Reviewer's report
Title:Combined effect of regulatory polymorphisms on transcription of UGT1A1
as a cause of Gilbert syndrome
Version: 2Date:5 February 2010
Reviewer: Libor Vítek
Reviewer's report:
The paper by Matsui et al. entitled ¨Combined effect of regulatory polymorphisms
on transcription of UGT1A1 as a cause of Gilbert syndrome¨ presents important
data on the role of various mutations in the regulatory region of UGT1A1 gene on
manifestation of Gilbert syndrome. This kind of information is very important to
account for the fact that only 50% A(TA)7TAA homozygotes manifest with
unconjugated hyperbilirubinemia. Nevertheless, there are several flaws, which
need to be clarified prior re-consideration of a paper for publication in BMC
Gastroenterology.
Major compulsory revisions:
1) The information on serum/plasma bilirubin levels in individual haplotypes is
completely lacking. This must be added to the Result section and Table 2, or
even depicted on the Figure, and discussed appropriately. In the Table 2,
information of numbers of subjects in individual haplotype groups should also be
added. This information seems to be essential to assess the clinical relevance of
studied haplotypes.
2) The authors state (page 5) that ¨the combined effect of homozygosity for both
A(TA)7TAA and c.-3275T>G is essential for manifestation of Gilbert syndrome¨
and that ¨Gilbert syndrome was observed only with homozygous c.-3275T>G at
gtPBREM¨ (page 14). The authors use references 22 and 25 as an evidence for
this statement. However, this statement not true, since there are at least two
reports demonstrating that homozygosity for c.-3275T>G is not always present in
Gilbert syndrome subjects (refs. 27,28, used by authors in different connotation).
This misstatement must be corrected.
Minor essential revisions:
Since CAR was convincingly shown to influence UGT1A1 transcription, the
authors should also comment, whether CAR mutations could explain some
variability in serum bilirubin levels common in Gilbert syndrome.
3) T-w/G-m/T-m/G-w depictions of expression vectors used in Figs 1 and 2
should be explained in the Figure legend to understand fully the Figs.
4) Supplementary data are not mentioned within the text. It is also not clear what
Study 1 and 2 really mean.
Discretionary comments
1) page 6: The term ¨50 Japanese population¨ looks weird and should be
substituted by a more appropriate term.
2) page 13: UGT1A1 gene should always be written in italics
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests
Reviewer's report
Title:Combined effect of regulatory polymorphisms on transcription of UGT1A1
as a cause of Gilbert syndrome
Version: 2Date:5 February 2010
Reviewer: Libor Vítek
Reviewer's report:
The paper by Matsui et al. entitled ¨Combined effect of regulatory polymorphisms
on transcription of UGT1A1 as a cause of Gilbert syndrome¨ presents important
data on the role of various mutations in the regulatory region of UGT1A1 gene on
manifestation of Gilbert syndrome. This kind of information is very important to
account for the fact that only 50% A(TA)7TAA homozygotes manifest with
unconjugated hyperbilirubinemia. Nevertheless, there are several flaws, which
need to be clarified prior re-consideration of a paper for publication in BMC
Gastroenterology.
Major compulsory revisions:
1) The information on serum/plasma bilirubin levels in individual haplotypes is
completely lacking. This must be added to the Result section and Table 2, or
even depicted on the Figure, and discussed appropriately. In the Table 2,
information of numbers of subjects in individual haplotype groups should also be
added. This information seems to be essential to assess the clinical relevance of
studied haplotypes.
2) The authors state (page 5) that ¨the combined effect of homozygosity for both
A(TA)7TAA and c.-3275T>G is essential for manifestation of Gilbert syndrome¨
and that ¨Gilbert syndrome was observed only with homozygous c.-3275T>G at
gtPBREM¨ (page 14). The authors use references 22 and 25 as an evidence for
this statement. However, this statement not true, since there are at least two
reports demonstrating that homozygosity for c.-3275T>G is not always present in
Gilbert syndrome subjects (refs. 27,28, used by authors in different connotation).
This misstatement must be corrected.
Minor essential revisions:
Since CAR was convincingly shown to influence UGT1A1 transcription, the
authors should also comment, whether CAR mutations could explain some
variability in serum bilirubin levels common in Gilbert syndrome.
3) T-w/G-m/T-m/G-w depictions of expression vectors used in Figs 1 and 2
should be explained in the Figure legend to understand fully the Figs.
4) Supplementary data are not mentioned within the text. It is also not clear what
Study 1 and 2 really mean.
Discretionary comments
1) page 6: The term ¨50 Japanese population¨ looks weird and should be
substituted by a more appropriate term.
2) page 13: UGT1A1 gene should always be written in italics
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests
Please review this paper.
user
Reviewer's report
Title:Combined effect of regulatory polymorphisms on transcription of UGT1A1
as a cause of Gilbert syndrome
Version: 2Date:5 February 2010
Reviewer: Libor Vítek
Reviewer's report:
The paper by Matsui et al. entitled ¨Combined effect of regulatory polymorphisms
on transcription of UGT1A1 as a cause of Gilbert syndrome¨ presents important
data on the role of various mutations in the regulatory region of UGT1A1 gene on
manifestation of Gilbert syndrome. This kind of information is very important to
account for the fact that only 50% A(TA)7TAA homozygotes manifest with
unconjugated hyperbilirubinemia. Nevertheless, there are several flaws, which
need to be clarified prior re-consideration of a paper for publication in BMC
Gastroenterology.
Major compulsory revisions:
1) The information on serum/plasma bilirubin levels in individual haplotypes is
completely lacking. This must be added to the Result section and Table 2, or
even depicted on the Figure, and discussed appropriately. In the Table 2,
information of numbers of subjects in individual haplotype groups should also be
added. This information seems to be essential to assess the clinical relevance of
studied haplotypes.
2) The authors state (page 5) that ¨the combined effect of homozygosity for both
A(TA)7TAA and c.-3275T>G is essential for manifestation of Gilbert syndrome¨
and that ¨Gilbert syndrome was observed only with homozygous c.-3275T>G at
gtPBREM¨ (page 14). The authors use references 22 and 25 as an evidence for
this statement. However, this statement not true, since there are at least two
reports demonstrating that homozygosity for c.-3275T>G is not always present in
Gilbert syndrome subjects (refs. 27,28, used by authors in different connotation).
This misstatement must be corrected.
Minor essential revisions:
Since CAR was convincingly shown to influence UGT1A1 transcription, the
authors should also comment, whether CAR mutations could explain some
variability in serum bilirubin levels common in Gilbert syndrome.
3) T-w/G-m/T-m/G-w depictions of expression vectors used in Figs 1 and 2
should be explained in the Figure legend to understand fully the Figs.
4) Supplementary data are not mentioned within the text. It is also not clear what
Study 1 and 2 really mean.
Discretionary comments
1) page 6: The term ¨50 Japanese population¨ looks weird and should be
substituted by a more appropriate term.
2) page 13: UGT1A1 gene should always be written in italics
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests
assistant