The Hypoxic Response Contributes to Altered Gene Expression and Pre-Capillary Pulmonary Hypertension in Patients with Sickle Cell Disease

Zhang, Xu; Zhang, Wei; Ma, Shwu-Fan; Desai, Ankit A.; Saraf, Santosh; Miasniakova, Galina; Sergueeva, Adelina; Ammosova, Tatiana; Xu, Min; Nekhai, Sergei; Abbasi, Taimur; Casanova, Nancy G.; Steinberg, Martin H.; Baldwin, Clinton T.; Sebastiani, Paola; Prchal, Josef T.; Kittles, Rick; Garcia, Joe G. N.; Machado, Roberto F.; Gordeuk, Victor R.

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The Hypoxic Response Contributes to Altered Gene Expression and Pre-Capillary Pulmonary Hypertension in Patients with Sickle Cell Disease

Published Date:

Feb 10 2014

Source:

Circulation. 129(16):1650-1658.

Language:

English

[PDF-967.56 KB]

Details:

Personal Authors:

Zhang, Xu ; Zhang, Wei ; Ma, Shwu-Fan ; Desai, Ankit A. ; Saraf, Santosh ; ... More ▼

Keywords:

[+]

Pubmed ID:

24515990

Pubmed Central ID:

PMC4287376

Description:

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 (VHLR200W 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.

Document Type:

Journal Article

Collection(s):

CDC Public Access

Funding:

Supporting Files:

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