Volume 139, Issue 1 , Pages 130-139.e24, July 2010
Kari E. Roberts, Steven M. Kawut, Michael J. Krowka, Robert S. Brown Jr, James F. Trotter, Vijay Shah, Inga Peter, Hocine Tighiouart, Nandita Mitra, Elizabeth Handorf, James A. Knowles, Steven Zacks, Michael B. Fallon
Received 2 December 2009; accepted 4 March 2010. published online 25 March 2010.
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.
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.
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.
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.
Keywords: Genetic Polymorphism, Portal Hypertension
Abbreviations used in this paper: 95% CI, 95% confidence interval, AIM, Ancestry Informative Marker, CART, classification and regression trees, CAV3, Caveolin 3, COL18A1, collagen, type XVIII, α-1, D, linkage disequilibrium coefficient, EGF, epidermal growth, ENG, endoglin, ESR2, Estrogen receptor 2, HIF1A, Hypoxia-inducible factor 1, α subunit, HPS, hepatopulmonary syndrome, HWE, Hardy–Weinberg equilibrium, MELD, Model for End-stage Liver Disease, NOX4, NADPH Oxidase 4, OR, odds ratio, PaO2, partial pressure of oxygen in arterial blood, PC, principal component regression analysis, RUNX1, Runt-related transcription factor 1, SAT2, Spermidine/spermine N1-acetyltransferase family member, SHBG, Steroid hormone binding globulin, SNP, single nucleotide polymorphism, TIE1, Tyrosine kinase with Ig and EGF factor homology domains 1, VWF, von Willebrand factor
A listing of additional members of the Pulmonary Vascular Complications of Liver Disease Study Group can be found in Appendix 1.
Conflicts of interest The authors disclose no conflicts.
Funding Supported by NIH grants DK064103, DK065958, RR00645, RR00585, RR00046, RR00032, HL67771, HL089812 and, in part, under a grant with the Pennsylvania Department of Health, which specifically disclaims responsibility for any analysis, interpretations, or conclusions.
© 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.