Keywords
CAKUT, vitamin A, vitamin D, nutrients, environmental factor, renal development
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Ozisik O, Ehrhart F, Evelo CT et al. Overlap of vitamin A and vitamin D target genes with CAKUT-related processes [version 1; peer review: 4 approved with reservations]. F1000Research 2021, 10:395 (https://doi.org/10.12688/f1000research.51018.1)
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Brief Report
Overlap of vitamin A and vitamin D target genes with CAKUT-related processes
[version 1; peer review: 4 approved with reservations]
PUBLISHED 18 May 2021
OPEN PEER REVIEW
REVIEWER STATUS
This article is included in the Cell & Molecular Biology gateway.
Abstract
Corresponding authors:
Ozan Ozisik, Anaı̈s Baudot
Competing interests:
No competing interests were disclosed.
Grant information:
This study has been conducted in context of the European Joint Programme on Rare Diseases (EJP RD) which has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement N°825575. Ozan Ozisik has received funding from the Excellence Initiative of Aix-Marseille University - A*Midex, a French “Investissements d’Avenir” programme.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Copyright:
© 2021 Ozisik O et al.
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
How to cite: Ozisik O, Ehrhart F, Evelo CT et al. Overlap of vitamin A and vitamin D target genes with CAKUT-related processes [version 1; peer review: 4 approved with reservations]. F1000Research 2021, 10:395 (https://doi.org/10.12688/f1000research.51018.1)
First published: 18 May 2021, 10:395 (https://doi.org/10.12688/f1000research.51018.1)
Latest published: 21 Apr 2022, 10:395 (https://doi.org/10.12688/f1000research.51018.2)
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Introduction
Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) are a group of abnormalities affecting the kidneys and their outflow tracts, including the ureters, the bladder, and the urethra. In the European Union, the overall prevalence of CAKUT (in live plus stillbirths) between 2011 and 2018 was approximately 35:10,000.1 The main anomalies observed in CAKUT are hydronephrosis (13.02:10,000) and multicystic renal dysplasia (4.33:10,000); these are followed by posterior urethral valves (1.26:10,000), bilateral renal agenesis (1.27:10,000) and bladder exstrophy/epispadia (0.62:10,000); many other anomalies with low prevalence can also be observed.1 This clinical variability observed in patients is accompanied by a variable severity of the phenotypes.2
Approximately 40 different genes are known to be associated with monogenic causes of CAKUT in humans, but they explain only 5% to 20% of the cases.3,4 The clinical variability and the complex aetiology of CAKUT cases suggest a multifactorial origin with complex interactions of both genetic and environmental factors contributing to the disease.2,3,5
The role of different environmental factors in CAKUT pathogenesis has been studied previously. It has been shown, for instance, that the drugs inhibiting the angiotensin-converting enzymes cause a specific form of CAKUT, namely tubular dysgenesis.6 Many prenatal and maternal factors were also assessed for their involvement in CAKUT and related anomalies. For example, studies have observed CAKUT associations with pregestational maternal diabetes mellitus,7,8,9 gestational maternal diabetes mellitus,8,10,11 abnormal volume of amniotic fluid,7,10 urogenital infections before the pregnancy,12 any infection during the pregnancy,12 maternal overweight and obesity,7,8,11,13 and lower infant birth weight.7,8,9,10 These maternal and prenatal factors are modulated by environmental risk factors. In particular, maternal diabetes and overweight/obesity as well as low birth weight are related to the nutrition of the maternal-fetal dyad. In this regard, trace nutrients, like vitamins, are likely to play important roles that still await full characterization.14
Vitamins are known to regulate renal development.15,16,17,18 The association of maternal vitamin A deficiency with nephron reduction was studied on a rat model.19 The inactivation of the retinoic acid nuclear receptors also resulted in renal malformations in mice.20 An additional study on rats showed that vitamin A deficiency downregulates RET expression which is essential for epithelial-mesenchymal interaction during renal development.21 Goodyear et al. compared a group of pregnant women in Bangalore with a high (55%) prevalence of vitamin A deficiency with a group of pregnant women in Montreal with negligible vitamin A deficiency.22 The authors found that renal volume in newborns, adjusted for body surface area, was significantly lower in the vitamin A-deficient population. While the two populations are different for other genetic and environmental reasons, these results suggest that vitamin A deficiency may have a role in human CAKUT. El-Khashab et al. reported a similar finding in their study on a cohort of Egyptian mother-child pairs;23 children of vitamin A deficient mothers had significantly lower kidney sizes.
