Background: Alcoholic cirrhosis represents 1% of all cause-of-deaths worldwide. Its incidence is higher in males and results from the combination of environmental and genetic factors. Among all the genetic determinants of alcoholic cirrhosis, the patatin-like phospholipase domain protein 3 (PNPLA3) rs738409 represents the most widely validated determinant. Recent cross-sectional studies on alcohol abusers identified transmembrane-6 superfamily member 2 (TM6SF2) rs58542926, membrane bound O-acyltransferase domain containing 7 (MBOAT7) rs641738, and cluster of differentiation 14 (CD14) rs2569190 as new genetic risk factors for alcoholic cirrhosis. We aimed to develop a gene-based risk score to predict the incidence of alcoholic cirrhosis in males with at-risk alcohol consumption.
Materials and methods: A total of 416 male at-risk alcohol drinkers were retrospectively examined. The association between alcoholic cirrhosis incidence and PNPLA3, CD14, TM6SF2, and MBOAT7 variants was tested. Age at onset of at-risk alcohol consumption, age, and body mass index (BMI) were included as covariates to determine the prediction score for alcoholic cirrhosis incidence by evaluating time-dependent receiver operating characteristic curves.
Results: We found that PNPLA3, CD14, and TM6SF2 were associated with alcoholic cirrhosis prevalence. PNPLA3 and CD14 were also associated with its incidence. The best predictive score formula was (age at onset of at-risk alcohol consumption × 0.1) + (number of CD14 allele T) + (number of PNPLA3 allele M) + (BMI × 0.1). A threshold of 7.27 was identified as cutoff for the predictive risk of alcoholic cirrhosis development in 36 years from the onset of at-risk alcohol consumption with 70.1% sensitivity and 78.7% specificity.
Conclusion: We developed the first score for alcoholic cirrhosis prediction that combines clinical and genetic factors.
Keywords: CD14; PNPLA3; alcoholic cirrhosis; predictive score.
Conflict of interest statement
Disclosure The authors reports no conflicts of interest in this work.
Genetic Variants in PNPLA3 and TM6SF2 Predispose to the Development of Hepatocellular Carcinoma in Individuals With Alcohol-Related CirrhosisF Stickel et al. Am J Gastroenterol 113 (10), 1475-1483. PMID 29535416.Carriage of TM6SF2 rs58542926 is an additional risk factor for the development of HCC in people with alcohol-related cirrhosis. Carriage of both PNPLA3 rs738409 and TM6SF …
PNPLA3 I148M (rs738409) Genetic Variant and Age at Onset of At-Risk Alcohol Consumption Are Independent Risk Factors for Alcoholic CirrhosisMA Burza et al. Liver Int 34 (4), 514-20. PMID 24102786.Age at onset of at-risk alcohol consumption and PNPLA3 I148M genetic variant are independently associated with alcoholic cirrhosis incidence.
PNPLA3 rs738409 and TM6SF2 rs58542926 Variants Increase the Risk of Hepatocellular Carcinoma in Alcoholic CirrhosisE Falleti et al. Dig Liver Dis 48 (1), 69-75. PMID 26493626.TM6SF2 C/T or T/T in conjunction with PNPLA3 G/G variants may be potential genetic risk factors for developing HCC in alcohol-related cirrhosis.
PNPLA3 Gene Polymorphism Is Associated With Predisposition to and Severity of Alcoholic Liver DiseaseH Salameh et al. Am J Gastroenterol 110 (6), 846-56. PMID 25964223. - ReviewPNPLA3 genetic polymorphism (rs738409 C>G) is associated with increased risk for the entire spectrum of ALD among drinkers including ALI, AC, and HCC. Studies are need …
Systematic Review With Meta-Analysis: The I148M Variant of Patatin-Like Phospholipase Domain-Containing 3 Gene (PNPLA3) Is Significantly Associated With Alcoholic Liver CirrhosisAJ Chamorro et al. Aliment Pharmacol Ther 40 (6), 571-81. PMID 25060292. - ReviewOur meta-analysis shows that the rs738409 variant of PNPLA3 is clearly associated with alcoholic liver cirrhosis.
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