Round 1

Reviewer 1 Report

This manuscript by Dr. Taliento AE, et al. entitled “Novel insights into the genetic landscape of nonalcoholic fatty liver disease.” summarized many studies to introduce us the genetic factors that play an important role in the development of NAFLD/NASH. NAFLD/NASH often leads to hepatic cirrhosis and hepatocellular carcinoma, thus posing an important health problem worldwide. Genetic factors are important for the development of NAFLD/NASH, as well as environmental factors.

This article is narrative (or literature) review, not a systematic review nor meta-analysis. This narrative review by Taliento, et al. seems to have an important role in education because they introduce us latest information about PNPLA3, TM6SF2, MBOAT7 and HSD17B13 in NAFLD progression, and this review seems to be well written. Therefore, it is appropriate to hand in to this journal.

Minor comment 1.

There was nothing written about the “Direction” in Table 1.

Minor comment 2.

A subtitle description shall bear the details in a specific manner. Please reconsider the expression of “liver disease progression” in subtitle 5.

Author Response

Comments and Suggestions for Authors

We thank the Reviewer for the positive comment on the manuscript.

Minor comment 1.

There was nothing written about the “Direction” in Table 1.

We apologize for the mistake; we have now added the direction of the associations in Table 1.

Minor comment 2.

A subtitle description shall bear the details in a specific manner. Please reconsider the expression of “liver disease progression” in subtitle 5.

As suggested, we have now modified Subtitle 5.

Author Response File: Author Response.docx

Reviewer 2 Report

In this work Taliento and colleagues review the role of genetic factors as risk factors for NAFLD onset and progression. The topic is highly interesting and relevant. Moreover, the tables and figures are informative and appropriate albeit not very novel. Unfortunately however, the manuscript is riddled with mistakes and inaccuracies, which require the reader to consult the original papers (or any of the vast number of alternative reviews on the topic). Below I provide a fraction of examples. However, as there are so many additional mistakes, similar to the ones provided below, assembly of a comprehensive list exceeds the time that can be expected to be invested from a reviewer. Possibly, some of these points are lost in translation and it would thus be highly recommended that the work should be proofread by a native speaker before publication to improve readability.

- Lines 50-51: “…aminotransferases levels, a marker of fat liver content…” – aminotransferases are not a direct measure of lipid content but rather of hepatic injury. This should be corrected.

- Lines 73-74: “The variant is most common in Hispanics, characterized by the susceptibility to accumulate liver fat [14].” – It is not clear what the authors want to state here. This sentence might be lost in translation and should be rephrased.

- Lines 83-85: “However, excessive adiposity is the environmental player that triggers the most I148M expression in individuals who do not exceed in alcohol consumption [19].” – Firstly, “I148M expression”, i.e. the expression of an amino acid exchange is not appropriate scientific terminology. Even if I assume that the authors refer to PNPLA3 expression, ref. 19 does not provide any data in this regard. Rather, ref. 19 refers to an interaction of adiposity with genetic risk factors and the authors of this reference very carefully state that “it is possible that obesity amplifies the effects of the three risk alleles by altering their expression”. However, the important information that this remains purely speculative is lost in the presented review.

- Table 1 should contain key references.

- Some work that could be discussed in the context of APOB variation and NAFLD: PMIDs 23723369, 28641782, 30076208.

- The authors should refer to previous key reviews on the topic and indicate how their contribution goes beyond these.

Author Response

Comments and Suggestions for Authors

As suggested, we have reassessed the manuscript for possible inaccuracies. We have highlighted the novelties of the present manuscript, as compared to previous reviews by our research group (e.g. Journal of Hepatology 2016, Current Pharmaceutical Design 2018). We believe the track record of the research group in the field of NAFLD genetics stands for the accuracy of the reported statements.

We thank the reviewer for the comment. Although it is true that aminotransferases are a marker of hepatic injury, but they are also strongly associated with hepatic fat content in individuals without chronic viral hepatitis and alcohol abuse. This is for example demonstrated by Makkonen et al., J Hepatol 2009 (ref. # 11), and Dongiovanni et al., J Intern Med 2019 (ref. #72) We have now cited these relevant studies.

We thank the reviewer for the comment, we have now rephrased the sentence.

We thank the reviewer for highlighting this point; in this sentence we meant to refer to I148M phenotypic expression (that is to the fraction of individuals that display the associated phenotype) and not to the gene expression. We have now rephrases the sentence.

- Table 1 should contain key references.

We apologize for the inattention; we have now cited the key references in the legend of Table 1.

- Some work that could be discussed in the context of APOB variation and NAFLD: PMIDs 23723369, 28641782, 30076208.

We thank the reviewer for the suggestions, we have now cited and discussed these relevant manuscripts in Paragraph 7.

- The authors should refer to previous key reviews on the topic and indicate how their contribution goes beyond these.

We thank the Reviewer for the suggestion; we have now cited previous key reviews and highlighted the novelties presented in this manuscript in the Introduction section (page 1, line 44).

Author Response File: Author Response.docx

Reviewer 3 Report

The manuscript collected current information about genetic factors that are related to NAFLD. NAFLD is a very complicate disease. According to the authors, it may also be lifestyle related. Therefore, it may be more accurate, if possible, to include the relative risk due to genetic factors in the epidemiological studies cited and compared to the risk due to other causes. Nevertheless, the review was well written and did a good job in summarizing the current knowledge, and provide some insight on the application of treatment for NAFLD basing on the pathology revealed by genetic analysis..

Author Response

Comments and Suggestions for Authors

We thank the Reviewer for the suggestion. Although lifestyle plays an important role in NAFLD development, the focus of the review was to give insights about the role of genetic risk factors in the pathogenesis of this condition. As suggested, we have now highlighted the specific impact of hereditability versus that of environmental factors (page 2 lines 54-55). Moreover, we confirmed the role of environmental factors, such as adiposity, in triggering the phenotypic expression of the genetic risk variants (page 3, lines 96-97).

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

None remaining.

Review Reports