cyclic guanosine monophosphate production compared with the wild-type enzyme and the purified α1-A680T sGC exhibited enhanced sensitivity to nitric oxide in vitro.

CONCLUSIONS:

The α1-A680T sGC variant may contribute to protection against high-altitude pulmonary hypertension and supports sGC as a pharmacological target for reducing pulmonary artery pressure in humans at altitude.

KEYWORDS:

cyclic nucleotide; exome; hypoxia; pulmonary hypertension

PMID:
25373139
DOI:
10.1161/CIRCGENETICS.114.000763
[Indexed for MEDLINE]
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