PNPLA3 I148M associations with liver carcinogenesis in Japanese chronic hepatitis C patients

Nakaoka, Kazunori; Hashimoto, Senju; Kawabe, Naoto; Nitta, Yoshifumi; Murao, Michihito; Nakano, Takuji; Shimazaki, Hiroaki; Kan, Toshiki; Takagawa, Yuka; Ohki, Masashi; Kurashita, Takamitsu; Takamura, Tomoki; Nishikawa, Toru; Ichino, Naohiro; Osakabe, Keisuke; Yoshioka, Kentaro

doi:10.1186/s40064-015-0870-5

Cited by 17 publications

(14 citation statements)

References 43 publications

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“…The data was heterogeneous ( I 2 = 65.9%, P = 0.081), with evidence of publication bias as assessed by Begg-Mazumdar test ( P = 0.036) and tendency for publication bias as assessed by Egger test ( P = 0.059). Sensitivity analysis after excluding studies with lowest[14] and highest[49] OR revealed similar effect size: 1.82 (95%CI: 1.41-2.34) with I 2 = 18.8%, P = 0.30. Additionally, when Dual and Tweedie trim and fall test was used to assess publication bias, 3 studies were trimmed with no change in effect size (OR = 1.39, 95%CI: 1.01-1.92).…”

Section: Resultsmentioning

confidence: 86%

PNPLA3polymorphism increases risk for and severity of chronic hepatitis C liver disease

Salameh

Masadeh

Hanayneh³

et al. 2016

WJH

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AIMTo examine the association of PNPLA3 polymorphisms in chronic hepatitis C patients and development of liver disease spectrum.METHODSLiterature was searched systematically from PubMed/MEDLINE, EMBASE, and Cochrane search engines for full-length articles written in English that examined PNPLA3 polymorphism in chronic hepatitis C (CHC) patients. Studies evaluating the association of PNPLA3 polymorphism spectrum (fatty liver, steatohepatitis, cirrhosis, and hepatocellular carcinoma) of CHC were included. Pooled data are reported as OR with 95%CI. Our study endpoint was the risk of the entire liver disease spectrum including: Steatosis/fatty liver, cirrhosis, and hepatocellular carcinoma in CHC patients with PNPLA3 polymorphisms.RESULTSOf 380 studies identified, a total of 53 studies were included for full-text review. Nineteen on chronic hepatitis C were eligible for analysis. Pooled ORs for rs738409 GG compared to CC and CG among patients with fatty liver was 2.214 (95%CI: 1.719-2.853). ORs among advanced fibrosis/cirrhosis were 1.762 (95%CI: 1.258-2.468). Similar odds ratios among hepatocellular carcinoma patients were 2.002 (95%CI: 1.519-2.639). Pooled ORs for rs738409 GG and CG compared to CC among patients with fatty liver were 1.750 (95%CI: 1.542-1.986). Pooled ORs for advanced fibrosis/cirrhosis patients were 1.613 (95%CI: 1.211-2.147). All analyses were homogenous and without publication bias except one. The associations were maintained after adjusting for publication bias and heterogeneity.CONCLUSIONPNPLA3 polymorphisms have strong association with increased risk and severity of the liver disease spectrum in CHC patients.

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Section: Resultsmentioning

confidence: 86%

PNPLA3polymorphism increases risk for and severity of chronic hepatitis C liver disease

Salameh

Masadeh

Hanayneh³

et al. 2016

WJH

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“…These include genetic factors such as PNPLA3. PNPLA3 rs738409 2 risk alleles has been identified a risk factor for developing HCC associated with NAFLD [ 44 ], alcoholic liver disease [ 45 ] or chronic HCV infection [ 46 , 47 ].The role of central obesity as a risk for HCC is also emerging as shown in a large European study [ 48 ]. The high prevalence of cirrhosis in Hispanics in South Texas seems to correlate with the high prevalence of HCC in this population.…”

Section: Discussionmentioning

confidence: 99%

Cirrhosis and Advanced Fibrosis in Hispanics in Texas: The Dominant Contribution of Central Obesity

Jiao

Watt²,

Lee

et al. 2016

PLoS ONE

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Liver cirrhosis is a leading cause of death in Hispanics and Hispanics who live in South Texas have the highest incidence of liver cancer in the United States. We aimed at determining the prevalence and associated risk factors of cirrhosis in this population. Clinical and demographic variables were extracted for 2466 participants in the community-based Cameron County Hispanic Cohort in South Texas. Aspartate transaminase to Platelet Ratio Index (APRI) was used to predict cirrhosis in Cameron County Hispanic Cohort. The prevalence of cirrhosis using APRI≥2 was 0.94%, which is nearly 4-fold higher than the national prevalence. Using APRI≥1, the overall prevalence of cirrhosis/advanced fibrosis was 3.54%. In both analyses, highest prevalence was observed in males, specifically in the 25–34 age group. Risk factors independently associated with APRI≥2 and APRI≥1 included hepatitis C, diabetes and central obesity with a remarkable population attributable fraction of 52.5% and 65.3% from central obesity, respectively. Excess alcohol consumption was also independently associated with APRI≥2. The presence of patatin-like phospholipase domain-containing-3 gene variants was independently associated with APRI≥1 in participants >50 years old. Males with both central obesity and excess alcohol consumption presented with cirrhosis/advanced fibrosis at a young age. Alarmingly high prevalence of cirrhosis and advanced fibrosis was identified in Hispanics in South Texas, affecting young males in particular. Central obesity was identified as the major risk factor. Public health efforts are urgently needed to increase awareness and diagnosis of advanced liver fibrosis in Hispanics.

