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Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE
Yong Chan Lee |
Professor of Medicine Director, Gastrointestinal Research Laboratory Veterans Affairs Medical Center, Univ. California San Francisco San Francisco, USA |
Jong Pil Im | Seoul National University College of Medicine, Seoul, Korea |
Robert S. Bresalier | University of Texas M. D. Anderson Cancer Center, Houston, USA |
Steven H. Itzkowitz | Mount Sinai Medical Center, NY, USA |
All papers submitted to Gut and Liver are reviewed by the editorial team before being sent out for an external peer review to rule out papers that have low priority, insufficient originality, scientific flaws, or the absence of a message of importance to the readers of the Journal. A decision about these papers will usually be made within two or three weeks.
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Jia-Hao Fan*, Ming-Que Xiang†, Qing-Ling Li‡, Hong-Tao Shi*, and Jin-Jun Guo*
Correspondence to: Jin-Jun Guo, Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Chongqing Medical University, 76 Linjiang Road, Yuzhong District, Chongqing 400010, China, Tel: +86-02363693326, Fax: +86-02368486780, E-mail: guojinjun1972@163.com
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Gut Liver 2016;10(3):456-463. https://doi.org/10.5009/gnl15261
Published online September 30, 2015, Published date May 15, 2016
Copyright © Gut and Liver.
The recognition of a correlation between patatin-like phospholipase domain containing-protein 3 ( We performed a comprehensive literature search from the PubMed, Embase, Web of Science, and Google Scholar databases up to December 31, 2014. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Statistical analyses were performed using Stata 12.0 software. The meta-analysis revealed the severity of liver fibrosis was significantly higher in CHC patients with Background/Aims
Methods
Results
Conclusions
Keywords: Patatin-like phospholipase domain containing protein 3 rs738409, Advanced liver fibrosis, Fatty liver, Hepatitis C, chronic, Meta-analysis
Nearly three percent of the worldwide population has been infected with the hepatitis C virus (HCV) and about 80% of these cases are chronic.1,2 Chronic hepatitis C (CHC) infection has become one of the leading causes of liver-related mortality. Yet, the clinical progression of CHC-related liver diseases is highly variable.3 Epidemiological studies have shown that the severity of liver disease in CHC is associated with older age, male gender, higher body mass index (BMI), insulin resistance, chronic alcohol consumption (>30 to 50 g/day), viral factors (especially HCV genotype 3), or coinfection with human immunodeficiency virus.4–8 However, even when combined these factors have an overall prediction rate of less than 30%.9 Investigative research has turned to the influence of genetics.
Several potential genetic risk factors have been identified as having a key role in the severity of CHC-associated liver disease. The best documented is the polymorphism rs738409 (C>G) of patatin-like phospholipase domain-containing protein 3 (
By increasing the sample size, the objective of this meta-analysis was to explore more accurately the association between
Relevant studies published before December 31, 2014 were found by searching the PubMed, Embase, and Web of Science databases, and the Google Scholar website for the query “(patatin-like phospholipase domain containing 3 or
The diagnosis of HCV infection in all patients of the selected studies was confirmed through serological examinations. Fibrosis and steatosis were confirmed by liver biopsy. Advanced fibrosis was defined as stage F3 (numerous septa without cirrhosis) or F4 (cirrhosis) according to the METAVIR score. The extent of steatosis was analyzed by calculating the percentage of lipid-containing hepatocytes in the total number of hepatocytes.
The selected studies conformed to the following criteria: (1) the studies focused on the polymorphism rs738409 (C>G) of
The following data of each study was extracted independently by two authors: the first author, year of publication, ethnicity of subjects, age, BMI, gender ratio, HCV genotype, treatments, accompanying hepatitis B virus (HBV) or human immunodeficiency virus (HIV) infection, number of subjects, genotype frequencies of single nucleotide polymorphisms, and Hardy-Weinberg equilibrium (HWE). Results that were not reported directly were calculated from the data by two authors independently. Disagreements were resolved by discussion with a third author.