The research on the effects of vitamin D deficiency on kidney development has generated interesting results. Rogers et al.24 observed that incubation of metanephroi with vitamin D3 prior to implantation into adult rats increased the number of glomeruli. Conversely, Maka et al.25 and Nascimento et al.26 observed that maternal vitamin D deficiency stimulated nephrogenesis in rats. Following these studies, Boyce et al. examined the long term effects of maternal vitamin D deficiency and observed that adult male rat offspring of vitamin D deficient dams had reduced creatinine clearance, indicating reduced renal functional capacity.27 They also observed a significant upregulation of renal renin mRNA expression in fetuses and adult male offspring, and reported smaller kidneys in the offspring. Miliku et al. examined the association of 25-hydroxyvitamin D levels during mid-pregnancy with childhood kidney outcomes among 4212 mother-child pairs.28 They observed that children of mothers who were vitamin D deficient during pregnancy had a larger combined kidney volume compared to children of mothers who had optimal vitamin D levels.
In this study, we assessed whether vitamin A and vitamin D target genes are related to gene sets involved in CAKUT and renal system development. We first created a list of vitamin A and vitamin D target genes, extracting information from the Comparative Toxicogenomics Database (CTD) as well as from two publications.29,30 We then constructed different gene sets relevant to CAKUT, including genes mutated in monogenic forms of CAKUT, genes involved in renal system development, and genes involved in different pathways of interest. Finally, we performed overlap analyses to identify the genes involved in these different gene sets as well as the significant overlaps.
Methods
Vitamin A target genes
We first queried vitamin A and downloaded all gene interactions of vitamin A and its descendants from the Comparative Toxicogenomics Database (CTD). We selected only the interactions supported by at least two references. This gave a list of 1086 target genes.
Balmer and Blomhoff29 reviewed published data from 1191 articles to identify genes regulated by retinoic acid (vitamin A acid) in humans and other species. The authors provide a list of retinoic acid target genes split into four categories ranging from strong evidence to indirect regulation through a transcriptional intermediary. We selected the genes from all of these categories, converted gene symbols to human orthologs, and updated gene symbols where necessary using the HUGO Gene Nomenclature Committee (HGNC), Rat Genome Database (RGD), Mouse Genome Database (MGD), BioMart and SynGo. The final list of genes obtained from Balmer and Blomhoff contains 521 target genes, of which 229 are common with genes from CTD.
Vitamin D target genes
We queried vitamin D and downloaded all gene interactions of vitamin D and its descendants from the CTD. We selected only the interactions supported by at least two references, and obtained a list of 263 target genes.
In Ramagopalan et al.,30 230 genes with significant expression changes in response to vitamin D were identified on lymphoblastoid cell lines using microarrays. We checked the gene names using HGNC and obtained a list of 210 target genes.
There are only 15 common genes between the list from CTD and the list from Ramagopalan et al. The combined list of vitamin D target genes (458 genes) has 134 genes in common with the combined list of vitamin A target genes (1378 genes).
CAKUT-related gene sets
We collected complementary gene sets relevant to CAKUT and renal system development from several sources, outlined below.
CAKUT causal genes set
First, we created a set of genes known to be mutated in the monogenic form of CAKUT. To do so, we combined two lists of genes provided in the studies of van der Ven et al.3,4 Only six genes are different between these two lists, and their union leads to 42 causal genes (see Extended data55).
GO kidney development gene sets
We extracted the genes annotated with the three terms below from Gene Ontology (GO).31,32 Please note that these terms have parent-child relationships.
