α1-A680T Variant in GUCY1A3 as a Candidate Conferring Protection From Pulmonary Hypertension Among Kyrgyz Highlanders

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 livin...

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Published in:	Circulation. Cardiovascular genetics Vol. 7; no. 6; pp. 920 - 929
Main Authors:	Wilkins, Martin R, Aldashev, Almaz A, Wharton, John, Rhodes, Christopher J, Vandrovcova, Jana, Kasperaviciute, Dalia, Bhosle, Shriram G, Mueller, Michael, Geschka, Sandra, Rison, Stuart, Kojonazarov, Baktybek, Morrell, Nicholas W, Neidhardt, Inga, Surmeli, Nur Basek, Aitman, Tim J, Stasch, Johannes-Peter, Behrends, Soenke, Marletta, Michael A
Format:	Journal Article
Language:	English
Published:	United States American Heart Association, Inc 01-12-2014
Subjects:	Alleles Altitude Sickness - genetics Altitude Sickness - pathology Amino Acid Sequence Animals Cyclic GMP - metabolism Female Genotype Guanylate Cyclase - genetics Guanylate Cyclase - metabolism HEK293 Cells High-Throughput Nucleotide Sequencing Humans Hypertension, Pulmonary - genetics Hypertension, Pulmonary - pathology Male Middle Aged Molecular Sequence Data Nitric Oxide - metabolism Phylogeny Polymorphism, Single Nucleotide Receptors, Cytoplasmic and Nuclear - genetics Receptors, Cytoplasmic and Nuclear - metabolism Sequence Alignment Sequence Analysis, DNA Signal Transduction Soluble Guanylyl Cyclase hypoxia exome cyclic nucleotide pulmonary hypertension
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Summary:	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.
ISSN:	1942-325X 1942-3268
DOI:	10.1161/CIRCGENETICS.114.000763