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


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).


CONCLUSIONS
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.
Mariana V
MV
Machado
André
A
Janeiro
Gabriel
G
Miltenberger-Miltenyi
Helena
H
Cortez-Pinto
D000328:Adult; D000368:Aged; D000428:Alcohol Drinking / Q000009:adverse effects*; D042501:Angiogenic Proteins / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000235:genetics*; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D008104:Liver Cirrhosis, Alcoholic / Q000175:diagnosis / Q000235:genetics*; D008113:Liver Neoplasms / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
D042501:Angiogenic Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2