Two authors independently assessed the quality of the included studies based on the Newcastle-Ottawa Scale (
The HWE of each study was tested using the chi-square test. Based on previous studies,16 the ORs, and 95% confidence intervals (CIs) were calculated under the recessive genetic model (i.e., GG compared to CC+CG). The Z test and p<0.05 were used to examine the statistical significance of the pooled ORs.
Cochran’s Q-test and the I2 test were used to evaluate the heterogeneity between the studies.17,18 If p≥0.1 of the Q-test, or I2≤50%, we considered that no significant heterogeneity existed, so the fixed effects model (Mantel-Haenszel method) was used in this meta-analysis. If not, the random effects model (DerSimonian and Laird method) would be considered. A subgroup analysis by ethnicity or genotype of HCV was performed to find sources of heterogeneity.
Sensitivity was determined by repeating the analysis and evaluating the stability of each result, after omitting in turn the data of each study. To assess the potential publication bias, we used Begger’s funnel plot and Egger’s linear regression test.19 Stata software for Windows version 12.0 (Stata, College Station, TX, USA) was used for all the statistical analyses.
Five studies were relevant to advanced fibrosis of the liver in CHC and comprised 2,037 patients. There were no statistically significant differences among them with regard to age, BMI, or gender ratio (specific data are not listed), including 651 patients with advanced fibrosis (METAVIR stages F3–F4). In four of these the subjects were Caucasian, and in one the subjects were Asian (Table 1). The four studies with Caucasian subjects also concerned steatosis of the liver with, in total, 694 subjects in whom the extent of steatosis was more than 5%. All of the patients had performed liver biopsies before received the treatment of pegylated interferon and ribavirin, and were without HBV or HIV infection.
Based on the results of the line probe assay VERSANT HCV Genotype 2.0 (Siemens, Tarrytown, NY, USA), two studies10,12 included patients infected with the HCV genotypes 1 or 4; in one study,13 patients were infected with HCV genotypes 1 or 2; and in the remaining two studies,11,14 patients were infected with HCV genotypes 1, 2, 3, or 4. The genotyping of
With regard to the association between
The subgroup analysis by ethnicity showed that in the Caucasian populations, CHC patients with genotype GG had a higher risk of advanced fibrosis of the liver compared with those with genotype CC+CG (OR, 2.51; 95% CI, 1.75 to 3.60; p<0.05). However, this association was not observed in the Asian population (OR, 1.31; 95% CI, 0.65 to 2.67; p=0.457).
We further performed a subgroup analysis based on HCV genotype in Caucasians. Subgroup A included two studies10,12 in which the CHC patients were infected with HCV-1 or HCV-4 only. Subgroup B included the other two studies11,14 comprising CHC patients infected with not only HCV-1 or HCV-4 but also HCV-2 or HCV-3. Although the two subgroups differed, the difference was not significant (subgroup A: OR, 3.57; 95% CI, 1.90 to 6.69; subgroup B: OR, 2.11; 95% CI, 1.35 to 3.29; p=0.17) (Fig. 2B).
With regard to the association between
We also performed a subgroup analysis stratified by HCV genotype, whereby in subgroup A, the CHC patients were infected with HCV-1 or HCV-4 only,10,12 and in subgroup B, the CHC patients were infected with HCV-1, 2, 3, or 4.11,14 Although the two subgroups differed, the difference was not significant (subgroup A: OR, 6.20; 95% CI, 2.16 to 17.79; subgroup B: OR, 3.79; 95% CI, 2.11 to 6.68; p=0.49).
For the sensitivity analysis we used the random effects model to recalculate the pooled ORs (95% CIs), and there were no significant changes in results. Furthermore, when any single study was deleted, the corresponding pooled ORs were not substantially altered (Fig. 4), suggesting that the results of this meta-analysis were stable.
