Gastroenterology

Gastroenterology

Volume 139, Issue 1, July 2010, Pages 130-139.e24
Gastroenterology

Clinical Advances in Liver, Pancrease, and Biliary Tract
Genetic Risk Factors for Hepatopulmonary Syndrome in Patients With Advanced Liver Disease

https://doi.org/10.1053/j.gastro.2010.03.044Get rights and content

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.

Section snippets

Patients and Methods

For other information regarding patients and methods, please see Supplementary Patients and Methods.

Results

There were 59 cases and 126 controls included in this analysis (Table 2). The mean age of the subjects was 53 ± 10 years, 39% were female, and the majority (83%) was non-Hispanic. The majority of subjects in both groups had liver disease because of hepatitis C infection (44%) or alcohol (41%). Subjects with HPS had a mean PaO2 of 75 ± 13 mm Hg and a median alveolar-arterial oxygen gradient of 25 mm Hg (interquartile range, 19–35 mm Hg).

Of the 1086 SNPs genotyped in candidate genes, 3 assays

Discussion

Using a hypothesis-generating approach, we have identified that the possession of common genetic variation in genes associated with vascular growth and development and estrogen action and signaling was associated with HPS in this case-control study. In contrast, we did not find any association between HPS and vasoregulatory genes such as nitric oxide, heme oxygenase, and the endothelin-B receptor, which have been specifically implicated in HPS.28, 29, 30, 31 Our findings are in line with recent

Acknowledgments

The authors thank May Huang; John Schlatterer; and John O'Connor, PhD, from the Irving Institute for Clinical and Translational Research at Columbia University for their technical assistance.

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    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.

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