Dataset Information

PNPLA3 I148M (rs738409) genetic variant and age at onset of at-risk alcohol consumption are independent risk factors for alcoholic cirrhosis.

ABSTRACT:

Background & aims

Environmental and genetic factors contribute to alcoholic cirrhosis onset. In particular, age at exposure to liver stressors has been shown to be important in progression to fibrosis in hepatitis C individuals. However, no definite data on the role of age at onset of at-risk alcohol consumption are available. Moreover, patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M (rs738409) variant has been associated with alcoholic cirrhosis, but only in cross-sectional studies. The aim of this study was to investigate the role of age at onset of at-risk alcohol consumption and PNPLA3 I148M variant on alcoholic cirrhosis incidence.

Methods

A total of 384 at-risk alcohol drinkers were retrospectively examined. The association among age at onset of at-risk alcohol consumption, PNPLA3 I148M variant and cirrhosis incidence was tested.

Results

A higher incidence of alcoholic cirrhosis was observed in individuals with an older (?24 years) compared with a younger (<24) age at onset of at-risk alcohol consumption (P-value < 0.001). Moreover, PNPLA3 148M allele carriers showed an increased incidence of cirrhosis (P-value < 0.001). Both age at onset of at-risk alcohol consumption and PNPLA3 148M allele were independent risk factors for developing cirrhosis (H.R. (95% C.I.): 2.76 (2.18-3.50), P-value < 0.001; 1.53(1.07-2.19), P-value = 0.021 respectively). The 148M allele was associated with a two-fold increased risk of cirrhosis in individuals with a younger compared with an older age at onset of at-risk alcohol consumption (H.R. (95% C.I.): 3.03(1.53-6.00) vs. 1.61(1.09-2.38).

Conclusions

Age at onset of at-risk alcohol consumption and PNPLA3 I148M genetic variant are independently associated with alcoholic cirrhosis incidence.

SUBMITTER: Burza MA

PROVIDER: S-EPMC4265268 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Publications

PNPLA3 I148M (rs738409) genetic variant and age at onset of at-risk alcohol consumption are independent risk factors for alcoholic cirrhosis.

Burza Maria Antonella MA Molinaro Antonio A Attilia Maria Luisa ML Rotondo Claudia C Attilia Fabio F Ceccanti Mauro M Ferri Flaminia F Maldarelli Federica F Maffongelli Angela A De Santis Adriano A Attili Adolfo Francesco AF Romeo Stefano S Ginanni Corradini Stefano S

Liver international : official journal of the International Association for the Study of the Liver 20130919 4

<h4>Background & aims</h4>Environmental and genetic factors contribute to alcoholic cirrhosis onset. In particular, age at exposure to liver stressors has been shown to be important in progression to fibrosis in hepatitis C individuals. However, no definite data on the role of age at onset of at-risk alcohol consumption are available. Moreover, patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M (rs738409) variant has been associated with alcoholic cirrhosis, but only in cross- ...[more]