Begger’s funnel plots (Fig. 5) and Egger’s linear regression test were performed to assess the publication bias of all included studies. The results indicated no evidence of publication bias (advanced fibrosis, p=0.144; steatosis, p=0.504).
Based on the Newcastle-Ottawa Scale, the quality evaluations of the included studies showed that all five of the included studies earned more than five stars, and therefore could be considered medium-high quality reports (Table 2). Disagreements were also resolved by discussion with a third author.
This meta-analysis investigated whether the
A previous study observed that
We also stratified the subjects according to HCV genotype. The genotype GG of
This is the first meta-analysis concerning the relatedness of the
This meta-analysis is limited in that only five studies were included, and therefore the sample size and statistical power may be insufficient. As more original studies are performed that investigate the association between
In conclusion, the results of this meta-analysis indicate that the genotype GG of
This work was supported in part by grants from the National Natural Science Foundation of China (grant number: 81071338).
No potential conflict of interest relevant to this article was reported.
Characteristics of the Cohorts of the Included Studies*
Author (year) | Ethnicity | HCV genotype | Fibrosis | Steatosis | HWE | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Mild or none | Advanced | <5% | ≥5% | p-value | |||||||
n | CC+CG/GG | n | CC+CG/GG | n | CC+CG/GG | n | CC+CG/GG | ||||
Stattermayer | Caucasian | 1, 4 | 159 | 155/4 | 43 | 36/7 | 87 | 85/2 | 115 | 106/9 | 0.56 |
Valenti | Caucasian | 1, 2, 3, 4 | 423 | 395/28 | 179 | 158/21 | 196 | 189/7 | 406 | 364/42 | 0.44 |
Stattermayer | Caucasian | 1, 4 | 322 | 308/14 | 156 | 138/18 | 147 | 145/2 | 213 | 190/23 | 0.69 |
Trepo | Caucasian | 1, 2, 3, 4 | 321 | 306/15 | 216 | 193/23 | 264 | 257/7 | 273 | 242/31 | 0.92 |
Miyashita | Asian | 1, 2 | 161 | 129/32 | 57 | 43/14 | - | - | - | - | 0.59 |
HCV, hepatitis C virus; HWE, Hardy-Weinberg equilibrium.
Gut and Liver 2016; 10(3): 456-463
Published online May 15, 2016 https://doi.org/10.5009/gnl15261
Copyright © Gut and Liver.
Jia-Hao Fan*, Ming-Que Xiang†, Qing-Ling Li‡, Hong-Tao Shi*, and Jin-Jun Guo*
*Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China, †Department of Infectious Diseases, The Ninth People’s Hospital of Chongqing, Chongqing, China, ‡Institute of Life Sciences, Chongqing Medical University, Chongqing, China
Correspondence to:Jin-Jun Guo, Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Chongqing Medical University, 76 Linjiang Road, Yuzhong District, Chongqing 400010, China, Tel: +86-02363693326, Fax: +86-02368486780, E-mail: guojinjun1972@163.com
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
The recognition of a correlation between patatin-like phospholipase domain containing-protein 3 ( We performed a comprehensive literature search from the PubMed, Embase, Web of Science, and Google Scholar databases up to December 31, 2014. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Statistical analyses were performed using Stata 12.0 software. The meta-analysis revealed the severity of liver fibrosis was significantly higher in CHC patients with Background/Aims
Methods
Results
Conclusions
Keywords: Patatin-like phospholipase domain containing protein 3 rs738409, Advanced liver fibrosis, Fatty liver, Hepatitis C, chronic, Meta-analysis
Nearly three percent of the worldwide population has been infected with the hepatitis C virus (HCV) and about 80% of these cases are chronic.1,2 Chronic hepatitis C (CHC) infection has become one of the leading causes of liver-related mortality. Yet, the clinical progression of CHC-related liver diseases is highly variable.3 Epidemiological studies have shown that the severity of liver disease in CHC is associated with older age, male gender, higher body mass index (BMI), insulin resistance, chronic alcohol consumption (>30 to 50 g/day), viral factors (especially HCV genotype 3), or coinfection with human immunodeficiency virus.4–8 However, even when combined these factors have an overall prediction rate of less than 30%.9 Investigative research has turned to the influence of genetics.
