Reviewer ’s report  
 
Title: CTRC gene polymorphism (p.G60=; c.180 C>T) in acute pancreatitis  
 
Version: 2 Date: 29 Aug 2016  
 
Reviewer: Ulrich Weiss  
 
Reviewer's report:  
 
The revised manuscript by Koziel et al has significantly improve d. However there remain some 
points that still need to be adressed.  
 
 
 
1) The introduction is not well structured, jumping between topics of AP CP and RAP. The 
following statement: "According to the current scientific knowledge, recurring AP 
(RAP), especiall y combined with hereditary pancreatitis and the consumption of alcohol, 
as well as smoking, may lead to chronic pancreatitis" does not really explain the concept 
how genetic risk factors predispose to acute pancreatitis and in combination with 
environmenta l stimuli and inflammatory mechanisms trigger the progression to recurrent 
and chronic disease.  
 
 
2) The findings do not support any role of the c.180C>T allele with disease severity. The 
half-sentence "but in patients with the TT genotype no severe AP was  observed, contrary 
to the patients with the CT genotype, where 30.8% of the incidences had a moderate or 
severe course" should definitely be removed from the abstract. It is misleading and 
suggests that in the cohort of 5 TT -carriers a difference of 1 -2 patients could be of 
clinical importance. However, the cohort size is just much too small and there is no 
statistical substantiation for any such assumption.  
 
 
3) The manuscript still lacks information which criteria were used to discriminate chronic 
pancrea titis from acute or recurrent acute pancreatitis and therefore to exclude these 
patients from the study. The sentence : "A diagnosis of chronic pancreatitis, which took 
place during interviews and imaging, was an exclusion criterion" is not informative.  
 
 
 
Minor points  
 
Page 3) Most genetic factors related to RAP / CP are also mechanisms that normally prevent the 
pancreas from trypsin activation inside the pancreas…  
 
A CP risk allele is no mechanism, but it may be involved in such mechanisms.  
Page 5) The gen erated sequences were compared relative to the reference sequence  
RefSeq (NM_007272.2) using the NCBI Blast Nucleotide.  
 
 
A word like "program" or "algorithm" is missing in this sentence.  
 
 
Page 4)  However it should be mentioned that this results are based o n the 147 cases with 
following genotype distributions CC: 113, CT:33, TT:13.  
 
 
Only 3 TT -genotypes have been analysed by GTEx, not 13 !   (indicating that the TT -Genotype 
is a rare genotype)  
 
 
 
 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the neces sary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to asse ss any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the pa st five years received reimbursements, fees, funding, or salary from an  
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation t hat may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you received reimbursements, f ees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this p aper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests  
 
I agree to the open peer review policy of t he journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the website along with the authors'  
responses. I agree for my report to be made available under a n Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as  confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Reviewer ’s report  
 
Title: CTRC gene polymorphism (p.G60=; c.180 C>T) in acute pancreatitis  
 
Version: 2 Date: 29 Aug 2016  
 
Reviewer: Ulrich Weiss  
 
Reviewer's report:  
 
The revised manuscript by Koziel et al has significantly improve d. However there remain some 
points that still need to be adressed.  
 
 
 
1) The introduction is not well structured, jumping between topics of AP CP and RAP. The 
following statement: "According to the current scientific knowledge, recurring AP 
(RAP), especiall y combined with hereditary pancreatitis and the consumption of alcohol, 
as well as smoking, may lead to chronic pancreatitis" does not really explain the concept 
how genetic risk factors predispose to acute pancreatitis and in combination with 
environmenta l stimuli and inflammatory mechanisms trigger the progression to recurrent 
and chronic disease.  
 
 
2) The findings do not support any role of the c.180C>T allele with disease severity. The 
half-sentence "but in patients with the TT genotype no severe AP was  observed, contrary 
to the patients with the CT genotype, where 30.8% of the incidences had a moderate or 
severe course" should definitely be removed from the abstract. It is misleading and 
suggests that in the cohort of 5 TT -carriers a difference of 1 -2 patients could be of 
clinical importance. However, the cohort size is just much too small and there is no 
statistical substantiation for any such assumption.  
 
