Reviewer's report
Title:A frequent variant in the human bile salt export pump gene ABCB11 is
associated with hepatitis C virus infection, but not liver stiffness in a German
population
Version: 1Date:13 March 2012
Reviewer: Andreas Geier
Reviewer's report:
Mullenbach and coworkers present a genetic cohort study investigating the
association of a genetic variant in the bile salt export pump gene ABCB11 to
hepatitis C infection per se and liver stiffness as a measure of its clinical course.
The main finding of this work is a significant overrepresentation of the ABCB11
SNP in hepatitis C patients compared to controls which confirms previous data
from another cohort. A significant association to advanced fibrosis or cirrhosis
defined in this study by an elevation of liver stiffness >13kPa has not been
observed but a trend towards more increased liver stiffness in the carriers of the
1331 C allele is at least suggestive of an influence on the clinical course of the
disease. This study is important for the future understanding of HCV virology and
indirect effects of bile acids beyond metabolism. However, parts of the
interpretation of the data and conclusions thereof need to be taken with caution
and the discussion needs to be revised according to specific points.
Specific points:
1. Table 2: The authors claim a significant overrepresentation of the ABCB11 C
allele (CC or CT genotype) in HCV cases compared to controls (P = 0.037). Is
this the p-value corrected for multiple testing? In case of an uncorrected p-value
a threshold of 0.018 (according to Bonferroni) should be applicable.
2. Discussion page 13: The authors mention the trend towards more increased
liver stiffness in the carriers of the 1331 C allele from their scatter plot. It should
be emphasized that a cut-off stiffness of 13kPa represents the lower end of the
range which does not exclude cirrhosis but still includes a substantial number of
non-cirrhotic patients. Compared to the histology-based study, using a stiffness
of >13kPa may overscore “cirrhosis” and explains the trend towards association
the the upper range of the stiffness spectrum.
3. Bile acid levels or cholesterol levels as clinical parameters would clearly add to
the study and would potentially support parts of the discussion. An association of
bile acid levels to liver stiffness would be of interest as well. The authors may add
such information if available.
4. Discussion page 13: The conclusions drawn from the report of Iwata et al.
need to be taken with caution. Reading the details of this report, it becomes clear
that the controls (like HCV patients) are from a different genetic background
(Swiss) than the NAFLD patients (British) and therefore given separately in the
respective table. This precludes a conclusion towards the significance of the
discussed differences in ABCB11 allelic frequency between HCV-controls from
Switzerland and NAFLD patients from Britain. The reviewer cannot find such
information in the referenced manuscript. For the same reason, “Swiss NAFLD
patients” needs to be rephrased at this occasion.
5. No information on the control group are given in the manuscript. Although
parts of the cohorts have been described elsewhere, a table of baseline
characteristics for patients and controls seems mandatory. HCV genotype
distribution is missing in table 1.
6. Data on power analysis may be added.
Minor comments:
1. Page 11: UDCA is a rather weak FXR agonist and other effects may be
predominant. This may be taken into account when rephrasing the discussion.
2. Page 11 line 7: Correct is that bile acid concentrations <8 uM are associated
with SVR or >8 uM associated with non-SVR.
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: Yes, and I have assessed the statistics in my report.
Declaration of competing interests:
The reviewer is senior-author of the refrenced publication by Iwata et al.
Reviewer's report
Title:A frequent variant in the human bile salt export pump gene ABCB11 is
associated with hepatitis C virus infection, but not liver stiffness in a German
population
Version: 1Date:13 March 2012
Reviewer: Andreas Geier
Reviewer's report:
Mullenbach and coworkers present a genetic cohort study investigating the
association of a genetic variant in the bile salt export pump gene ABCB11 to
hepatitis C infection per se and liver stiffness as a measure of its clinical course.
The main finding of this work is a significant overrepresentation of the ABCB11
SNP in hepatitis C patients compared to controls which confirms previous data
from another cohort. A significant association to advanced fibrosis or cirrhosis
defined in this study by an elevation of liver stiffness >13kPa has not been
observed but a trend towards more increased liver stiffness in the carriers of the
1331 C allele is at least suggestive of an influence on the clinical course of the
disease. This study is important for the future understanding of HCV virology and
indirect effects of bile acids beyond metabolism. However, parts of the
interpretation of the data and conclusions thereof need to be taken with caution
and the discussion needs to be revised according to specific points.
Specific points:
1. Table 2: The authors claim a significant overrepresentation of the ABCB11 C
allele (CC or CT genotype) in HCV cases compared to controls (P = 0.037). Is
this the p-value corrected for multiple testing? In case of an uncorrected p-value
a threshold of 0.018 (according to Bonferroni) should be applicable.
2. Discussion page 13: The authors mention the trend towards more increased
liver stiffness in the carriers of the 1331 C allele from their scatter plot. It should
be emphasized that a cut-off stiffness of 13kPa represents the lower end of the
range which does not exclude cirrhosis but still includes a substantial number of
non-cirrhotic patients. Compared to the histology-based study, using a stiffness
of >13kPa may overscore “cirrhosis” and explains the trend towards association
the the upper range of the stiffness spectrum.