• GO:0072001 Renal system development (315 genes)
• GO:0001822 Kidney development (306 genes)
• GO:0060993 Kidney morphogenesis (96 genes)
Reactome pathways
We selected different pathways of interest for CAKUT. The renin-angiotensin system is essential for kidney development and mutations in the genes of this system result in CAKUT.33 In addition, Davis et al. discussed the role of RET signaling in kidney development and CAKUT.34 In multiple studies35,36,37,38,39,40 the roles of WNT, NOTCH, and Hedgehog signaling in kidney development and kidney diseases are discussed. Based on these studies we included the following Reactome41 pathways:
• R-HSA-2022377 Metabolism of angiotensinogen to angiotensins (18 genes)
• R-HSA-8853659 RET signaling (38 genes)
• R-HSA-195721 Signaling by WNT (328 genes)
• R-HSA-157118 Signaling by NOTCH (233 genes)
• R-HSA-5358351 Signaling by Hedgehog (149 genes)
WikiPathways
From WikiPathways Rare Disease Portal42 we obtained the following four CAKUT-related pathways:
Overlap analyses
We computed the overlaps between vitamin target gene sets and the gene sets of interest defined previously. After obtaining the overlap results, we calculated the significance of the overlaps (hypergeometric test, p-values adjusted by Benjamini-Hochberg (BH) method) (see Underlying data and Extended data55).
Results and discussion
The results of the overlap analyses between vitamin A and D target genes and CAKUT-related gene sets are presented in Tables 1 and 2, and the corresponding data is available in Underlying data.55
Table 1. Overlap analysis results for vitamin A.
Pub: Publications,3,4 GO: Gene Ontology, Reac: Reactome, WP: WikiPathways.
Table 2. Overlap analysis results for vitamin D.
Pub: Publications,3,4 GO: Gene Ontology, Reac: Reactome, WP: WikiPathways.
Vitamin A target genes and CAKUT-related gene sets show significant overlaps
Vitamin A target genes obtained from both CTD and Balmer and Blomhoff are significantly enriched in the set of CAKUT causal genes, with an overlap of ten and six genes, respectively (Table 1).
A significant overlap is also observed focusing on GO terms related to renal system development, kidney development, and kidney morphogenesis. These results are expected due to the recognized role of vitamin A in differentiation.43,44 It should be noted that all overlapping CAKUT causal genes except NRIP1 are also part of the kidney development GO term.
Concerning the overlap with Reactome pathways, the vitamin A target genes obtained from CTD are significantly enriched in signaling by NOTCH. The NOTCH signalling pathway is mainly involved in cell-to-cell communication,45 and it plays a role in the development of most organs and tissues.46 Other Reactome terms also have overlapping genes, even if not significant. This includes the WNT signalling pathway (which is mainly involved in developmental processes such as patterning, differentiation/proliferation shift, and migration) and the metabolism of angiotensinogen to angiotensins pathway, from which CTSD, CTSG and MME are vitamin A targets and play roles in the generation of different angiotensin peptides.47,48,49 The impaired conversion of angiotensin I to angiotensin II is the pharmacodynamic adverse mechanism underlying the fetopathy caused by ACE-inhibiting drugs.50 One main feature of this teratogen-induced fetopathy, namely renal tubular dysgenesis, belongs to the CAKUT spectrum. In addition, an overproduction of angiotensin II might have a role in CAKUT anomalies involving renal tubules, as observed in cases of the autosomal recessive polycystic kidney disease.51
Finally, vitamin A target genes extracted from both CTD and Balmer and Blomhoff are significantly enriched in the development of ureteric collection system, genes controlling nephrogenesis, and GDNF/RET signalling axis pathways, as defined in WikiPathways. The target genes extracted from CTD are also significantly enriched in nephrogenesis. Signaling by GDNF through the RET receptor is required for normal growth of the ureteric bud.52 Localized expression of GDNF by the metanephric mesenchyme is important to elicit and correctly position the initial budding event from the Wolffian duct and to promote the continued branching of the ureteric bud. Cells that lack RET are unable to contribute to the tip of the ureteric bud.52
Overall, the significant overlaps observed between vitamin A and the CAKUT gene sets indicate that vitamin A might be relevant to a broad range of urogenital abnormalities.
