Title: Risk of gallstones based on ABCG8 rs11887534 single nucleotide polymorphism among
Taiwanese men and women
Version: 0 Date: 09 Aug 2021
Reviewer's report:
The study tested the association between a genetic variant, ABCG8 D19H, and gallstone disease
in a cohort of approximately 21,000 Taiwanese individuals. The variant was associated with
gallstones, as expected (ABCG8 D19H is the first identified and widely replicated common
genetic risk factor for gallstone disease).
Data presentation is clear and comprehensive, and the findings of the study are robust. The main
weakness of the paper is that the association of the variant with gallstone disease is already
firmly established in cohorts from across the globe (albeit not in Taiwanese cohorts).
Comments
1. Abstract, Methods: state the number of gallstone cases and that gallstones were self-reported.
2. Abstract: state frequency of ABCG8 D19H in the cohort.
3. Methods page 5: please add a reference to Taiwan Biobank here.
4. Please explain why GC and CC genotypes were combined in all main analyses.
5. It would be helpful to show the number of carriers of each of the 3 genotypes (GG, GC, and
CC), and the associations with gallstone disease for GC and CC individually, compared to GG.
Even if there is very low power for the CC-homozygotes, it would be interesting to have these
data in the paper.
6. Overall, the manuscript is easy to follow. But it would benefit from additional revision for
grammar and word usage. Some examples:
a) Introduction page 4: ‘The burden of gallstone in Taiwan…’ Revise to: ‘The burden of
gallstone disease in Taiwan…’
b) Introduction page 4:’…gallstone stone disease’. delete stone.
c) Introduction page 4: ‘Gallstone is a multifactorial….’, Revise: ‘Gallstone disease is a
multifactorial…’
d) Introduction page 4: ‘Gallstone is a multifactorial disorder having both genetic and non-
genetic onset.’ Revise.
e) Introduction page 5: ‘It is substantial to validate…’, Revise to ‘It is important to validate…’
f) Introduction page 5: ‘Moreover, the association between gallstone ABCG8 rs11887534
polymorphism…’. Suggest revising to: ‘Moreover, the association between ABCG8 rs11887534
…’.
g) Methods, page 5: ‘Each participant signed an informed consent form was enrolled into the
study only after fulfilling the eligibility criteria.’ Revise.
h) Methods, page 6: ‘In addition to self-reports, fasting glucose >126’. Please include unit.
i) Abstract: ‘G-WAS’, revise to ‘GWAS’.
j) Discussion. ‘Genetic aberrations in this gene are associated with cardiovascular diseases,
coronary atherosclerosis, and gallstones, cancer of the biliary tract [17, 19, 20, 26, 35-37]’ Revise
to ‘Genetic variation in this gene is associated with cardiovascular disease,  gallstones, and
cancer of the biliary tract [17, 19, 20, 26, 35-37]’
7. Methods, page 7: ‘Levels of aspartate aminotransferase (AST), alanine transaminase (ALT),
high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and
triglyceride (TG) were determined using biochemical tests.’ Which biochemical tests?
8. Relevant citations to include (two new GWAS for gallstone disease): PMID: 30325047 and
PMID: 30504769.
Title: Risk of gallstones based on ABCG8 rs11887534 single nucleotide polymorphism among
Taiwanese men and women
Version: 0 Date: 09 Aug 2021
Reviewer's report:
The study tested the association between a genetic variant, ABCG8 D19H, and gallstone disease
in a cohort of approximately 21,000 Taiwanese individuals. The variant was associated with
gallstones, as expected (ABCG8 D19H is the first identified and widely replicated common
genetic risk factor for gallstone disease).
Data presentation is clear and comprehensive, and the findings of the study are robust. The main
weakness of the paper is that the association of the variant with gallstone disease is already
firmly established in cohorts from across the globe (albeit not in Taiwanese cohorts).
Comments
1. Abstract, Methods: state the number of gallstone cases and that gallstones were self-reported.
2. Abstract: state frequency of ABCG8 D19H in the cohort.
3. Methods page 5: please add a reference to Taiwan Biobank here.
4. Please explain why GC and CC genotypes were combined in all main analyses.
5. It would be helpful to show the number of carriers of each of the 3 genotypes (GG, GC, and
CC), and the associations with gallstone disease for GC and CC individually, compared to GG.
Even if there is very low power for the CC-homozygotes, it would be interesting to have these
data in the paper.
