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. 2024 Feb 28;39(3):463-472.
doi: 10.1093/ndt/gfad202.

Genetic and environmental factors driving congenital solitary functioning kidney

Sander Groen In 't Woud  1   2 , Marleen M H J van Gelder  1 , Iris A L M van Rooij  1 , Wout F J Feitz  3 , Nel Roeleveld  1 , Michiel F Schreuder  2 , Loes F M van der Zanden  1 ; SOFIA study group
Collaborators, Affiliations

Genetic and environmental factors driving congenital solitary functioning kidney

Sander Groen In 't Woud et al. Nephrol Dial Transplant. .

Abstract

Background: Congenital solitary functioning kidney (CSFK) is an anomaly predisposing to hypertension, albuminuria and chronic kidney disease. Its aetiology is complex and includes genetic and environmental factors. The role of gene-environment interactions (G×E), although relevant for other congenital anomalies, has not yet been investigated. Therefore, we performed a genome-wide G×E analysis with six preselected environmental factors to explore the role of these interactions in the aetiology of CSFK.

Methods: In the AGORA (Aetiologic research into Genetic and Occupational/environmental Risk factors for Anomalies in children) data- and biobank, genome-wide single-nucleotide variant (SNV) data and questionnaire data on prenatal exposure to environmental risk factors were available for 381 CSFK patients and 598 healthy controls. Using a two-step strategy, we first selected independent significant SNVs associated with one of the six environmental risk factors. These SNVs were subsequently tested in G×E analyses using logistic regression models, with Bonferroni-corrected P-value thresholds based on the number of SNVs selected in step one.

Results: In step one, 7-40 SNVs were selected per environmental factor, of which only rs3098698 reached statistical significance (P = .0016, Bonferroni-corrected threshold 0.0045) for interaction in step two. The interaction between maternal overweight and this SNV, which results in lower expression of the Arylsulfatase B (ARSB) gene, could be explained by lower insulin receptor activity in children heterozygous for rs3098698. Eight other G×E interactions had a P-value <.05, of which two were biologically plausible and warrant further study.

Conclusions: Interactions between genetic and environmental factors may contribute to the aetiology of CSFK. To better determine their role, large studies combining data on genetic and environmental risk factors are warranted.

Keywords: CAKUT; aetiology; congenital anomaly; gene–environment interaction; solitary functioning kidney.

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Conflict of interest statement

None declared.

Figures

Graphical Abstract
Graphical Abstract
Figure 1:
Figure 1:
Flowchart of inclusion of patients and controls.
Figure 2:
Figure 2:
Single-tissue eQTL normalized expression scores of ARSB for rs3098698 in different cell types. Figure created using GTEx portal (https://gtexportal.org/).
See this image and copyright information in PMC

References

    1. Groen In ‘t Woud S, Roeleveld N, Westland R et al. Uncovering risk factors for kidney injury in children with a solitary functioning kidney. Kidney Int 2023;103:156–65. 10.1016/j.kint.2022.09.028 - DOI - PubMed
    1. Hiraoka M, Tsukahara H, Ohshima Y et al. Renal aplasia is the predominant cause of congenital solitary kidneys. Kidney Int 2002;61:1840–4. 10.1046/j.1523-1755.2002.00322.x - DOI - PubMed
    1. Jacobs DR, Woo JG, Sinaiko AR et al. Childhood cardiovascular risk factors and adult cardiovascular events. N Engl J Med 2022;386:1877–88 10.1056/NEJMoa2109191 - DOI - PMC - PubMed
    1. Westland R, Renkema KY, Knoers NVAM. Clinical integration of genome diagnostics for congenital anomalies of the kidney and urinary tract. Clin J Am Soc Nephrol 2021;16:128–37. 10.2215/CJN.14661119 - DOI - PMC - PubMed
    1. Nicolaou N, Renkema KY, Bongers EMHF et al. Genetic, environmental, and epigenetic factors involved in CAKUT. Nat Rev Nephrol 2015;11:720–31. 10.1038/nrneph.2015.140 - DOI - PubMed