Association of Rare Variants in Kidney Developmental Genes With Chronic Kidney Disease and Blood Pressure: A UK Biobank Study.

Introduction: Chronic kidney disease (CKD) and hypertension are heritable traits. The source of this heritability remains largely unknown, and exploration has been limited principally to common genetic variants, with few studies having examined rare variants.

Methods: In this cross-sectional observational study, we evaluate whole exome sequencing data using the UK Biobank to identify the ability of rare variants in 58 kidney developmental genes to predict CKD or elevated blood pressure using logistic regression models with subgroup analysis performed by ancestry.

Results: Significant predictors of CKD included rare variants in CLCN5 (OR 1.59; 99% CI, 1.02-2.47; P = 0.007). Predictors of blood pressure included rare variants in SIX1 (OR 0.57; 99% CI, 0.35-0.94; P = 0.004) and NPHS1 (OR 0.84; 99% CI, 0.72-0.99; P = 0.005), which were protective against blood pressure elevation, and WT1 (OR 1.58; 99% CI, 1.02-2.45; P = 0.007), which was associated with elevated blood pressure. In individuals of White British ancestry, rare variants in SIX1 protected against elevated blood pressure (OR 0.58; 99% CI, 0.34-0.99; P = 0.009). Among individuals of non-White British ancestry, predictors of CKD included rare variants in SLC12A3 (OR 2.02; 99% CI, 1.08-3.78; P = 0.004) and CALB1 (OR 3.12; 99% CI, 1.15-8.47; P = 0.003). Presence of rare variants in WT1 significantly predicted elevated blood pressure (OR 2.49; 99% CI, 1.08-5.78; P = 0.005).

Conclusions: From this study, we conclude that rare variants in kidney developmental genes contribute to the risk of developing CKD and elevated blood pressure. These associations vary by ancestry.