Several potential genetic risk factors have been identified as having a key role in the severity of CHC-associated liver disease. The best documented is the polymorphism rs738409 (C>G) of patatin-like phospholipase domain-containing protein 3 (
By increasing the sample size, the objective of this meta-analysis was to explore more accurately the association between
Relevant studies published before December 31, 2014 were found by searching the PubMed, Embase, and Web of Science databases, and the Google Scholar website for the query “(patatin-like phospholipase domain containing 3 or
The diagnosis of HCV infection in all patients of the selected studies was confirmed through serological examinations. Fibrosis and steatosis were confirmed by liver biopsy. Advanced fibrosis was defined as stage F3 (numerous septa without cirrhosis) or F4 (cirrhosis) according to the METAVIR score. The extent of steatosis was analyzed by calculating the percentage of lipid-containing hepatocytes in the total number of hepatocytes.
The selected studies conformed to the following criteria: (1) the studies focused on the polymorphism rs738409 (C>G) of
The following data of each study was extracted independently by two authors: the first author, year of publication, ethnicity of subjects, age, BMI, gender ratio, HCV genotype, treatments, accompanying hepatitis B virus (HBV) or human immunodeficiency virus (HIV) infection, number of subjects, genotype frequencies of single nucleotide polymorphisms, and Hardy-Weinberg equilibrium (HWE). Results that were not reported directly were calculated from the data by two authors independently. Disagreements were resolved by discussion with a third author.
Two authors independently assessed the quality of the included studies based on the Newcastle-Ottawa Scale (
The HWE of each study was tested using the chi-square test. Based on previous studies,16 the ORs, and 95% confidence intervals (CIs) were calculated under the recessive genetic model (i.e., GG compared to CC+CG). The Z test and p<0.05 were used to examine the statistical significance of the pooled ORs.
Cochran’s Q-test and the I2 test were used to evaluate the heterogeneity between the studies.17,18 If p≥0.1 of the Q-test, or I2≤50%, we considered that no significant heterogeneity existed, so the fixed effects model (Mantel-Haenszel method) was used in this meta-analysis. If not, the random effects model (DerSimonian and Laird method) would be considered. A subgroup analysis by ethnicity or genotype of HCV was performed to find sources of heterogeneity.
Sensitivity was determined by repeating the analysis and evaluating the stability of each result, after omitting in turn the data of each study. To assess the potential publication bias, we used Begger’s funnel plot and Egger’s linear regression test.19 Stata software for Windows version 12.0 (Stata, College Station, TX, USA) was used for all the statistical analyses.
Five studies were relevant to advanced fibrosis of the liver in CHC and comprised 2,037 patients. There were no statistically significant differences among them with regard to age, BMI, or gender ratio (specific data are not listed), including 651 patients with advanced fibrosis (METAVIR stages F3–F4). In four of these the subjects were Caucasian, and in one the subjects were Asian (Table 1). The four studies with Caucasian subjects also concerned steatosis of the liver with, in total, 694 subjects in whom the extent of steatosis was more than 5%. All of the patients had performed liver biopsies before received the treatment of pegylated interferon and ribavirin, and were without HBV or HIV infection.
Based on the results of the line probe assay VERSANT HCV Genotype 2.0 (Siemens, Tarrytown, NY, USA), two studies10,12 included patients infected with the HCV genotypes 1 or 4; in one study,13 patients were infected with HCV genotypes 1 or 2; and in the remaining two studies,11,14 patients were infected with HCV genotypes 1, 2, 3, or 4. The genotyping of
With regard to the association between
The subgroup analysis by ethnicity showed that in the Caucasian populations, CHC patients with genotype GG had a higher risk of advanced fibrosis of the liver compared with those with genotype CC+CG (OR, 2.51; 95% CI, 1.75 to 3.60; p<0.05). However, this association was not observed in the Asian population (OR, 1.31; 95% CI, 0.65 to 2.67; p=0.457).
