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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. 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 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.

SUBMITTER: Zhang X

PROVIDER: S-EPMC4287376 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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

Zhang Xu X Zhang Wei W Ma Shwu-Fan SF Desai Ankit A AA Saraf Santosh S Miasniakova Galina G Sergueeva Adelina A Ammosova Tatiana T Xu Min M Nekhai Sergei S Abbasi Taimur T Casanova Nancy G NG Steinberg Martin H MH Baldwin Clinton T CT Sebastiani Paola P Prchal Josef T JT Kittles Rick R Garcia Joe G N JG Machado Roberto F RF Gordeuk Victor R VR

Circulation 20140210 16

<h4>Background</h4>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.<h4>Methods and results</h4>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 ...[more]

PMID: 24515990

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Project description:BackgroundAlthough pulmonary vascular bed has been the main subject of research for many years in pulmonary hypertension (PH), interest has recently started to divert towards the possibility of a co-existing peripheral microangiopathy. The aim of the current study was to investigate the presence of nailfold video-capillaroscopic (NVC) structural changes in patients with precapillary PH and to identify possible associations of NVC measurements with markers of disease severity.Methods? prospective case-control study was performed in 28 consecutive patients with precapillary PH [14 with idiopathic pulmonary arterial hypertension (IPAH) and 14 with chronic thromboembolic pulmonary hypertension (CTEPH)] and 30 healthy controls. NVC quantitative and qualitative parameters were evaluated using Optilia Digital Capillaroscope. To ensure inter-observer repeatability capillaroscopic images were reviewed by two independent investigators. For multiple comparisons among continuous variables, one-way ANOVA or the Kruskal-Wallis test were used. Differences between the groups were tested with post-hoc analysis with adjustment for multiple comparisons (Bonferroni test).ResultsBoth IPAH (71.4% were women, mean age 53.1?±?13.4 years) and CTEPH (64.3% women, mean age 60.9?±?14.4 years) groups presented reduced capillary density compared to healthy controls (8.4?±?1.2 loops/mm and 8.0?±?1.2 loops/mm vs. 9.7?±?0.81 loops/mm, p?<?0.001) and increased loop width (15.7?±?3.9 ?m and 15.8?±?1.9 ?m vs. 11.5?±?2.3 ?m, p?<?0.001). More than half of patients with IPAH presented microhaemorrhages on capillary nailfold, while increased shape abnormalities in capillary morphology and more capillary thrombi per linear mm were detected in patients with CTEPH compared to patients with IPAH and healthy controls. All PH patients presented a non-specific NVC pattern compared to controls (p?<?0.001).ConclusionThe findings of the study reveal a degree of significant peripheral microvascular alterations in patients with IPAH and CTEPH, suggesting a generalized impairment of peripheral microvasculature in pulmonary vascular disease.

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

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

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