3. Bile acid levels or cholesterol levels as clinical parameters would clearly add to
the study and would potentially support parts of the discussion. An association of
bile acid levels to liver stiffness would be of interest as well. The authors may add
such information if available.
4. Discussion page 13: The conclusions drawn from the report of Iwata et al.
need to be taken with caution. Reading the details of this report, it becomes clear
that the controls (like HCV patients) are from a different genetic background
(Swiss) than the NAFLD patients (British) and therefore given separately in the
respective table. This precludes a conclusion towards the significance of the
discussed differences in ABCB11 allelic frequency between HCV-controls from
Switzerland and NAFLD patients from Britain. The reviewer cannot find such
information in the referenced manuscript. For the same reason, “Swiss NAFLD
patients” needs to be rephrased at this occasion.
5. No information on the control group are given in the manuscript. Although
parts of the cohorts have been described elsewhere, a table of baseline
characteristics for patients and controls seems mandatory. HCV genotype
distribution is missing in table 1.
6. Data on power analysis may be added.
Minor comments:
1. Page 11: UDCA is a rather weak FXR agonist and other effects may be
predominant. This may be taken into account when rephrasing the discussion.
2. Page 11 line 7: Correct is that bile acid concentrations <8 uM are associated
with SVR or >8 uM associated with non-SVR.
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: Yes, and I have assessed the statistics in my report.
Declaration of competing interests:
The reviewer is senior-author of the refrenced publication by Iwata et al.
Please review this paper.
user
Reviewer's report
Title:A frequent variant in the human bile salt export pump gene ABCB11 is
associated with hepatitis C virus infection, but not liver stiffness in a German
population
Version: 1Date:13 March 2012
Reviewer: Andreas Geier
Reviewer's report:
Mullenbach and coworkers present a genetic cohort study investigating the
association of a genetic variant in the bile salt export pump gene ABCB11 to
hepatitis C infection per se and liver stiffness as a measure of its clinical course.
The main finding of this work is a significant overrepresentation of the ABCB11
SNP in hepatitis C patients compared to controls which confirms previous data
from another cohort. A significant association to advanced fibrosis or cirrhosis
defined in this study by an elevation of liver stiffness >13kPa has not been
observed but a trend towards more increased liver stiffness in the carriers of the
1331 C allele is at least suggestive of an influence on the clinical course of the
disease. This study is important for the future understanding of HCV virology and
indirect effects of bile acids beyond metabolism. However, parts of the
interpretation of the data and conclusions thereof need to be taken with caution
and the discussion needs to be revised according to specific points.
Specific points:
1. Table 2: The authors claim a significant overrepresentation of the ABCB11 C
allele (CC or CT genotype) in HCV cases compared to controls (P = 0.037). Is
this the p-value corrected for multiple testing? In case of an uncorrected p-value
a threshold of 0.018 (according to Bonferroni) should be applicable.
2. Discussion page 13: The authors mention the trend towards more increased
liver stiffness in the carriers of the 1331 C allele from their scatter plot. It should
be emphasized that a cut-off stiffness of 13kPa represents the lower end of the
range which does not exclude cirrhosis but still includes a substantial number of
non-cirrhotic patients. Compared to the histology-based study, using a stiffness
of >13kPa may overscore “cirrhosis” and explains the trend towards association
the the upper range of the stiffness spectrum.
3. Bile acid levels or cholesterol levels as clinical parameters would clearly add to
the study and would potentially support parts of the discussion. An association of
bile acid levels to liver stiffness would be of interest as well. The authors may add
such information if available.
4. Discussion page 13: The conclusions drawn from the report of Iwata et al.
need to be taken with caution. Reading the details of this report, it becomes clear
that the controls (like HCV patients) are from a different genetic background
(Swiss) than the NAFLD patients (British) and therefore given separately in the
respective table. This precludes a conclusion towards the significance of the
discussed differences in ABCB11 allelic frequency between HCV-controls from
Switzerland and NAFLD patients from Britain. The reviewer cannot find such
information in the referenced manuscript. For the same reason, “Swiss NAFLD
patients” needs to be rephrased at this occasion.
5. No information on the control group are given in the manuscript. Although
parts of the cohorts have been described elsewhere, a table of baseline
characteristics for patients and controls seems mandatory. HCV genotype
distribution is missing in table 1.
6. Data on power analysis may be added.
Minor comments:
1. Page 11: UDCA is a rather weak FXR agonist and other effects may be
predominant. This may be taken into account when rephrasing the discussion.
2. Page 11 line 7: Correct is that bile acid concentrations <8 uM are associated
with SVR or >8 uM associated with non-SVR.
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: Yes, and I have assessed the statistics in my report.
Declaration of competing interests:
The reviewer is senior-author of the refrenced publication by Iwata et al.
assistant