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Genetic polymorphisms of proangiogenic factors seem to favor hepatocellular carcinoma development in alcoholic cirrhosis

Machado, Mariana V.a; Janeiro, Andréb; Miltenberger-Miltenyi, Gabrielb; Cortez-Pinto, Helenaa

European Journal of Gastroenterology & Hepatology: April 2014 - Volume 26 - Issue 4 - p 438–443
doi: 10.1097/MEG.0000000000000044
Original Articles: Hepatocellular Carcinoma

Objective Angiogenesis has been associated with hepatic cirrhosis and hepatocellular carcinoma (HCC). Alcohol promotes liver hypoxia, a trigger of angiogenesis. We aimed to evaluate whether the frequency of three polymorphisms in hypoxia-induced factor-1α (HIF-1α), vascular endothelial growth factor A (VEGFA), and KDR (encoding vascular endothelial growth factor receptor 2) genes was higher in alcoholics presenting liver disease (ALD) and ALD patients who developed HCC.

Materials and methods Functional HIF-1α 1744C/T, VEGFA 2578C/A, and KDR 1416A/T single-nucleotide polymorphisms were studied in 125 ALD patients and 88 heavy drinkers without liver disease (NLD). ALD patients were followed up to 9 years or until they died; 26 patients developed HCC.

Results ALD patients were older than NLD (56±11 vs. 50±13, P<0.001), but drank less (215±164 vs. 331±293 g/day, P<0.001). No differences were found between HIF-1α, VEGFA, or KDR allelic frequencies or genotypes, isolated or simultaneously, between ALD and NLD. In ALD patients, those who developed HCC had a higher KDR 1416T allele frequency (36 vs. 15%, P=0.004; odds ratio 2.72; 95% confidence interval 1.35–5.46). There was also a progressive increase in genotypes with one or two T alleles in patients who developed HCC: AA 50 vs. 73%, AT 35 vs. 23%, and TT 15 vs. 4% (P=0.009). The simultaneous presence of KDR 1416T and VEGFA 2578A was associated with an increased risk of HCC (odds ratio 3.088; 95% confidence interval 1.20–7.96).

Conclusion Genetic polymorphisms in proangiogenic factors did not associate with the risk of ALD in heavy drinkers. However, KDR and VEFGA polymorphisms may confer an increased risk of HCC in patients with ALD.

aDepartment of Gastroenterology, Hospital Santa Maria, CHLN, Unit of Nutrition and Metabolism

bGenoMed Institute of Molecular Medicine, Faculty of Medicine of Lisbon, Lisbon, Portugal

Correspondence to Helena Cortez-Pinto, Department of Gastroenterology, Nutrition and Metabolism Unit, Hospital of Santa Maria, Molecular Medicine Institute, Lisbon Medicine University, Av. Prof. Egas Moniz, 1649 035 Lisbon, Portugal Tel: +351 217 985 187; fax: +351 217 985 142; e-mail:

Received November 1, 2013

Accepted December 16, 2013

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins