<scp><i>PNPLA3</i></scp> in end‐stage liver disease: Alcohol consumption, hepatocellular carcinoma development, and transplantation‐free survival

Friedrich, Kilian; Wannhoff, Andreas; Kattner, Stefan; Brune, Maik; Hov, Johannes R.; Weiss, Karl Heinz; Antoni, Christoph; Dollinger, Matthias; Seufferlein, Thomas; Schemmer, Peter; Schirmacher, Peter; Stremmel, Wolfgang; Gotthardt, Daniel

doi:10.1111/jgh.12540

Cited by 40 publications

(47 citation statements)

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“…Interestingly, in spite of their association with the development of ASH/ NASH related HCC, the correlation of the SNP with clinical characteristics and the prognostic significance was not established in this report. In contrast, previous studies demonstrated that survival free of liver transplantation was significantly lower in patients with ASH when carrying one or two G allele compared with wild-type (Friedrich et al, 2014).…”

Section: Discussionmentioning

confidence: 60%

“…Interestingly, although PNPLA3 polymorphism has been related to hepatic steatosis in patients with HCV infection, its association with HCC development is less clear with conflicting results. Some studies have demonstrated that the GG genotype effect the risk of HCC development (Falleti et al, 2011;Sato et al, 2014), while most other studies have reported no such association (Nischalke et al, 2011;Guyot et al, 2013;Friedrich et al, 2014). For patients with HBV infection, recent data reported that PNPLA3 polymorphism was independently associated with hepatic steatosis, but not with advanced fibrosis and HCC development (Vigano et al, 2013;Brouwer et al, 2015;Zampino et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

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Association of PNPLA3 Polymorphism with Hepatocellular Carcinoma Development and Prognosis in Viral and Non-Viral Chronic Liver Diseases

Khlaiphuengsin¹,

Kiatbumrung²,

Payungporn³

et al. 2016

Asian Pacific Journal of Cancer Prevention

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Background: The aim of this study was to evaluate any association between a single nucleotide polymorphism (SNP) in the patatin-like phospholipase domain containing 3 (PNPLA3) (rs738409, C>G) and the development and prognosis in patients with hepatocellular carcinoma (HCC). Materials and Methods: Two hundred heathy controls and 388 HCC cases were included: 211 with HBV, 98 patients with HCV, 29 with alcoholic steatohepatitis (ASH) and 52 with non-alcoholic steatohepatitis (NASH). The SNP was determined by real-time PCR based on TaqMan assays. Results: The prevalence of rs738409 genotypes CC, CG and GG in controls was 91 (45.5%), 88 (44.0%), and 21 (10.5%), respectively, while the corresponding genotypes in all patients with HCC was 158 (40.7%), 178 (45.9%), and 52 (13.4%). The GG genotype had significantly higher distribution in patients with ASH/NASH-related HCC compared with controls (OR=2.34, 95% CI=1.16-4.71, P=0.018), and viral-related HCC cases (OR=2.15, 95% CI=1.13-4.08, P=0.020). However, the frequency of the GG genotype was similar between controls and patients with viral-related HCC. At initial diagnosis, HBV-related HCC were larger and at more advanced BCLC stage than the other HCC groups. There were no significant differences between the GG and non-GG groups regarding clinical characteristics, tumor stage and overall survival. Conclusions: These data suggest an influence of the PNPLA3 polymorphism on the occurrence of HCC in patients with ASH/NASH but not among those with chronic viral hepatitis. However, the polymorphism was not associated with the prognosis of HCC.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Association of PNPLA3 Polymorphism with Hepatocellular Carcinoma Development and Prognosis in Viral and Non-Viral Chronic Liver Diseases

Khlaiphuengsin¹,

Kiatbumrung²,

Payungporn³

et al. 2016

Asian Pacific Journal of Cancer Prevention

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“…Severe alcoholic hepatitis has considerable associated mortality [8,9,[11][12][13] but apart from one small series, published in abstract form [33], which identified rs738409:G as a risk factor for developing severe alcoholic hepatitis, the potential impact of this genetic polymorphism on disease presentation, progression and outcome has not been evaluated. The results of the present study have helped clarify these associations.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore there is growing evidence that rs738409:G influences several other important aspects of alcohol-related liver disease; thus, carriage of the G allele is associated with earlier development of cirrhosis, independently of the age of onset of at-risk alcohol consumption [32]; more rapid progression towards decompensated disease [33]; a reduction in transplantation-free survival [33] and poorer outcomes following development of hepatocellular carcinoma [34].…”

Section: Introductionmentioning

confidence: 99%

Homozygosity for rs738409:G in PNPLA3 is associated with increased mortality following an episode of severe alcoholic hepatitis

Atkinson

Way

McQuillin

et al. 2017

Journal of Hepatology

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Background & Aims: Carriage of rs738409:G in PNPLA3 is associated with an increased risk of developing alcohol-related cirrhosis and has a significant negative effect on survival. Short-term mortality in patients with severe alcoholic hepatitis is high; drinking behaviour is a major determinant of outcome in survivors. The aim of this study was to determine whether carriage of rs738409:G has an additional detrimental effect on survival in this patient group. Methods: Genotyping was undertaken in 898 cases with severe alcoholic hepatitis, recruited through the UK Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial, and 1,188 white British/Irish alcohol dependent controls with no liver injury recruited via University College London. Subsequent drinking behaviour was classified, in cases surviving ≥90 days, as abstinent or drinking. The relationship between rs738409 genotype, drinking behaviour and survival was explored. Results: The frequency of rs738409:G was significantly higher in cases than controls (29.5% vs. 18.9%;). Case-mortality at days 28, 90 and 450 was, 16%, 25% and 41% respectively. There was no association between rs738409:G and 28-day mortality. Mortality in the period day 90-450 was higher in survivors who subsequently resumed drinking (Hazard Ratio [HR] 2.77, 95% Confidence Interval [CI] 1.79-4.29; p<0.0001) and individuals homozygous for rs738409:G (HR 1.69, 95% CI 1.02-2.81, p=0.04). Conclusion: Homozygosity for rs738409:G in PNPLA3 confers significant additional risk of medium-term mortality in patients with severe alcoholic hepatitis. Rs738409 genotype may be an additional factor when considering treatment options in these patients.Response to Reviewers: Reviewer statistics 1.Imputing missing drinking behavior at 90 days based on observed values at 1 year is tricky, even in sensitivity analyses. Actually, this corresponds to sort of conditioning on the future, which should be avoided because it may lead to biased results (see works by Terry Therneau, for instance). Since it is a sensitivity analyses, the issue is less severe than for a primary analysis, but the limit should be stated. 2.The authors explain that now they only kept subgroup analyses where a significant interaction was found, but in the manuscript, it remains "Separate models were fitted for clinically relevant features and biochemical parameters", thus without conditioning on a significant interaction. 3.My point on the sentence "Individuals homozygous for rs738409:G had a significantly lower 450-day survival, even if abstinent" has been misunderstood, and it is certainly because I was not clear enough. I did not mean that there was no significant difference in any of the whole population and the subgroup analyses, but that it was not possible to claim that 450 days mortality would be lower in patients homozygous for rs738409:G because this was not analyzed. What the study shows is that among patients still alive at 90 days, the 450 days mortality was different, which is different. Simply stating "450 day...

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“…Among them, variants in the PNPLA3 gene had the strongest signal with GWAS-significance. Interestingly, a crosssectional study following 105 alcoholic cirrhotic patients with end-stage liver disease reported that rs738409 [G] was associated with shorter time to hepatic decompensation and reduced transplantation-free survival [31]. These potentially interesting findings linking PNPLA3 to patient prognosis are still awaiting replication.…”

Section: Alcoholic Liver Diseasementioning

confidence: 99%

PNPLA3 gene in liver diseases

Trépo

Romeo

Zucman‐Rossi

et al. 2016

Journal of Hepatology

232

196

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PNPLA3 in end‐stage liver disease: Alcohol consumption, hepatocellular carcinoma development, and transplantation‐free survival

Cited by 40 publications

References 28 publications

Association of PNPLA3 Polymorphism with Hepatocellular Carcinoma Development and Prognosis in Viral and Non-Viral Chronic Liver Diseases

Association of PNPLA3 Polymorphism with Hepatocellular Carcinoma Development and Prognosis in Viral and Non-Viral Chronic Liver Diseases

Homozygosity for rs738409:G in PNPLA3 is associated with increased mortality following an episode of severe alcoholic hepatitis

PNPLA3 gene in liver diseases

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