 
3) The manuscript still lacks information which criteria were used to discriminate chronic 
pancrea titis from acute or recurrent acute pancreatitis and therefore to exclude these 
patients from the study. The sentence : "A diagnosis of chronic pancreatitis, which took 
place during interviews and imaging, was an exclusion criterion" is not informative.  
 
 
 
Minor points  
 
Page 3) Most genetic factors related to RAP / CP are also mechanisms that normally prevent the 
pancreas from trypsin activation inside the pancreas…  
 
A CP risk allele is no mechanism, but it may be involved in such mechanisms.  
Page 5) The gen erated sequences were compared relative to the reference sequence  
RefSeq (NM_007272.2) using the NCBI Blast Nucleotide.  
 
 
A word like "program" or "algorithm" is missing in this sentence.  
 
 
Page 4)  However it should be mentioned that this results are based o n the 147 cases with 
following genotype distributions CC: 113, CT:33, TT:13.  
 
 
Only 3 TT -genotypes have been analysed by GTEx, not 13 !   (indicating that the TT -Genotype 
is a rare genotype)  
 
 
 
 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the neces sary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to asse ss any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the pa st five years received reimbursements, fees, funding, or salary from an  
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation t hat may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you received reimbursements, f ees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this p aper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests  
 
I agree to the open peer review policy of t he journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the website along with the authors'  
responses. I agree for my report to be made available under a n Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as  confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Please review this paper.
user
Reviewer ’s report  
 
Title: CTRC gene polymorphism (p.G60=; c.180 C>T) in acute pancreatitis  
 
Version: 2 Date: 29 Aug 2016  
 
Reviewer: Ulrich Weiss  
 
Reviewer's report:  
 
The revised manuscript by Koziel et al has significantly improve d. However there remain some 
points that still need to be adressed.  
 
 
 
1) The introduction is not well structured, jumping between topics of AP CP and RAP. The 
following statement: "According to the current scientific knowledge, recurring AP 
(RAP), especiall y combined with hereditary pancreatitis and the consumption of alcohol, 
as well as smoking, may lead to chronic pancreatitis" does not really explain the concept 
how genetic risk factors predispose to acute pancreatitis and in combination with 
environmenta l stimuli and inflammatory mechanisms trigger the progression to recurrent 
and chronic disease.  
 
 
2) The findings do not support any role of the c.180C>T allele with disease severity. The 
half-sentence "but in patients with the TT genotype no severe AP was  observed, contrary 
to the patients with the CT genotype, where 30.8% of the incidences had a moderate or 
severe course" should definitely be removed from the abstract. It is misleading and 
suggests that in the cohort of 5 TT -carriers a difference of 1 -2 patients could be of 
clinical importance. However, the cohort size is just much too small and there is no 
statistical substantiation for any such assumption.  
 
 
3) The manuscript still lacks information which criteria were used to discriminate chronic 
pancrea titis from acute or recurrent acute pancreatitis and therefore to exclude these 
patients from the study. The sentence : "A diagnosis of chronic pancreatitis, which took 
place during interviews and imaging, was an exclusion criterion" is not informative.  
 
 
 
Minor points  
 
Page 3) Most genetic factors related to RAP / CP are also mechanisms that normally prevent the 
pancreas from trypsin activation inside the pancreas…  
 
A CP risk allele is no mechanism, but it may be involved in such mechanisms.  
Page 5) The gen erated sequences were compared relative to the reference sequence  
RefSeq (NM_007272.2) using the NCBI Blast Nucleotide.  
 
 
A word like "program" or "algorithm" is missing in this sentence.  
 
 
Page 4)  However it should be mentioned that this results are based o n the 147 cases with 
following genotype distributions CC: 113, CT:33, TT:13.  
 
 
Only 3 TT -genotypes have been analysed by GTEx, not 13 !   (indicating that the TT -Genotype 
is a rare genotype)  
 
 
 
 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the neces sary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to asse ss any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the pa st five years received reimbursements, fees, funding, or salary from an  
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation t hat may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you received reimbursements, f ees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this p aper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests  
 
I agree to the open peer review policy of t he journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the website along with the authors'  
responses. I agree for my report to be made available under a n Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as  confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
assistant