6. Overall, the manuscript is easy to follow. But it would benefit from additional revision for
grammar and word usage. Some examples:
a) Introduction page 4: ‘The burden of gallstone in Taiwan…’ Revise to: ‘The burden of
gallstone disease in Taiwan…’
b) Introduction page 4:’…gallstone stone disease’. delete stone.
c) Introduction page 4: ‘Gallstone is a multifactorial….’, Revise: ‘Gallstone disease is a
multifactorial…’
d) Introduction page 4: ‘Gallstone is a multifactorial disorder having both genetic and non-
genetic onset.’ Revise.
e) Introduction page 5: ‘It is substantial to validate…’, Revise to ‘It is important to validate…’
f) Introduction page 5: ‘Moreover, the association between gallstone ABCG8 rs11887534
polymorphism…’. Suggest revising to: ‘Moreover, the association between ABCG8 rs11887534
…’.
g) Methods, page 5: ‘Each participant signed an informed consent form was enrolled into the
study only after fulfilling the eligibility criteria.’ Revise.
h) Methods, page 6: ‘In addition to self-reports, fasting glucose >126’. Please include unit.
i) Abstract: ‘G-WAS’, revise to ‘GWAS’.
j) Discussion. ‘Genetic aberrations in this gene are associated with cardiovascular diseases,
coronary atherosclerosis, and gallstones, cancer of the biliary tract [17, 19, 20, 26, 35-37]’ Revise
to ‘Genetic variation in this gene is associated with cardiovascular disease,  gallstones, and
cancer of the biliary tract [17, 19, 20, 26, 35-37]’
7. Methods, page 7: ‘Levels of aspartate aminotransferase (AST), alanine transaminase (ALT),
high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and
triglyceride (TG) were determined using biochemical tests.’ Which biochemical tests?
8. Relevant citations to include (two new GWAS for gallstone disease): PMID: 30325047 and
PMID: 30504769.
Please review this paper.
user
Title: Risk of gallstones based on ABCG8 rs11887534 single nucleotide polymorphism among
Taiwanese men and women
Version: 0 Date: 09 Aug 2021
Reviewer's report:
The study tested the association between a genetic variant, ABCG8 D19H, and gallstone disease
in a cohort of approximately 21,000 Taiwanese individuals. The variant was associated with
gallstones, as expected (ABCG8 D19H is the first identified and widely replicated common
genetic risk factor for gallstone disease).
Data presentation is clear and comprehensive, and the findings of the study are robust. The main
weakness of the paper is that the association of the variant with gallstone disease is already
firmly established in cohorts from across the globe (albeit not in Taiwanese cohorts).
Comments
1. Abstract, Methods: state the number of gallstone cases and that gallstones were self-reported.
2. Abstract: state frequency of ABCG8 D19H in the cohort.
3. Methods page 5: please add a reference to Taiwan Biobank here.
4. Please explain why GC and CC genotypes were combined in all main analyses.
5. It would be helpful to show the number of carriers of each of the 3 genotypes (GG, GC, and
CC), and the associations with gallstone disease for GC and CC individually, compared to GG.
Even if there is very low power for the CC-homozygotes, it would be interesting to have these
data in the paper.
6. Overall, the manuscript is easy to follow. But it would benefit from additional revision for
grammar and word usage. Some examples:
a) Introduction page 4: ‘The burden of gallstone in Taiwan…’ Revise to: ‘The burden of
gallstone disease in Taiwan…’
b) Introduction page 4:’…gallstone stone disease’. delete stone.
c) Introduction page 4: ‘Gallstone is a multifactorial….’, Revise: ‘Gallstone disease is a
multifactorial…’
d) Introduction page 4: ‘Gallstone is a multifactorial disorder having both genetic and non-
genetic onset.’ Revise.
e) Introduction page 5: ‘It is substantial to validate…’, Revise to ‘It is important to validate…’
f) Introduction page 5: ‘Moreover, the association between gallstone ABCG8 rs11887534
polymorphism…’. Suggest revising to: ‘Moreover, the association between ABCG8 rs11887534
…’.
g) Methods, page 5: ‘Each participant signed an informed consent form was enrolled into the
study only after fulfilling the eligibility criteria.’ Revise.
h) Methods, page 6: ‘In addition to self-reports, fasting glucose >126’. Please include unit.
i) Abstract: ‘G-WAS’, revise to ‘GWAS’.
j) Discussion. ‘Genetic aberrations in this gene are associated with cardiovascular diseases,
coronary atherosclerosis, and gallstones, cancer of the biliary tract [17, 19, 20, 26, 35-37]’ Revise
to ‘Genetic variation in this gene is associated with cardiovascular disease,  gallstones, and
cancer of the biliary tract [17, 19, 20, 26, 35-37]’
7. Methods, page 7: ‘Levels of aspartate aminotransferase (AST), alanine transaminase (ALT),
high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and
triglyceride (TG) were determined using biochemical tests.’ Which biochemical tests?
8. Relevant citations to include (two new GWAS for gallstone disease): PMID: 30325047 and
PMID: 30504769.
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