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

Xu Zhang, Wei Zhang, Shwu Fan Ma, Ankit A. Desai, Santosh Saraf, Galina Miasniakova, 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 Machado, Victor R. Gordeuk

Research output: Contribution to journalArticle

18 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)1650-1658
Number of pages9
JournalCirculation
Volume129
Issue number16
DOIs
StatePublished - Apr 22 2014
Externally publishedYes

Fingerprint

Sickle Cell Anemia
Pulmonary Hypertension
Gene Expression
Quantitative Trait Loci
Gene Frequency
Anemia
Odds Ratio
Genotype
Genes
Sickle Hemoglobin
Polycythemia
Pulmonary Wedge Pressure
Homozygote
Cardiac Catheterization
Mitogen-Activated Protein Kinases
Pulmonary Artery
Cell Differentiation
Blood Cells
Up-Regulation
Down-Regulation

Keywords

  • anemia
  • anoxia
  • gene expression
  • genetic association studies
  • hypertension
  • mitogen-activated protein kinase 8
  • pulmonary
  • quantitative trait loci
  • sickle cell

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Hypoxic response contributes to altered gene expression and precapillary 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; Gordeuk, Victor R.

In: Circulation, Vol. 129, No. 16, 22.04.2014, p. 1650-1658.

Research output: Contribution to journalArticle

Zhang, X, Zhang, W, Ma, SF, 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, R & Gordeuk, VR 2014, 'Hypoxic response contributes to altered gene expression and precapillary pulmonary hypertension in patients with sickle cell disease', Circulation, vol. 129, no. 16, pp. 1650-1658. https://doi.org/10.1161/CIRCULATIONAHA.113.005296
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 ; Gordeuk, Victor R. / Hypoxic response contributes to altered gene expression and precapillary pulmonary hypertension in patients with sickle cell disease. In: Circulation. 2014 ; Vol. 129, No. 16. pp. 1650-1658.
@article{a5d6d3091b254e41aea50bb1f09d69ae,
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. 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 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.",
keywords = "anemia, anoxia, gene expression, genetic association studies, hypertension, mitogen-activated protein kinase 8, pulmonary, quantitative trait loci, sickle cell",
author = "Xu Zhang and Wei Zhang and Ma, {Shwu Fan} and Desai, {Ankit A.} and Santosh Saraf and Galina Miasniakova and Adelina Sergueeva and Tatiana Ammosova and Min Xu and Sergei Nekhai and Taimur Abbasi and Casanova, {Nancy G.} and Steinberg, {Martin H.} and Baldwin, {Clinton T.} and Paola Sebastiani and Prchal, {Josef T.} and Rick Kittles and Garcia, {Joe G.N.} and Roberto Machado and Gordeuk, {Victor R.}",
year = "2014",
month = "4",
day = "22",
doi = "10.1161/CIRCULATIONAHA.113.005296",
language = "English (US)",
volume = "129",
pages = "1650--1658",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "16",

}

TY - JOUR

T1 - Hypoxic response contributes to altered gene expression and precapillary pulmonary hypertension in patients with sickle cell disease

AU - Zhang, Xu

AU - Zhang, Wei

AU - Ma, Shwu Fan

AU - Desai, Ankit A.

AU - Saraf, Santosh

AU - Miasniakova, Galina

AU - Sergueeva, Adelina

AU - Ammosova, Tatiana

AU - Xu, Min

AU - Nekhai, Sergei

AU - Abbasi, Taimur

AU - Casanova, Nancy G.

AU - Steinberg, Martin H.

AU - Baldwin, Clinton T.

AU - Sebastiani, Paola

AU - Prchal, Josef T.

AU - Kittles, Rick

AU - Garcia, Joe G.N.

AU - Machado, Roberto

AU - Gordeuk, Victor R.

PY - 2014/4/22

Y1 - 2014/4/22

N2 - 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 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.

AB - 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 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.

KW - anemia

KW - anoxia

KW - gene expression

KW - genetic association studies

KW - hypertension

KW - mitogen-activated protein kinase 8

KW - pulmonary

KW - quantitative trait loci

KW - sickle cell

UR - http://www.scopus.com/inward/record.url?scp=84899473094&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84899473094&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.113.005296

DO - 10.1161/CIRCULATIONAHA.113.005296

M3 - Article

VL - 129

SP - 1650

EP - 1658

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 16

ER -