{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T20:24:58Z","timestamp":1777580698158,"version":"3.51.4"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2019,8]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              Human genetic variation in the\n              <jats:italic>NPR1<\/jats:italic>\n              (natriuretic peptide receptor 1 gene, encoding NPR-A, atrial natriuretic peptide receptor 1) was recently shown to affect blood pressure (BP). NPR-A catalyzes the intracellular conversion of guanosine triphosphate to cGMP (cyclic 3\u2032,5\u2032-guanosine monophosphate) on binding of ANP, BNP (atrial or brain natriuretic peptide). Increased levels of cGMP decrease BP by inducing natriuresis, diuresis, and vasodilation.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              We performed a meta-analysis of low-frequency and rare\n              <jats:italic>NPR1<\/jats:italic>\n              variants for BP association in up to 491\u2009584 unrelated individuals. To examine whether the identified BP-associated variants affect NPR-A function, the cGMP response to ANP and BNP was measured in cells expressing wild-type\n              <jats:italic>NPR1<\/jats:italic>\n              and cells expressing the\n              <jats:italic>NPR1<\/jats:italic>\n              variants.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              In this study, we identified BP associations of 3 amino acid altering variants of\n              <jats:italic>NPR1<\/jats:italic>\n              . The minor alleles of rs35479618 (p.E967K, gnomAD non-Finnish European allele frequency 0.017) and rs116245325 (p.L1034F, allele frequency 0.0007) were associated with higher BP (\n              <jats:italic>P<\/jats:italic>\n              =4.0\u00d710\n              <jats:sup>\u221225<\/jats:sup>\n              and\n              <jats:italic>P<\/jats:italic>\n              =9.9\u00d710\n              <jats:sup>\u22128<\/jats:sup>\n              , respectively), while the minor allele of rs61757359 (p.G541S, allele frequency 0.003) was associated with lower BP (\n              <jats:italic>P<\/jats:italic>\n              =1.8\u00d710\n              <jats:sup>\u22129<\/jats:sup>\n              ). Cells transiently expressing 967K or 1034F NPR-A displayed decreased cGMP production in response to ANP and BNP (all\n              <jats:italic>P<\/jats:italic>\n              &lt;10\n              <jats:sup>\u20136<\/jats:sup>\n              ), while cells expressing 541S NPR-A produced more cGMP compared with cells expressing wild-type NPR-A (\n              <jats:italic>P<\/jats:italic>\n              \u22644.13\u00d710\n              <jats:sup>\u22125<\/jats:sup>\n              for ANP and\n              <jats:italic>P<\/jats:italic>\n              \u22644.24\u00d710\n              <jats:sup>\u22123<\/jats:sup>\n              for BNP).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              In summary, the loss or gain of guanylate cyclase activity for these\n              <jats:italic>NPR1<\/jats:italic>\n              allelic variants could explain the higher or lower BP observed for carriers in large population-based studies.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.119.002472","type":"journal-article","created":{"date-parts":[[2019,8,20]],"date-time":"2019-08-20T18:00:17Z","timestamp":1566324017000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":17,"title":["Blood Pressure-Associated Genetic Variants in the Natriuretic Peptide Receptor 1 Gene Modulate Guanylate Cyclase Activity"],"prefix":"10.1161","volume":"12","author":[{"given":"Sara","family":"Vandenwijngaert","sequence":"first","affiliation":[{"name":"Department of Anesthesia, Critical Care, and Pain Medicine (S.V., C.D.L., F.W., E.S.B., D.B.B.), Massachusetts General Hospital Research Institute and Harvard Medical School, Boston."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clara D.","family":"Ledsky","sequence":"additional","affiliation":[{"name":"Department of Anesthesia, Critical Care, and Pain Medicine (S.V., C.D.L., F.W., E.S.B., D.B.B.), Massachusetts General Hospital Research Institute and Harvard Medical School, Boston."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Najim","family":"Lahrouchi","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine (N.L., C.N.-C.), Massachusetts General Hospital Research Institute and Harvard Medical School, Boston."},{"name":"Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, the Netherlands (N.L., M.A.F.K., C.R.B.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohsin A.F.","family":"Khan","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, University of Amsterdam, Heart Center (M.A.F.K., C.R.B.)."},{"name":"Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, the Netherlands (N.L., M.A.F.K., C.R.B.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Florian","family":"Wunderer","sequence":"additional","affiliation":[{"name":"Department of Anesthesia, Critical Care, and Pain Medicine (S.V., C.D.L., F.W., E.S.B., D.B.B.), Massachusetts General Hospital Research Institute and Harvard Medical School, Boston."},{"name":"Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, UniversityHospital Frankfurt, Germany (F.W.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Ames","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research (L.A., T.H., J.L.D.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshiyuki","family":"Honda","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research (L.A., T.H., J.L.D.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John L.","family":"Diener","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research (L.A., T.H., J.L.D.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Connie R.","family":"Bezzina","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, University of Amsterdam, Heart Center (M.A.F.K., C.R.B.)."},{"name":"Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, the Netherlands (N.L., M.A.F.K., C.R.B.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emmanuel S.","family":"Buys","sequence":"additional","affiliation":[{"name":"Department of Anesthesia, Critical Care, and Pain Medicine (S.V., C.D.L., F.W., E.S.B., D.B.B.), Massachusetts General Hospital Research Institute and Harvard Medical School, Boston."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donald B.","family":"Bloch","sequence":"additional","affiliation":[{"name":"Department of Anesthesia, Critical Care, and Pain Medicine (S.V., C.D.L., F.W., E.S.B., D.B.B.), Massachusetts General Hospital Research Institute and Harvard Medical School, Boston."},{"name":"Division of Rheumatology, Allergy and Immunology, Department of Medicine (D.B.B.), Massachusetts General Hospital Research Institute and Harvard Medical School, Boston."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher","family":"Newton-Cheh","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine (N.L., C.N.-C.), Massachusetts General Hospital Research Institute and Harvard Medical School, Boston."},{"name":"Cardiovascular Research Center, Department of Medicine (C.N.-C.), Massachusetts General Hospital Research Institute and Harvard Medical School, Boston."},{"name":"Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (C.N.-C.)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"the CHARGE+ Exome Chip Blood Pressure Consortium, the CHD Exome+ 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