Genetic Risk Factors for Hepatopulmonary Syndrome in Patients With Advanced Liver Disease

Kari E. Roberts, Steven M. Kawut, Michael Joseph Krowka, Robert S. Brown, James F. Trotter, Vijay Shah, Inga Peter, Hocine Tighiouart, Nandita Mitra, Elizabeth Handorf, James A. Knowles, Steven Zacks, Michael B. Fallon

Research output: Contribution to journalArticle

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Abstract

Background & Aims: Hepatopulmonary syndrome (HPS) affects 10%-30% of patients with cirrhosis and portal hypertension and significantly increases mortality. Studies in experimental models indicate that pulmonary angiogenesis contributes to the development of HPS, but pathogenesis in humans is poorly understood. We investigated genetic risk factors for HPS in patients with advanced liver disease. Methods: We performed a multicenter case-control study of patients with cirrhosis being evaluated for liver transplantation. Cases had an alveolar-arterial oxygen gradient ≥ 15 mm Hg (or ≥20 mm Hg if age > 64 years) and contrast echocardiography with late appearance of microbubbles after venous injection of agitated saline (intrapulmonary vasodilatation); controls did not meet both criteria for case status. The study sample included 59 cases and 126 controls. We genotyped 1086 common single nucleotide polymorphisms (SNPs) in 94 candidate genes. Results: Forty-two SNPs in 21 genes were significantly associated with HPS after adjustments for race and smoking. Eight genes had at least 2 SNPs associated with disease: CAV3, ENG, NOX4, ESR2, VWF, RUNX1, COL18A1, and TIE1. For example, rs237872 in CAV3 showed an odds ratio of 2.75 (95% confidence interval: 1.65-4.60, P = .0001) and rs4837192 in ENG showed an odds ratio of 0.35 (95% confidence interval: 0.14-0.89, P = .027). Furthermore, variation in CAV3 and RUNX1 was associated with HPS in gene-based analyses. Conclusions: Polymorphisms in genes involved in the regulation of angiogenesis are associated with the risk of HPS. Further investigation of these biologic pathways might elucidate the mechanisms that mediate the development of HPS in certain patients with severe liver disease.

Original languageEnglish (US)
JournalGastroenterology
Volume139
Issue number1
DOIs
StatePublished - Jul 2010

Fingerprint

Hepatopulmonary Syndrome
Liver Diseases
Single Nucleotide Polymorphism
Genes
Fibrosis
Odds Ratio
Confidence Intervals
Microbubbles
Portal Hypertension
Vasodilation
Liver Transplantation
Echocardiography
Case-Control Studies
Theoretical Models
Smoking
Oxygen
Lung
Injections
Mortality

Keywords

  • Genetic Polymorphism
  • Portal Hypertension

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Genetic Risk Factors for Hepatopulmonary Syndrome in Patients With Advanced Liver Disease. / Roberts, Kari E.; Kawut, Steven M.; Krowka, Michael Joseph; Brown, Robert S.; Trotter, James F.; Shah, Vijay; Peter, Inga; Tighiouart, Hocine; Mitra, Nandita; Handorf, Elizabeth; Knowles, James A.; Zacks, Steven; Fallon, Michael B.

In: Gastroenterology, Vol. 139, No. 1, 07.2010.

