Document Detail


The Hypoxic Response Contributes to Altered Gene Expression and Pre-Capillary Pulmonary Hypertension in Patients with Sickle Cell Disease.
MedLine Citation:
PMID:  24515990     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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.
METHODS AND 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 SCD subjects with hemoglobin SS genotype and 15 Chuvash polycythemia subjects (VHL(R200W) homozygotes with constitutive up-regulation of hypoxia inducible factors in the absence of anemia or hypoxia). At 5% false discovery rate, 1040 genes exhibited >1.15 fold change in both conditions; 297 were up-regulated and 743 down-regulated 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 SCD patients identified expression quantitative trait loci (eQTL) for 103 of these hypoxia response genes. In a University of Illinois SCD cohort the A allele of a MAPK8 eQTL, rs10857560, was associated with pre-capillary pulmonary hypertension defined as mean pulmonary artery pressure ≥25 and pulmonary capillary wedge pressure ≤15 mm Hg at right heart catheterization (allele frequency=0.66; OR=13.8, P=0.00036, n=238). This association was confirmed in an independent Walk-PHaSST cohort (allele frequency=0.65; OR=11.3, P=0.0025, n=519). The homozygous AA genotype of rs10857560 was associated with decreased MAPK8 expression and present in all 14 identified pre-capillary pulmonary hypertension cases among the combined 757 patients.
CONCLUSIONS: Our study demonstrates a prominent hypoxic transcription component in SCD and a MAPK8 eQTL associated with pre-capillary pulmonary hypertension.
Authors:
Xu Zhang; Wei Zhang; Shwu-Fan Ma; Ankit A Desai; Santosh Saraf; Galina Miasnikova; Adelina Sergueeva; Tatiana Ammosova; Min Xu; Sergei Nekhai; Taimur Abbasi; Nancy G Casanova; Martin H Steinberg; Clinton T Baldwin; Paola Sebastiani; Josef T Prchal; Rick Kittles; Joe G N Garcia; Roberto F Machado; Victor R Gordeuk
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-2-10
Journal Detail:
Title:  Circulation     Volume:  -     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2014 Feb 
Date Detail:
Created Date:  2014-2-11     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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