Vitamin D target genes overlap with renal system development
In the analyses of vitamin D target gene sets, we observed very few significant overlaps with CAKUT-related gene sets overall. Vitamin D target genes obtained from CTD are only significantly enriched in renal system development, kidney development, and kidney morphogenesis GO terms. It should be noted that in each case 80% of the enriched genes are also vitamin A target genes (according to CTD or Balmer and Blomhoff).
CTSZ, which cleaves angiotensin I to yield angiotensin II,53 is the only vitamin D target in the metabolism angiotensinogen to angiotensins pathway. Thus, within CAKUT, vitamin D might also have a role in renal tubular defects related to anomalies of the renin-angiotensin system.
WNT and NOTCH signaling pathways have genes that are targets of vitamin D but there is a small, non-significant overlap, and the overlapping genes are not the WNT and NOTCH receptors nor ligands.
Conclusions
In this study we examined the overlaps of vitamin A and vitamin D target gene sets extracted from different databases and publications with CAKUT-related genes and biological processes. While we only observed significant enrichment of vitamin D target genes in GO kidney development terms, there is significant enrichment of vitamin A target genes in most of the gene sets we tested. Indeed, we observed that vitamin A target genes are enriched in CAKUT causal genes set, kidney development pathways, the signaling by NOTCH pathway, and the GDNF/RET signalling axis pathway. There is a strong overlap with the signaling by the WNT pathway, although it is not statistically significant. Overall, the significant overlaps observed between vitamin A and CAKUT gene sets indicate that vitamin A might be relevant to a broad range of urogenital abnormalities. Several environmental chemicals may impinge on retinoid-regulated pathways,54 and the influence of environment and nutrition cannot be ruled out. Our study is dedicated to the generation of hypotheses. Further study is needed, using up-to-date datasets obtained with new omics techniques, to investigate the fine-grained effects of vitamin excess and deficiency on CAKUT, and to decipher the pathophysiological mechanisms.
Data availability
Underlying data
Zenodo: Overlap of vitamin A and vitamin D target genes with CAKUT-related processes. https://www.doi.org/10.5281/zenodo.4501624.55
This project contains the following underlying data in the ‘Data’ folder:
• VitA-Balmer2002-Genes.txt (list of vitamin A target genes from Balmer and Blomhoff used for overlap analyses).
• VitA-CTD-Genes.txt (list of vitamin A target genes from CTD used for overlap analyses).
• VitD-Ramagopalan2010.txt (list of vitamin D target genes from Ramagopalan et al. used for overlap analyses).
• VitD-CTD-Genes.txt (list of vitamin D target genes from CTD used for overlap analyses).
• PathwaysOfInterest.gmt (CAKUT-related gene sets used for overlap analyses).
• PathwaysOfInterestBackground.txt (list indicating which background GMT file to be used for the analysis of each CAKUT-related gene set).
• hsapiens.GO:BP.name.gmt (all gene sets from GO:BP used as background information for overlap analyses).
• hsapiens.REAC.name.gmt (all gene sets from Reactome used as background information for overlap analyses).
• hsapiens.WP.name.gmt (all gene sets from WikiPathways used as background information for overlap analyses).
This project contains the following underlying data in the ‘Result’ folder:
• VitA-CTD-Genes.csv (overlap analysis results for vitamin A targets from CTD).
• VitA-Balmer2002-Genes.csv (overlap analysis results for vitamin A targets from Balmer and Blomhoff).
• VitA-Merged.csv (merged table for the results presented in VitA-CTD-Genes.csv and VitA-Balmer2002-Genes.csv).
• VitA-MergedTexVersion.txt (merged table in LaTeX format for the results presented in VitA-CTD-Genes.csv and VitA-Balmer2002-Genes.csv).
• VitD-CTD-Genes.csv (overlap analysis results for vitamin D targets from CTD).
• VitD-Ramagopalan2010.csv (overlap analysis results for vitamin D targets from Ramagopalan et al.).
• VitD-Merged.csv (merged table for the results presented in VitD-CTD-Genes.csv and VitD-Ramagopalan2010.csv).
