Hypoxic response contributes to altered gene expression and precapillary pulmonary hypertension in patients with sickle cell disease.

TitleHypoxic response contributes to altered gene expression and precapillary pulmonary hypertension in patients with sickle cell disease.
Publication TypeJournal Article
Year of Publication2014
AuthorsZhang X, Zhang W, Ma S-F, Desai AA, Saraf S, Miasniakova G, Sergueeva A, Ammosova T, Xu M, Nekhai S, Abbasi T, Casanova NG, Steinberg MH, Baldwin CT, Sebastiani P, Prchal JT, Kittles R, Garcia JGN, Machado RF, Gordeuk VR
JournalCirculation
Volume129
Issue16
Pagination1650-8
Date Published2014 Apr 22
ISSN Number1524-4539
KeywordsAdult, Anemia, Sickle Cell, Apoptosis, Cell Hypoxia, Cohort Studies, Female, Gene Expression Regulation, Enzymologic, Humans, Hypertension, Pulmonary, Inflammation, Leukocytes, Mononuclear, Male, Mitogen-Activated Protein Kinase 8, Prospective Studies, Quantitative Trait Loci, T-Lymphocytes
Abstract

<p><b>BACKGROUND: </b>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.</p><p><b>METHODS AND RESULTS: </b>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.</p><p><b>CONCLUSIONS: </b>Our study demonstrates a prominent hypoxic transcription component in SCD and a MAPK8 expression quantitative trait locus associated with precapillary pulmonary hypertension.</p>

DOI10.1161/CIRCULATIONAHA.113.005296
Alternate JournalCirculation
PubMed ID24515990
PubMed Central IDPMC4287376
Grant ListUL1 TR000430 / TR / NCATS NIH HHS / United States
HL RC2 101212 / HL / NHLBI NIH HHS / United States
R01 HL079912-04 / HL / NHLBI NIH HHS / United States
P01CA108671 / CA / NCI NIH HHS / United States
R01 HL111656 / HL / NHLBI NIH HHS / United States
SC1 GM082325 / GM / NIGMS NIH HHS / United States
R01 HL125005 / HL / NHLBI NIH HHS / United States
G12 MD007597 / MD / NIMHD NIH HHS / United States
G12 RR003048 / RR / NCRR NIH HHS / United States
K23 HL098454 / HL / NHLBI NIH HHS / United States
P30 HL107253 / HL / NHLBI NIH HHS / United States
P50 HL118006 / HL / NHLBI NIH HHS / United States
P01 CA108671 / CA / NCI NIH HHS / United States
R01 HL 87681 / HL / NHLBI NIH HHS / United States
8G12MD007597 / MD / NIMHD NIH HHS / United States
1P30HL107253 / HL / NHLBI NIH HHS / United States
R25 HL003679 / HL / NHLBI NIH HHS / United States
R01 HL079912 / HL / NHLBI NIH HHS / United States
2 R25-HL03679-08 / HL / NHLBI NIH HHS / United States
SC1GM082325 / GM / NIGMS NIH HHS / United States
K23HL098454 / HL / NHLBI NIH HHS / United States
R01 HL087681 / HL / NHLBI NIH HHS / United States
2G12RR003048 / RR / NCRR NIH HHS / United States
M01-PR10284 / PR / OCPHP CDC HHS / United States