{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T19:02:32Z","timestamp":1774119752989,"version":"3.50.1"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"16","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2014,4,22]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>We postulated that the hypoxic response in sickle cell disease (SCD) contributes to altered gene expression and pulmonary hypertension, a complication associated with early mortality.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              To identify genes regulated by the hypoxic response and not other effects of chronic anemia, we compared expression variation in peripheral blood mononuclear cells from 13 subjects with SCD with hemoglobin SS genotype and 15 subjects with Chuvash polycythemia (\n              <jats:italic>VHL<\/jats:italic>\n              <jats:sup>\n                <jats:italic>R200W<\/jats:italic>\n              <\/jats:sup>\n              homozygotes with constitutive upregulation of hypoxia-inducible factors in the absence of anemia or hypoxia). At a 5% false discovery rate, 1040 genes exhibited &gt;1.15-fold change in both conditions; 297 were upregulated and 743 downregulated including\n              <jats:italic>MAPK8<\/jats:italic>\n              encoding a mitogen-activated protein kinase important for apoptosis, T-cell differentiation, and inflammatory responses. Association mapping with a focus on local regulatory polymorphisms in 61 patients with SCD identified expression quantitative trait loci for 103 of these hypoxia response genes. In a University of Illinois SCD cohort, the A allele of a\n              <jats:italic>MAPK8<\/jats:italic>\n              expression quantitative trait locus, rs10857560, was associated with precapillary pulmonary hypertension defined as mean pulmonary artery pressure \u226525 mm Hg and pulmonary capillary wedge pressure \u226415 mm Hg at right heart catheterization (allele frequency, 0.66; odds ratio, 13.8; n=238). This association was confirmed in an independent Walk\u2013Treatment of Pulmonary Hypertension and Sickle Cell Disease With Sildenafil Therapy cohort (allele frequency, 0.65; odds ratio, 11.3; n=519). The homozygous AA genotype of rs10857560 was associated with decreased\n              <jats:italic>MAPK8<\/jats:italic>\n              expression and present in all 14 of the identified precapillary pulmonary hypertension cases among the combined 757 patients.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>\n              Our study demonstrates a prominent hypoxic transcription component in SCD and a\n              <jats:italic>MAPK8<\/jats:italic>\n              expression quantitative trait locus associated with precapillary pulmonary hypertension.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.113.005296","type":"journal-article","created":{"date-parts":[[2014,2,11]],"date-time":"2014-02-11T05:33:37Z","timestamp":1392096817000},"page":"1650-1658","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":35,"title":["Hypoxic Response Contributes to Altered Gene Expression and Precapillary Pulmonary Hypertension in Patients With Sickle Cell Disease"],"prefix":"10.1161","volume":"129","author":[{"given":"Xu","family":"Zhang","sequence":"first","affiliation":[{"name":"From the Comprehensive Sickle Cell Center, Section of Hematology\/Oncology (X.Z., S.S., V.R.G.), Section of Cardiology (A.A.D.), and Section of Pulmonary, Critical Care, and Sleep Medicine (J.G.N.G., R.F.M.), Department of Medicine, Institute of Human Genetics (W.Z., R.K.), Department of Pediatrics (W.Z.), and Institute for Personalized Respiratory Medicine (A.A.D., T.A., N.G.C., J.G.N.G., R.F.M.), University of Illinois at Chicago, Chicago, IL; Section of Pulmonary\/Critical Care, Department of..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"From the Comprehensive Sickle Cell Center, Section of Hematology\/Oncology (X.Z., S.S., V.R.G.), Section of Cardiology (A.A.D.), and Section of Pulmonary, Critical Care, and Sleep Medicine (J.G.N.G., R.F.M.), Department of Medicine, Institute of Human Genetics (W.Z., R.K.), Department of Pediatrics (W.Z.), and Institute for Personalized Respiratory Medicine (A.A.D., T.A., N.G.C., J.G.N.G., R.F.M.), University of Illinois at Chicago, Chicago, IL; Section of Pulmonary\/Critical Care, Department of..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shwu-Fan","family":"Ma","sequence":"additional","affiliation":[{"name":"From the Comprehensive Sickle Cell Center, Section of Hematology\/Oncology (X.Z., S.S., V.R.G.), Section of Cardiology (A.A.D.), and Section of Pulmonary, Critical Care, and Sleep Medicine (J.G.N.G., R.F.M.), Department of Medicine, Institute of Human Genetics (W.Z., R.K.), Department of Pediatrics (W.Z.), and Institute for Personalized Respiratory Medicine (A.A.D., T.A., N.G.C., J.G.N.G., R.F.M.), University of Illinois at Chicago, Chicago, IL; Section of Pulmonary\/Critical Care, Department of..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ankit A.","family":"Desai","sequence":"additional","affiliation":[{"name":"From the Comprehensive Sickle Cell Center, Section of Hematology\/Oncology (X.Z., S.S., V.R.G.), Section of Cardiology (A.A.D.), and Section of Pulmonary, Critical Care, and Sleep Medicine (J.G.N.G., R.F.M.), Department of Medicine, Institute of Human Genetics (W.Z., R.K.), Department of Pediatrics (W.Z.), and Institute for Personalized Respiratory Medicine (A.A.D., T.A., N.G.C., J.G.N.G., R.F.M.), University of Illinois at Chicago, Chicago, IL; Section of Pulmonary\/Critical Care, Department of..