TY - JOUR
T1 - Genetic and environmental factors driving congenitcal solitary functioning kidney
AU - van Wijk, Joanna
AU - Groen in 't Woud, S.
AU - van Gelder, Marleen M H J
AU - van Rooij, Iris A L M
AU - Feitz, Wout F J
AU - Roeleveld, Nel
AU - Schreuder, Michiel F
AU - van der Zanden, Loes F M
AU - SOFIA study group
N1 - © The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.
PY - 2023/9/20
Y1 - 2023/9/20
N2 - 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 (GxE), although relevant for other congenital anomalies, has not yet been investigated. Therefore, we performed a genome-wide GxE analysis with six preselected environmental factors to explore the role of these interactions in the aetiology of CSFK.METHODS: In the AGORA 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 single-nucleotide variants associated with one of the six environmental risk factors. These SNVs were subsequently tested in GxE 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 to 40 SNVs were selected per environmental factor, of which only rs3098698 reached statistical significance (p = 0.0016, 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 ARSB gene, could be explained by lower insulin receptor activity in children heterozygous for rs3098698. Eight other GxE interactions had a p-value < 0.05, 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.
AB - 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 (GxE), although relevant for other congenital anomalies, has not yet been investigated. Therefore, we performed a genome-wide GxE analysis with six preselected environmental factors to explore the role of these interactions in the aetiology of CSFK.METHODS: In the AGORA 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 single-nucleotide variants associated with one of the six environmental risk factors. These SNVs were subsequently tested in GxE 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 to 40 SNVs were selected per environmental factor, of which only rs3098698 reached statistical significance (p = 0.0016, 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 ARSB gene, could be explained by lower insulin receptor activity in children heterozygous for rs3098698. Eight other GxE interactions had a p-value < 0.05, 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.
U2 - https://doi.org/10.1093/ndt/gfad202
DO - https://doi.org/10.1093/ndt/gfad202
M3 - Article
C2 - 37738450
SN - 0931-0509
SP - 2631
EP - 2641
JO - Nephrology, dialysis, transplantation
JF - Nephrology, dialysis, transplantation
M1 - 37738450
ER -