Research output: Contribution to journalArticle

Roberts, KE, Kawut, SM, Krowka, MJ, Brown, RS, Trotter, JF, Shah, V, Peter, I, Tighiouart, H, Mitra, N, Handorf, E, Knowles, JA, Zacks, S & Fallon, MB 2010, 'Genetic Risk Factors for Hepatopulmonary Syndrome in Patients With Advanced Liver Disease', Gastroenterology, vol. 139, no. 1. https://doi.org/10.1053/j.gastro.2010.03.044
Roberts, Kari E. ; Kawut, Steven M. ; Krowka, Michael Joseph ; Brown, Robert S. ; Trotter, James F. ; Shah, Vijay ; Peter, Inga ; Tighiouart, Hocine ; Mitra, Nandita ; Handorf, Elizabeth ; Knowles, James A. ; Zacks, Steven ; Fallon, Michael B. / Genetic Risk Factors for Hepatopulmonary Syndrome in Patients With Advanced Liver Disease. In: Gastroenterology. 2010 ; Vol. 139, No. 1.
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abstract = "Background & Aims: Hepatopulmonary syndrome (HPS) affects 10{\%}-30{\%} of patients with cirrhosis and portal hypertension and significantly increases mortality. Studies in experimental models indicate that pulmonary angiogenesis contributes to the development of HPS, but pathogenesis in humans is poorly understood. We investigated genetic risk factors for HPS in patients with advanced liver disease. Methods: We performed a multicenter case-control study of patients with cirrhosis being evaluated for liver transplantation. Cases had an alveolar-arterial oxygen gradient ≥ 15 mm Hg (or ≥20 mm Hg if age > 64 years) and contrast echocardiography with late appearance of microbubbles after venous injection of agitated saline (intrapulmonary vasodilatation); controls did not meet both criteria for case status. The study sample included 59 cases and 126 controls. We genotyped 1086 common single nucleotide polymorphisms (SNPs) in 94 candidate genes. Results: Forty-two SNPs in 21 genes were significantly associated with HPS after adjustments for race and smoking. Eight genes had at least 2 SNPs associated with disease: CAV3, ENG, NOX4, ESR2, VWF, RUNX1, COL18A1, and TIE1. For example, rs237872 in CAV3 showed an odds ratio of 2.75 (95{\%} confidence interval: 1.65-4.60, P = .0001) and rs4837192 in ENG showed an odds ratio of 0.35 (95{\%} confidence interval: 0.14-0.89, P = .027). Furthermore, variation in CAV3 and RUNX1 was associated with HPS in gene-based analyses. Conclusions: Polymorphisms in genes involved in the regulation of angiogenesis are associated with the risk of HPS. Further investigation of these biologic pathways might elucidate the mechanisms that mediate the development of HPS in certain patients with severe liver disease.",
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AU - Kawut, Steven M.

AU - Krowka, Michael Joseph

AU - Brown, Robert S.

AU - Trotter, James F.

AU - Shah, Vijay

AU - Peter, Inga

AU - Tighiouart, Hocine

AU - Mitra, Nandita

AU - Handorf, Elizabeth

AU - Knowles, James A.

AU - Zacks, Steven

AU - Fallon, Michael B.

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AB - Background & Aims: Hepatopulmonary syndrome (HPS) affects 10%-30% of patients with cirrhosis and portal hypertension and significantly increases mortality. Studies in experimental models indicate that pulmonary angiogenesis contributes to the development of HPS, but pathogenesis in humans is poorly understood. We investigated genetic risk factors for HPS in patients with advanced liver disease. Methods: We performed a multicenter case-control study of patients with cirrhosis being evaluated for liver transplantation. Cases had an alveolar-arterial oxygen gradient ≥ 15 mm Hg (or ≥20 mm Hg if age > 64 years) and contrast echocardiography with late appearance of microbubbles after venous injection of agitated saline (intrapulmonary vasodilatation); controls did not meet both criteria for case status. The study sample included 59 cases and 126 controls. We genotyped 1086 common single nucleotide polymorphisms (SNPs) in 94 candidate genes. Results: Forty-two SNPs in 21 genes were significantly associated with HPS after adjustments for race and smoking. Eight genes had at least 2 SNPs associated with disease: CAV3, ENG, NOX4, ESR2, VWF, RUNX1, COL18A1, and TIE1. For example, rs237872 in CAV3 showed an odds ratio of 2.75 (95% confidence interval: 1.65-4.60, P = .0001) and rs4837192 in ENG showed an odds ratio of 0.35 (95% confidence interval: 0.14-0.89, P = .027). Furthermore, variation in CAV3 and RUNX1 was associated with HPS in gene-based analyses. Conclusions: Polymorphisms in genes involved in the regulation of angiogenesis are associated with the risk of HPS. Further investigation of these biologic pathways might elucidate the mechanisms that mediate the development of HPS in certain patients with severe liver disease.

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