title: Hypoxic response contributes to altered gene expression and precapillary pulmonary hypertension in patients with sickle cell disease.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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 (VHL(R200W) homozygotes with constitutive upregulation of hypoxia-inducible factors in the absence of anemia or hypoxia). At a 5% false discovery rate, 1040 genes exhibited >1.15-fold change in both conditions; 297 were upregulated and 743 downregulated including MAPK8 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 MAPK8 expression quantitative trait locus, rs10857560, was associated with precapillary pulmonary hypertension defined as mean pulmonary artery pressure ≥25 mm Hg and pulmonary capillary wedge pressure ≤15 mm Hg at right heart catheterization (allele frequency, 0.66; odds ratio, 13.8; n=238). This association was confirmed in an independent Walk-Treatment 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 MAPK8 expression and present in all 14 of the identified precapillary pulmonary hypertension cases among the combined 757 patients.
  
  
  CONCLUSIONS
  Our study demonstrates a prominent hypoxic transcription component in SCD and a MAPK8 expression quantitative trait locus associated with precapillary pulmonary hypertension.
authors: 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 Medicine, University of Chicago, Chicago, IL (S-F.M.); Chuvash Republic Clinical Hospital 2, Cheboksary, Russia (G.M.); Cheboksary Children's Hospital, Cheboksary, Russia (A.S.); Center for Sickle Cell Disease, Howard University, Washington, DC (T.A., M.X., S.N.); Department of Medicine, Boston University School of Medicine, Boston, MA (M.H.S., C.T.B.); Department of Biostatistics, Boston University School of Public Health, Boston, MA (P.S.); Hematology Division, University of Utah, Salt Lake City, UT (J.T.P.).
authors: Xu
authors: X
authors: Zhang
authors: Wei
authors: W
authors: Zhang
authors: Shwu-Fan
authors: SF
authors: Ma
authors: Ankit A
authors: AA
authors: Desai
authors: Santosh
authors: S
authors: Saraf
authors: Galina
authors: G
authors: Miasniakova
authors: Adelina
authors: A
authors: Sergueeva
authors: Tatiana
authors: T
authors: Ammosova
authors: Min
authors: M
authors: Xu
authors: Sergei
authors: S
authors: Nekhai
authors: Taimur
authors: T
authors: Abbasi
authors: Nancy G
authors: NG
authors: Casanova
authors: Martin H
authors: MH
authors: Steinberg
authors: Clinton T
authors: CT
authors: Baldwin
authors: Paola
authors: P
authors: Sebastiani
authors: Josef T
authors: JT
authors: Prchal
authors: Rick
authors: R
authors: Kittles
authors: Joe G N
authors: JG
authors: Garcia
authors: Roberto F
authors: RF
authors: Machado
authors: Victor R
authors: VR
authors: Gordeuk
mesh_terms: D000328:Adult; D000755:Anemia, Sickle Cell / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology; D017209:Apoptosis / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D015331:Cohort Studies; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006976:Hypertension, Pulmonary / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology; D007249:Inflammation / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology; D008297:Male; D048055:Mitogen-Activated Protein Kinase 8 / Q000096:biosynthesis / Q000235:genetics*; D011446:Prospective Studies; D040641:Quantitative Trait Loci / Q000502:physiology; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology
chemical_list: D048055:Mitogen-Activated Protein Kinase 8
keywords: anemia, sickle cell; anoxia; gene expression; genetic association studies; hypertension, pulmonary; mitogen-activated protein kinase 8; quantitative trait loci