PMID: 24102786

Similar Datasets

Project description:ImportanceAlcohol drinking and obesity are associated with an increased risk of cirrhosis and hepatocellular carcinoma (HCC), but the risk is not uniform among people with these risk factors. Genetic variants, such as I148M in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene, may play an important role in modulating cirrhosis and HCC risk.ObjectiveTo investigate the joint associations of the PNPLA3 I148M variant, alcohol intake, and obesity with the risk of cirrhosis, HCC, and liver disease-related mortality.Design, setting, and participantsThis prospective cohort study analyzed 414 209 participants enrolled in the UK Biobank study from March 2006 to December 2010. Participants had no previous diagnosis of cirrhosis and HCC and were followed up through March 2021.ExposuresSelf-reported alcohol intake (nonexcessive vs excessive), obesity (body mass index ≥30 [calculated as weight in kilograms divided by height in meters squared]), and PNPLA3 I148M variant status (noncarrier, heterozygous carrier, or homozygous carrier) from initial assessment.Main outcomes and measuresThe primary outcomes were incident cirrhosis and HCC cases and liver disease-related death ascertained from inpatient hospitalization records and death registry. The risks were calculated by Cox proportional hazards regression models.ResultsA total of 414 209 participants (mean [SD] age, 56.3 [8.09] years; 218 567 women [52.8%]; 389 452 White race and ethnicity [94.0%]) were included. Of these participants, 2398 participants (0.6%) developed cirrhosis (5.07 [95% CI, 4.87-5.28] cases per 100 person-years), 323 (0.1%) developed HCC (0.68 [95% CI, 0.61-0.76] cases per 100 person-years), and 878 (0.2%) died from a liver disease-related cause (1.76 [95% CI, 1.64-1.88] cases per 100 person-years) during a median follow-up of 10.9 years. Synergistic interactions between the PNPLA3 I148M variant, obesity, and alcohol intake were associated with the risk of cirrhosis, HCC, and liver disease-related mortality. The risk of cirrhosis increased supramultiplicatively (adjusted hazard ratio [aHR], 17.52; 95% CI, 12.84-23.90) in individuals with obesity, with excessive drinking, and who were homozygous carriers compared with those with no obesity, with nonexcessive drinking, and who were noncarriers. Supramultiplicative associations between the 3 factors and risks of HCC were found in individuals with 3 risk factors (aHR, 30.13; 95% CI, 16.51-54.98) and liver disease-related mortality (aHR, 21.82; 95% CI, 13.78-34.56). The PNPLA3 I148M variant status significantly differentiated the risk of cirrhosis, HCC, and liver disease-related mortality in persons with excessive drinking and obesity.Conclusions and relevanceThis study found synergistic associations of the PNPLA3 I148M variant, excessive alcohol intake, and obesity with increased risk of cirrhosis, HCC, and liver disease-related death in the general population. The PNPLA3 I148M variant status may help refine the risk stratification for liver disease in persons with excessive drinking and obesity who may need early preventive measures.

Project description:BACKGROUND: An isoleucine>methionine mutation at position 148 in the PNPLA3 gene (p.I148M, rs738409) has recently been identified as a susceptibility factor for liver damage in steatohepatitis. Here, we studied whether the PNPLA3 rs738409 polymorphism also affects predisposition to hepatocellular carcinoma (HCC). METHODS: We compared distributions of PNPLA3 genotypes in 80 and 81 Caucasian patients with alcoholic and hepatitis C virus (HCV)-associated HCC to 80 and 81 age- and sex-matched patients with alcohol-related and HCV-related cirrhosis without HCC, respectively. PNPLA3 genotypes in 190 healthy individuals from the same population served as reference. Potential confounders obesity, diabetes, HCV genotype and HBV co-infection were controlled by univariate and multivariate logistic regression with forward variable selection. RESULTS: PNPLA3 genotypes were in Hardy-Weinberg equilibrium for all study groups. The frequency of the 148M allele was significantly (p<0.001) increased in alcoholic cirrhosis with (53.7%) and without HCC (36.2%) but was not different between healthy controls (22.9%) and patients with cirrhosis (25.3%; p?=?0.545) and HCC (30.2%; p?=?0.071) due to hepatitis C. HCC risk was highest in 148M/M homozygous patients with alcoholic liver disease (odds ratio (OR) 16.8 versus healthy controls; 95% confidence interval (CI) 6.68-42.43, p<0.001). Finally, multivariate regression confirmed 148M/M homozygosity (OR 2.8; 95%-CI: 1.24-6.42; p?=?0.013) as HCC risk factor in alcoholic cirrhosis. In HCV-related cirrhosis only HCV genotype 1 was confirmed as a HCC risk factor (OR 4.2; 95%-CI: 1.50-11.52; p?=?0.006). CONCLUSION: The PNPLA3 148M variant is a prominent risk factor for HCC in patients with alcoholic cirrhosis, while its effects are negligible in patients with cirrhosis due to HCV. This polymorphism provides an useful tool to identify individuals with particularly high HCC risk in patients with alcoholic liver disease that should be taken into account in future HCC prevention studies.

