Title: Association between single nucleotide polymorphisms in PNPLA3, TM6SF2 and
MBOAT7 genes and markers of cancer aggressiveness in a Sri Lankan NASH-related HCC
cohort
Version: 3 Date: 04 Feb 2025
Reviewer:  Zhaohui Tang
Reviewer's report:
Thank you for the author's patient and meticulous answers. However, I still have some doubts
that need to be clarified:
1. How was the study powered to detect associations for “TM6SF2” and “MBOAT7” SNPs,
given their lack of significance?
2. Were multiple testing corrections applied? If not, how might uncorrected p-values impact the
interpretation of “PNPLA3” associations?
3. Can the authors elaborate on the biological mechanisms linking “PNPLA3” rs2281135 to
miR-122 elevation and tumor nodularity?
4. Why were cirrhotic and non-cirrhotic HCC patients not stratified in analyses, given prior
evidence of SNP associations with cirrhosis?
5. Could the observed age/BMI associations with “PNPLA3” rs2281135 reflect survivorship
bias or confounding factors (e.g., comorbidities)?
6. Overrepresentation of Sinhalese individuals (47/48) limits generalizability to other ethnic
groups in Sri Lanka or globally.
Title: Association between single nucleotide polymorphisms in PNPLA3, TM6SF2 and
MBOAT7 genes and markers of cancer aggressiveness in a Sri Lankan NASH-related HCC
cohort
Version: 3 Date: 04 Feb 2025
Reviewer:  Zhaohui Tang
Reviewer's report:
Thank you for the author's patient and meticulous answers. However, I still have some doubts
that need to be clarified:
1. How was the study powered to detect associations for “TM6SF2” and “MBOAT7” SNPs,
given their lack of significance?
2. Were multiple testing corrections applied? If not, how might uncorrected p-values impact the
interpretation of “PNPLA3” associations?
3. Can the authors elaborate on the biological mechanisms linking “PNPLA3” rs2281135 to
miR-122 elevation and tumor nodularity?
4. Why were cirrhotic and non-cirrhotic HCC patients not stratified in analyses, given prior
evidence of SNP associations with cirrhosis?
5. Could the observed age/BMI associations with “PNPLA3” rs2281135 reflect survivorship
bias or confounding factors (e.g., comorbidities)?
6. Overrepresentation of Sinhalese individuals (47/48) limits generalizability to other ethnic
groups in Sri Lanka or globally.
Please review this paper.
user
Title: Association between single nucleotide polymorphisms in PNPLA3, TM6SF2 and
MBOAT7 genes and markers of cancer aggressiveness in a Sri Lankan NASH-related HCC
cohort
Version: 3 Date: 04 Feb 2025
Reviewer:  Zhaohui Tang
Reviewer's report:
Thank you for the author's patient and meticulous answers. However, I still have some doubts
that need to be clarified:
1. How was the study powered to detect associations for “TM6SF2” and “MBOAT7” SNPs,
given their lack of significance?
2. Were multiple testing corrections applied? If not, how might uncorrected p-values impact the
interpretation of “PNPLA3” associations?
3. Can the authors elaborate on the biological mechanisms linking “PNPLA3” rs2281135 to
miR-122 elevation and tumor nodularity?
4. Why were cirrhotic and non-cirrhotic HCC patients not stratified in analyses, given prior
evidence of SNP associations with cirrhosis?
5. Could the observed age/BMI associations with “PNPLA3” rs2281135 reflect survivorship
bias or confounding factors (e.g., comorbidities)?
6. Overrepresentation of Sinhalese individuals (47/48) limits generalizability to other ethnic
groups in Sri Lanka or globally.
assistant