A two gene-based risk score predicts alcoholic cirrhosis development in males with at-risk alcohol consumption

BACKGROUND & AIMS: Alcoholic cirrhosis (AC) has a multifactorial combination of environmental and genetic factors and has a higher incidence in males than in females. Our previous study showed for the first time that age at onset of at-risk alcohol consumption is an independent risk factor for alcoholic cirrhosis and this is independent by the PNPLA3 I148M genetic variant in at-risk drinkers. The increased liver sensitivity to alcohol with age may be ascribed to an increased sensitivity of the liver to its chronic effects with age, as a consequence of age-related reduced alcohol metabolism in the liver and of cellular senescence with impaired hepatocyte function. Conflicting results have been published on the association of this disease with the rs2569190 polymorphism (C159T) in the promoter region of the CD14 gene. This CD14 variant is associated with protein overexpression on Kupffer cells promoting cell activation and inflammation. Most studies on genetic predisposition to AC are cross-sectional and include subjects of both sexes. We aimed to develop a gene-based risk score to predict the incidence over time of AC in males with at-risk alcohol consumption. METHODS: A total of 416 consecutive at-risk alcohol male drinkers were retrospectively examined. At-risk alcohol consumption was defined as ≥3 alcohol units/day for at least five years. The patterns and the amount of alcohol consumption from the onset of at-risk alcohol consumption were obtained by interview using the Lifetime Drinking History. The diagnosis of AC was defined by examining patients’ past and present clinical data (physical examination, blood tests, imaging, endoscopy) at first visit or at follow-up. The association between AC incidence and PNPLA3 I148M variant, CD14 C159T variant, age at onset of at-risk alcohol consumption, patient age, BMI and diabetes was tested in order to create a score for the prediction of AC incidence in 36 years from the onset of at-risk alcohol consumption by calculating time-dependent ROC curves. RESULTS: AC diagnosis was done in 90 (22%) subjects. The distribution of polymorphisms for PNPLA3 and CD14 were significantly different in the two groups (p<0.001 and p=0.008, respectively), with a higher allele frequency of PNPLA3 allele M (0.52 vs 0.32) and CD14 allele T (0.49 vs 0.62) in the AC group than in the ALD group. The best predictive score formula was: (age at onset of at-risk alcohol consumption * 0.1)+(number of CD14 C159T allele)+(number of PNPLA3 I148M allele)+(BMI * 0.1). The threshold of 7.27 performed well in predicting the risk of AC diagnosis in 36 years from the onset of at-risk alcohol consumption with sensitivity of 70.1% and specificity of 78.7%, the AUC was 75%. CONCLUSIONS: In male subjects with at-risk alcohol consumption, our score based on two common genetic polymorphisms has a good accuracy to predict the risk of AC development. This is the first score for AC prediction which combines clinical and genetic factors.