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Background: Prior studies show chronic kidney disease (CKD) is heritable but only a few common variants have been associated with CKD and kidney dysfunction. Much of CKD heritability remains unknown and limited studies have explored the role of rare genetic variants in this missing heritability. Objectives: Identify rare genetic variants in renal developmental genes associated with hypertension and CKD. Methods: We examined the association between rare variants in 58 candidate genes from five renal developmental compartments and presence of CKD and elevated blood pressure (BP) in 49,989 individuals using whole exome sequencing and phenotypic data from the UK Biobank. Criteria for qualifying rare variants included a minor allele frequency < 0.1% and classification as pathogenic, likely pathogenic, or variant of uncertain significance (VUS) using in-house characterization software. Logistic regression models were generated for each compartment to determine the predictive ability of qualifying variants for the outcomes of elevated BP and CKD, with additional subgroup analysis by genetic ethnicity. Genes were selected for inclusion in regression models based on p < 0.25 using Chi-square univariate analysis. Genes included for each developmental compartment’s regression model are summarized in Tables 1 & 2. Results: Qualifying variants in 5 genes across 3 developmental compartments were significant predictors of elevated BP; qualifying variants in 4 genes across 4 developmental compartments were predictive of CKD. In subgroup analysis of individuals genetically identified as Caucasian, qualifying variants in 4 genes across 3 compartments were predictive of elevated BP; qualifying variants in 3 genes across 2 compartments were predictive of CKD. For individuals genetically identified as non-Caucasian qualifying variants in 3 genes across 2 compartments were predictive of elevated BP; qualifying variants in 6 genes across 2 compartments were predictive of CKD (Tables 1 & 2). The distribution of qualifying variant types (i.e. pathogenic, likely pathogenic, VUS) within genes containing rare variants predictive of disease were predominately VUSs (Figure 1). Conclusion: Rare variants in some renal developmental genes are associated with elevated BP and CKD and may help explain a portion of the missing heritability. However, the significances of variants differ by ethnicity, and the majority are classified as VUSs requiring further characterization.
Nephrology | Pediatrics
Spector, Benjamin; Yoo, Byunggil; Miller, Neil; and Willig, Laurel K., "Rare variants in renal developmental genes and the risk of hypertension and CKD: a UK Biobank study" (2022). Posters. 270.