We further performed a subgroup analysis based on HCV genotype in Caucasians. Subgroup A included two studies10,12 in which the CHC patients were infected with HCV-1 or HCV-4 only. Subgroup B included the other two studies11,14 comprising CHC patients infected with not only HCV-1 or HCV-4 but also HCV-2 or HCV-3. Although the two subgroups differed, the difference was not significant (subgroup A: OR, 3.57; 95% CI, 1.90 to 6.69; subgroup B: OR, 2.11; 95% CI, 1.35 to 3.29; p=0.17) (Fig. 2B).
With regard to the association between
We also performed a subgroup analysis stratified by HCV genotype, whereby in subgroup A, the CHC patients were infected with HCV-1 or HCV-4 only,10,12 and in subgroup B, the CHC patients were infected with HCV-1, 2, 3, or 4.11,14 Although the two subgroups differed, the difference was not significant (subgroup A: OR, 6.20; 95% CI, 2.16 to 17.79; subgroup B: OR, 3.79; 95% CI, 2.11 to 6.68; p=0.49).
For the sensitivity analysis we used the random effects model to recalculate the pooled ORs (95% CIs), and there were no significant changes in results. Furthermore, when any single study was deleted, the corresponding pooled ORs were not substantially altered (Fig. 4), suggesting that the results of this meta-analysis were stable.
Begger’s funnel plots (Fig. 5) and Egger’s linear regression test were performed to assess the publication bias of all included studies. The results indicated no evidence of publication bias (advanced fibrosis, p=0.144; steatosis, p=0.504).
Based on the Newcastle-Ottawa Scale, the quality evaluations of the included studies showed that all five of the included studies earned more than five stars, and therefore could be considered medium-high quality reports (Table 2). Disagreements were also resolved by discussion with a third author.
This meta-analysis investigated whether the
A previous study observed that
We also stratified the subjects according to HCV genotype. The genotype GG of
This is the first meta-analysis concerning the relatedness of the
This meta-analysis is limited in that only five studies were included, and therefore the sample size and statistical power may be insufficient. As more original studies are performed that investigate the association between
In conclusion, the results of this meta-analysis indicate that the genotype GG of
This work was supported in part by grants from the National Natural Science Foundation of China (grant number: 81071338).
No potential conflict of interest relevant to this article was reported.
Table 1 Characteristics of the Cohorts of the Included Studies*
Author (year) | Ethnicity | HCV genotype | Fibrosis | Steatosis | HWE | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Mild or none | Advanced | <5% | ≥5% | p-value | |||||||
n | CC+CG/GG | n | CC+CG/GG | n | CC+CG/GG | n | CC+CG/GG | ||||
Stattermayer | Caucasian | 1, 4 | 159 | 155/4 | 43 | 36/7 | 87 | 85/2 | 115 | 106/9 | 0.56 |
Valenti | Caucasian | 1, 2, 3, 4 | 423 | 395/28 | 179 | 158/21 | 196 | 189/7 | 406 | 364/42 | 0.44 |
Stattermayer | Caucasian | 1, 4 | 322 | 308/14 | 156 | 138/18 | 147 | 145/2 | 213 | 190/23 | 0.69 |
Trepo | Caucasian | 1, 2, 3, 4 | 321 | 306/15 | 216 | 193/23 | 264 | 257/7 | 273 | 242/31 | 0.92 |
Miyashita | Asian | 1, 2 | 161 | 129/32 | 57 | 43/14 | - | - | - | - | 0.59 |
HCV, hepatitis C virus; HWE, Hardy-Weinberg equilibrium.