• VitD-MergedTexVersion.txt (merged table in LaTeX format for the results presented in VitD-CTD-Genes.csv and VitD-Ramagopalan2010.csv).
Extended data
Zenodo: Overlap of vitamin A and vitamin D target genes with CAKUT-related processes. https://www.doi.org/10.5281/zenodo.4501624.55
This project contains the following extended data:
This project contains the following extended data in the ‘Supp’ folder:
• CAKUT-CausalGenesPMC5748921-6115658Comb.txt (list of genes known to be mutated in the monogenic form of CAKUT).
• targetsFromDifferentSourcesOverlap.odt (contains the information on vitamin A and D targets from different sources (CTD, publications), presents source specific genes and common genes).
• VitA-Balmer2002-GeneMapping.csv (detailed table for the gene list from Balmer and Blomhoff).
Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).
Author contributions
Ozisik O: Conceptualization, Data Curation, Formal Analysis, Project Administration, Writing – Original Draft Preparation; Ehrhart F: Conceptualization, Writing – Review & Editing; Evelo C: Conceptualization, Supervision, Writing – Review & Editing; Mantovani A: Conceptualization, Supervision, Writing – Original Draft Preparation; Baudot A: Conceptualization, Data Curation, Project Administration, Supervision, Writing – Original Draft Preparation.
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how to cite this article
Ozisik O, Ehrhart F, Evelo CT et al. Overlap of vitamin A and vitamin D target genes with CAKUT-related processes [version 1; peer review: 4 approved with reservations]. F1000Research 2021, 10:395 (https://doi.org/10.12688/f1000research.51018.1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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PUBLISHED 18 May 2021
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How to cite this report:
Eddy S. Reviewer Report For: Overlap of vitamin A and vitamin D target genes with CAKUT-related processes [version 1; peer review: 4 approved with reservations]. F1000Research 2021, 10:395 (https://doi.org/10.5256/f1000research.54123.r100885)
The direct URL for this report is:
https://f1000research.com/articles/10-395/v1#referee-response-100885
https://f1000research.com/articles/10-395/v1#referee-response-100885
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Reviewer Report 17 Dec 2021
Sean Eddy,
Division of Nephrology, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA
Approved with Reservations
VIEWS 13
This study involves generating curated vitamin A and D gene sets from the public domain and assessing the relevance of the genes to CAKUT and CAKUT related pathways. The authors meticulously report their results and curation efforts so the findings
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CITE
HOW TO CITE THIS REPORT
Eddy S. Reviewer Report For: Overlap of vitamin A and vitamin D target genes with CAKUT-related processes [version 1; peer review: 4 approved with reservations]. F1000Research 2021, 10:395 (https://doi.org/10.5256/f1000research.54123.r100885)
The direct URL for this report is:
https://f1000research.com/articles/10-395/v1#referee-response-100885
https://f1000research.com/articles/10-395/v1#referee-response-100885
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Author Response 25 Apr 2022Ozan Ozisik, Aix Marseille University, France25 Apr 2022Author ResponseWe thank the reviewer for the valuable comments. We present the reviewer comments, our answers to them, and quoted texts from the revised manuscript below.
Given that patient CAKUT ... Continue reading
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Author Response 25 Apr 2022Ozan Ozisik, Aix Marseille University, France25 Apr 2022Author ResponseWe thank the reviewer for the valuable comments. We present the reviewer comments, our answers to them, and quoted texts from the revised manuscript below.
Given that patient CAKUT ... Continue reading
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Angelin-Bonnet O. Reviewer Report For: Overlap of vitamin A and vitamin D target genes with CAKUT-related processes [version 1; peer review: 4 approved with reservations]. F1000Research 2021, 10:395 (https://doi.org/10.5256/f1000research.54123.r98474)
The direct URL for this report is:
https://f1000research.com/articles/10-395/v1#referee-response-98474
https://f1000research.com/articles/10-395/v1#referee-response-98474
NOTE: it is important to ensure the information in square brackets after the title is included in this citation.
