Title: PNPLA3 genotype and fibrosis-4 index predict cardiovascular diseases of Japanese
patients with histopathologically-confirmed NAFLD
Version: 1 Date: 12 Oct 2021
Reviewer's report:
Summary
The aim of this study was to test the association of noninvasive metrics with the development
of cardiovascular disease (CVD), any cancer, and liver-related events in patients with
nonalcoholic fatty liver disease (NAFLD). The cohort comprised n=477 Japanese patients with
histopathologically confirmed NAFLD, followed for a median of 5.9 years. Main findings were
that a high baseline Fib-4 was  associated with increased rates of CVD, cancer, and liver-related
events. The PNPLA3 CC-genotype (that associates with lowest risk of NAFLD compared to CG
and GG) was associated with increased risk of CVD development in the cohort.
Comments
1) How were the clinical events defined? Please describe in Methods.
2) It was not clear why liver cancer is excluded as a cancer outcome. Please consider including
liver cancer as a separate outcome.
3) The limited number of events during follow-up limits statistical power. This should be
acknowledged.
3) Table 3: please include numbers of events and participants.
4) Figures: Consider removing the ticks denoting censoring on the KM-curves. They obscure
the lines.
5) page 13, bottom:
‘Mendelian randomization analysis recently indicated that the PNPLA3 genetic variant might
not be causally associated with the risk of CVDs.’
Please provide citation: PMID: 29228164, in addition to ref #22.
6) might the association between PNPLA3 CC and increased CVD rate be due to collider
bias? Please see https://www.nature.com/articles/s41467-020-19478-2 among other places for
the reasoning behind this comment.
7) The paper is easy to understand, and the figures and tables are clearly designed. Nevertheless,
the paper would benefit from revision for language and grammar.
Title: PNPLA3 genotype and fibrosis-4 index predict cardiovascular diseases of Japanese
patients with histopathologically-confirmed NAFLD
Version: 1 Date: 12 Oct 2021
Reviewer's report:
Summary
The aim of this study was to test the association of noninvasive metrics with the development
of cardiovascular disease (CVD), any cancer, and liver-related events in patients with
nonalcoholic fatty liver disease (NAFLD). The cohort comprised n=477 Japanese patients with
histopathologically confirmed NAFLD, followed for a median of 5.9 years. Main findings were
that a high baseline Fib-4 was  associated with increased rates of CVD, cancer, and liver-related
events. The PNPLA3 CC-genotype (that associates with lowest risk of NAFLD compared to CG
and GG) was associated with increased risk of CVD development in the cohort.
Comments
1) How were the clinical events defined? Please describe in Methods.
2) It was not clear why liver cancer is excluded as a cancer outcome. Please consider including
liver cancer as a separate outcome.
3) The limited number of events during follow-up limits statistical power. This should be
acknowledged.
3) Table 3: please include numbers of events and participants.
4) Figures: Consider removing the ticks denoting censoring on the KM-curves. They obscure
the lines.
5) page 13, bottom:
‘Mendelian randomization analysis recently indicated that the PNPLA3 genetic variant might
not be causally associated with the risk of CVDs.’
Please provide citation: PMID: 29228164, in addition to ref #22.
6) might the association between PNPLA3 CC and increased CVD rate be due to collider
bias? Please see https://www.nature.com/articles/s41467-020-19478-2 among other places for
the reasoning behind this comment.
7) The paper is easy to understand, and the figures and tables are clearly designed. Nevertheless,
the paper would benefit from revision for language and grammar.
Please review this paper.
user
Title: PNPLA3 genotype and fibrosis-4 index predict cardiovascular diseases of Japanese
patients with histopathologically-confirmed NAFLD
Version: 1 Date: 12 Oct 2021
Reviewer's report:
Summary
The aim of this study was to test the association of noninvasive metrics with the development
of cardiovascular disease (CVD), any cancer, and liver-related events in patients with
nonalcoholic fatty liver disease (NAFLD). The cohort comprised n=477 Japanese patients with
histopathologically confirmed NAFLD, followed for a median of 5.9 years. Main findings were
that a high baseline Fib-4 was  associated with increased rates of CVD, cancer, and liver-related
events. The PNPLA3 CC-genotype (that associates with lowest risk of NAFLD compared to CG
and GG) was associated with increased risk of CVD development in the cohort.
Comments
1) How were the clinical events defined? Please describe in Methods.
2) It was not clear why liver cancer is excluded as a cancer outcome. Please consider including
liver cancer as a separate outcome.
3) The limited number of events during follow-up limits statistical power. This should be
acknowledged.
3) Table 3: please include numbers of events and participants.
4) Figures: Consider removing the ticks denoting censoring on the KM-curves. They obscure
the lines.
5) page 13, bottom:
‘Mendelian randomization analysis recently indicated that the PNPLA3 genetic variant might
not be causally associated with the risk of CVDs.’
Please provide citation: PMID: 29228164, in addition to ref #22.
6) might the association between PNPLA3 CC and increased CVD rate be due to collider
bias? Please see https://www.nature.com/articles/s41467-020-19478-2 among other places for
the reasoning behind this comment.
7) The paper is easy to understand, and the figures and tables are clearly designed. Nevertheless,
the paper would benefit from revision for language and grammar.
assistant