Project description:AIM:To investigate the influence of PNPLA3 genotype in heavy drinkers on serum markers and liver stiffness (LS) during alcohol withdrawal and its association with histology. METHODS:Caucasian heavy drinkers (n = 521) with a mean alcohol consumption of 192.1 g/d (median alcohol consumption: 169.0 g/d; 95%CI: 179.0-203.3) were enrolled at the Salem Medical Center, University of Heidelberg. LS was measured by transient elastography (Fibroscan, Echosens SA, Paris, France). LS and serum markers were prospectively studied in these patients with all stages of alcoholic liver disease (steatosis, steatohepatitis, fibrosis) prior and after alcohol detoxification with a mean observation interval of 6.2 ± 3.2 d. A liver biopsy with histological analysis including the Kleiner score was obtained in 80 patients. RESULTS:The PNPLA3 rs738409 genotype distribution for CC, CG and GG was 39.2%, 52.6% and 8.2%. GG genotype primarily correlated with histological steatohepatitis (r = 0.404, P < 0.005), ballooning (r = 0.319, P < 0.005) and less with steatosis (r = 0.264, P < 0.05). Mean LS was lowest in CC carriers (13.1 kPa) as compared to CG and GG carriers (17.6 and 17.2 kPa). Notably, LS primarily correlated with fibrosis stage (r = 0.828, P < 0.005), ballooning (r = 0.516, P < 0.005), steatohepatitis (r = 0.319, P < 0.005) but not with steatosis. After alcohol withdrawal, LS did not change in CC carriers, significantly decreased in CG-carriers from 17.6 to 12.7 kPa but to a lesser extent in GG carriers from 17.6 to 14.5 kPa. This was due to prolonged resolution of inflammation with significantly elevated aspartate transaminase levels after alcohol withdrawal in GG carriers. Non-invasive fibrosis assessment by LS in all patients showed a significantly higher F0 rate as compared to the biopsy cohort (47% vs 6%) with 3.8% more CC carriers while 3.7% less were seen in the F4 cirrhosis group. Thus, about 20% of patients with alcoholic liver cirrhosis would be attributable to PNPLA3 G variants. The OR to develop cirrhosis corrected for age, gender and body mass index was 1.295 (95%CI: 0.787-2.131) for CG + GG carriers. CONCLUSION:In heavy drinkers, PNPLA3 GG primarily correlates with ballooning/steatohepatitis but not steatosis resulting in a delayed inflammation-associated resolution of LS. Consequently, sustained ballooning-associated LS elevation seems to be a potential risk factor for fibrosis progression in PNPLA3 GG carriers.

Project description:Genetic variants of PNPLA3 have been implicated in hepatocellular carcinoma (HCC) susceptibility; however, published findings have been both conflicting and inconclusive. To obtain a more precise estimate of the association of the PNPLA3 rs738409 (C > G) polymorphism with the overall risk of HCC and in patients with cirrhosis, we performed a meta-analysis of nine eligible studies identified through an online search of Ovid, PubMed, EBSCO, the Cochrane Library, the Web of Science, the China National Knowledge Infrastructure, Wanfang, and Chinese Biomedicine databases. The studies comprised 1175 patients with HCC, 876 with cirrhosis, and 3026 healthy controls. Pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated to assess associations, using fixed-effects models. Etiology subgroup and sensitivity analyses were also performed. Our results showed that rs738409 was associated with overall HCC risk and in patients with cirrhosis in the genetic contrast modes: G vs. C, GG + CG vs. CC, GG vs. CG + GG, and GG vs. CC. Stratification by etiology did not reveal any significant association between this polymorphism and hepatitis C virus (HCV)-related HCC in patients with HCV-related cirrhosis (P > 0.05). However, healthy individuals harboring two copies of the rs738409 G variant had a higher risk of HCC (GG vs. CC: OR = 4.40, 95% CI: 3.28-5.91) than those carrying a single G allele (CG vs. CC: OR = 1.62, 95% CI: 1.34-1.59); these significant association were also present in each subgroup. Furthermore, the association was more pronounced in alcohol vs. HCV-related HCC. The present meta-analysis suggests that the PNPLA3 rs738409 G allele is a risk factor for HCC except in patients with HCV-related cirrhosis, and that two copies of the rs738409 G variant conferred a higher risk for HCC in controls, especially for alcohol-related HCC. Further studies with a larger sample size are needed to ascertain the association in different ethnicities.

Dataset Information

PNPLA3 I148M (rs738409) genetic variant and age at onset of at-risk alcohol consumption are independent risk factors for alcoholic cirrhosis.

Background & aims

Methods

Results

Conclusions

Publications

PNPLA3 I148M (rs738409) genetic variant and age at onset of at-risk alcohol consumption are independent risk factors for alcoholic cirrhosis.

Similar Datasets

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