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“…Importantly, additional GWAS have identified a nonsynonymous SNP rs738409 (C > G; p. I148M) in patatin‐like phospholipase domain‐containing 3 ( PNPLA3 ) and a SNP rs58542926 (C > T; p. E167K) of transmembrane 6 superfamily 2 ( TM6SF2 ), two genes involved in lipid metabolism, as associated with development of NAFLD . PNPLA3 rs738409 has also been associated with HCC in case–control study and prospective cohorts in alcohol‐related cirrhosis whereas the role in HCC development on HCV related cirrhosis or on NAFLD remains controversial in the literature . TM6SF2 rs58542926 was associated with HCC occurrence in patients with alcoholic cirrhosis but few data were available in other etiologies .…”

Section: Introductionmentioning

confidence: 99%

“…[11][12][13][14] PNPLA3 rs738409 has also been associated with HCC in case-control study and prospective cohorts in alcohol-related cirrhosis whereas the role in HCC development on HCV related cirrhosis or on NAFLD remains controversial in the literature. [15][16][17][18][19][20] TM6SF2 rs58542926 was associated with HCC occurrence in patients with alcoholic cirrhosis but few data were available in other etiologies. 13,[21][22][23] Moreover, whether these aforementioned variants predispose to HCC developed on a nonfibrotic liver is currently unknown.…”

Section: Introductionmentioning

confidence: 99%

PNPLA3 and TM6SF2 variants as risk factors of hepatocellular carcinoma across various etiologies and severity of underlying liver diseases

Yang

Trépo

Nahon

et al. 2018

Intl Journal of Cancer

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Few single nucleotide polymorphisms (SNPs) have been reproducibly associated with hepatocellular carcinoma (HCC). Our aim was to test the association between nine SNPs and HCC occurrence. SNPs in genes linked to HCC (DEPDC5, GRIK1, KIF1B, STAT4, MICA, DLC1, DDX18) or to liver damage (PNPLA3‐rs738409, TM6SF2‐rs58542926) in GWAS were genotyped in discovery cohorts including 1,020 HCC, 2,021 controls with chronic liver disease and 2,484 healthy individuals and replication was performed in prospective cohorts of cirrhotic patients with alcoholic liver disease (ALD, n = 249) and hepatitis C (n = 268). In the discovery cohort, PNPLA3 and TM6SF2 SNPs were associated with HCC (OR = 1.67 [CI95%:1.16–2.40], p = 0.005; OR = 1.45 [CI95%:1.08–1.94], p = 0.01) after adjustment for fibrosis, age, gender and etiology. In contrast, STAT4‐rs7574865 was associated with HCC only in HBV infected patients (p = 0.03) and the other tested SNP were not linked with HCC risk. PNPLA3 and TM6SF2 variants were independently associated with HCC in patients with ALD (OR = 3.91 [CI95%:2.52–6.06], p = 1.14E‐09; OR = 1.79 [CI95%:1.25–2.56], p = 0.001) but not with other etiologies. PNPLA3 SNP was also significantly associated with HCC developed on a nonfibrotic liver (OR = 2.19 [CI95%:1.22–3.92], p = 0.007). The association of PNPLA3 and TM6SF2 with HCC risk was confirmed in the prospective cohort with ALD. A genetic score including PNPLA3 and TM6SF2 minor alleles showed a progressive significant increased risk of HCC in ALD patients. In conclusion, PNPLA3‐rs738409 and TM6SF2‐rs58542926 are inherited risk variants of HCC development in patients with ALD in a dose dependent manner. The link between PNPLA3 and HCC on nonfibrotic liver suggests a direct role in liver carcinogenesis.

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PNPLA3 I148M associations with liver carcinogenesis in Japanese chronic hepatitis C patients

Cited by 17 publications

References 43 publications

PNPLA3polymorphism increases risk for and severity of chronic hepatitis C liver disease

PNPLA3polymorphism increases risk for and severity of chronic hepatitis C liver disease

Cirrhosis and Advanced Fibrosis in Hispanics in Texas: The Dominant Contribution of Central Obesity

PNPLA3 and TM6SF2 variants as risk factors of hepatocellular carcinoma across various etiologies and severity of underlying liver diseases

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