Reviewer Report 15 Dec 2021
Approved with Reservations
VIEWS 18
The article "Overlap of vitamin A and vitamin D target genes with CAKUT-related processes" investigates the overlap between vitamin A and D target genes and genes associated with congenital anomalies of the kidney and urinary tract (CAKUT). More specifically, the
... Continue reading
CITE
HOW TO CITE THIS REPORT
Angelin-Bonnet O. Reviewer Report For: Overlap of vitamin A and vitamin D target genes with CAKUT-related processes [version 1; peer review: 4 approved with reservations]. F1000Research 2021, 10:395 (https://doi.org/10.5256/f1000research.54123.r98474)
The direct URL for this report is:
https://f1000research.com/articles/10-395/v1#referee-response-98474
https://f1000research.com/articles/10-395/v1#referee-response-98474
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Simons M. Reviewer Report For: Overlap of vitamin A and vitamin D target genes with CAKUT-related processes [version 1; peer review: 4 approved with reservations]. F1000Research 2021, 10:395 (https://doi.org/10.5256/f1000research.54123.r95476)
The direct URL for this report is:
https://f1000research.com/articles/10-395/v1#referee-response-95476
https://f1000research.com/articles/10-395/v1#referee-response-95476
NOTE: it is important to ensure the information in square brackets after the title is included in this citation.
Reviewer Report 27 Oct 2021
Matias Simons,
Laboratory of Epithelial Biology and Disease, Imagine Institute, Université Paris Descartes‐Sorbonne, Paris, France
Approved with Reservations
VIEWS 20
The paper by Ozisik et al investigates associations of Vitamin A and D target genes with renal development and CAKUT pathways. They find that a significant overlap for vitamin A target genes but less so for vitamin D target genes.
... Continue reading
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Simons M. Reviewer Report For: Overlap of vitamin A and vitamin D target genes with CAKUT-related processes [version 1; peer review: 4 approved with reservations]. F1000Research 2021, 10:395 (https://doi.org/10.5256/f1000research.54123.r95476)
The direct URL for this report is:
https://f1000research.com/articles/10-395/v1#referee-response-95476
https://f1000research.com/articles/10-395/v1#referee-response-95476
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Menegola E. Reviewer Report For: Overlap of vitamin A and vitamin D target genes with CAKUT-related processes [version 1; peer review: 4 approved with reservations]. F1000Research 2021, 10:395 (https://doi.org/10.5256/f1000research.54123.r85565)
The direct URL for this report is:
https://f1000research.com/articles/10-395/v1#referee-response-85565
https://f1000research.com/articles/10-395/v1#referee-response-85565
NOTE: it is important to ensure the information in square brackets after the title is included in this citation.
Reviewer Report 25 Jun 2021
Elena Menegola,
Department of Environmental Sciences and Policies, Università degli Studi di Milano, Milan, Italy
Approved with Reservations
VIEWS 31
The manuscript "Overlap if vitamin A and vitamin D target genes with CAKUT-related processes" is aimed to indirectly evaluate the possible relationship between Vitamin A and D intake imbalance and congenital anomalies of the kidney and urinary tract (CAKUT). The work considers genes
... Continue reading
CITE
HOW TO CITE THIS REPORT
Menegola E. Reviewer Report For: Overlap of vitamin A and vitamin D target genes with CAKUT-related processes [version 1; peer review: 4 approved with reservations]. F1000Research 2021, 10:395 (https://doi.org/10.5256/f1000research.54123.r85565)
The direct URL for this report is:
https://f1000research.com/articles/10-395/v1#referee-response-85565
https://f1000research.com/articles/10-395/v1#referee-response-85565
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Author Response 25 Apr 2022Ozan Ozisik, Aix Marseille University, France25 Apr 2022Author ResponseWe thank the reviewer for the detailed summary and valuable comments. We present the reviewer comments, our answers to them, and quoted texts from the revised manuscript below.
Abstract
... Continue reading
COMMENTS ON THIS REPORT
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Author Response 25 Apr 2022Ozan Ozisik, Aix Marseille University, France25 Apr 2022Author ResponseWe thank the reviewer for the detailed summary and valuable comments. We present the reviewer comments, our answers to them, and quoted texts from the revised manuscript below.
Abstract
... Continue reading
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