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Santosh","family":"Saraf","sequence":"additional","affiliation":[{"name":"From the Comprehensive Sickle Cell Center, Section of Hematology\/Oncology (X.Z., S.S., V.R.G.), Section of Cardiology (A.A.D.), and Section of Pulmonary, Critical Care, and Sleep Medicine (J.G.N.G., R.F.M.), Department of Medicine, Institute of Human Genetics (W.Z., R.K.), Department of Pediatrics (W.Z.), and Institute for Personalized Respiratory Medicine (A.A.D., T.A., N.G.C., J.G.N.G., R.F.M.), University of Illinois at Chicago, Chicago, IL; Section of Pulmonary\/Critical Care, Department of..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Galina","family":"Miasniakova","sequence":"additional","affiliation":[{"name":"From the Comprehensive Sickle Cell Center, Section of Hematology\/Oncology (X.Z., S.S., V.R.G.), Section of Cardiology (A.A.D.), and Section of Pulmonary, Critical Care, and Sleep Medicine (J.G.N.G., R.F.M.), Department of Medicine, Institute of Human Genetics (W.Z., R.K.), Department of Pediatrics (W.Z.), and Institute for Personalized Respiratory Medicine (A.A.D., T.A., N.G.C., J.G.N.G., R.F.M.), University of Illinois at Chicago, Chicago, IL; Section of Pulmonary\/Critical Care, Department of..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adelina","family":"Sergueeva","sequence":"additional","affiliation":[{"name":"From the Comprehensive Sickle Cell Center, Section of Hematology\/Oncology (X.Z., S.S., V.R.G.), Section of Cardiology (A.A.D.), and Section of Pulmonary, Critical Care, and Sleep Medicine (J.G.N.G., R.F.M.), Department of Medicine, Institute of Human Genetics (W.Z., R.K.), Department of Pediatrics (W.Z.), and Institute for Personalized Respiratory Medicine (A.A.D., T.A., N.G.C., J.G.N.G., R.F.M.), University of Illinois at Chicago, Chicago, IL; Section of Pulmonary\/Critical Care, Department of..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatiana","family":"Ammosova","sequence":"additional","affiliation":[{"name":"From the Comprehensive Sickle Cell Center, Section of Hematology\/Oncology (X.Z., S.S., V.R.G.), Section of Cardiology (A.A.D.), and Section of Pulmonary, Critical Care, and Sleep Medicine (J.G.N.G., R.F.M.), Department of Medicine, Institute of Human Genetics (W.Z., R.K.), Department of Pediatrics (W.Z.), and Institute for Personalized Respiratory Medicine (A.A.D., T.A., N.G.C., J.G.N.G., R.F.M.), University of Illinois at Chicago, Chicago, IL; Section of Pulmonary\/Critical Care, Department of..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Xu","sequence":"additional","affiliation":[{"name":"From the Comprehensive Sickle Cell Center, Section of Hematology\/Oncology (X.Z., S.S., V.R.G.), Section of Cardiology (A.A.D.), and Section of Pulmonary, Critical Care, and Sleep Medicine (J.G.N.G., R.F.M.), Department of Medicine, Institute of Human Genetics (W.Z., R.K.), Department of Pediatrics (W.Z.), and Institute for Personalized Respiratory Medicine (A.A.D., T.A., N.G.C., J.G.N.G., R.F.M.), University of Illinois at Chicago, Chicago, IL; Section of Pulmonary\/Critical Care, Department of..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergei","family":"Nekhai","sequence":"additional","affiliation":[{"name":"From the Comprehensive Sickle Cell Center, Section of Hematology\/Oncology (X.Z., S.S., V.R.G.), Section of Cardiology (A.A.D.), and Section of Pulmonary, Critical Care, and Sleep Medicine (J.G.N.G., R.F.M.), Department of Medicine, Institute of Human Genetics (W.Z., R.K.), Department of Pediatrics (W.Z.), and Institute for Personalized Respiratory Medicine (A.A.D., T.A., N.G.C., J.G.N.G., R.F.M.), University of Illinois at Chicago, Chicago, IL; Section of Pulmonary\/Critical Care, Department of..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taimur","family":"Abbasi","sequence":"additional","affiliation":[{"name":"From the Comprehensive Sickle Cell Center, Section of Hematology\/Oncology (X.Z., S.S., V.R.G.), Section of Cardiology (A.A.D.), and Section of Pulmonary, Critical Care, and Sleep Medicine (J.G.N.G., R.F.M.), Department of Medicine, Institute of Human Genetics (W.Z., R.K.), Department of Pediatrics (W.Z.), and Institute for Personalized Respiratory Medicine (A.A.D., T.A., N.G.C., J.G.N.G., R.F.M.), University of Illinois at Chicago, Chicago, IL; Section of Pulmonary\/Critical Care, Department of..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nancy G.","family":"Casanova","sequence":"additional","affiliation":[{"name":"From the Comprehensive Sickle Cell Center, Section of Hematology\/Oncology (X.Z., S.S., V.R.G.), Section of Cardiology (A.A.D.), and Section of Pulmonary, Critical Care, and Sleep Medicine (J.G.N.G., R.F.M.), Department of Medicine, Institute of Human Genetics (W.Z., R.K.), Department of Pediatrics (W.Z.), and Institute for Personalized Respiratory Medicine (A.A.D., T.A., N.G.C., J.G.N.G., R.F.M.), University of Illinois at Chicago, Chicago, IL; Section of Pulmonary\/Critical Care, Department of..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin H.","family":"Steinberg","sequence":"additional","affiliation":[{"name":"From the Comprehensive Sickle Cell Center, Section of Hematology\/Oncology (X.Z., S.S., V.R.G.), Section of Cardiology (A.A.D.), and Section of Pulmonary, Critical Care, and Sleep Medicine (J.G.N.G., R.F.M.), Department of Medicine, Institute of Human Genetics (W.Z., R.K.), Department of Pediatrics (W.Z.), and Institute for Personalized Respiratory Medicine (A.A.D., T.A., N.G.C., J.G.N.G., R.F.M.), University of Illinois at Chicago, Chicago, IL; 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