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  • Title: Evaluation of a genetic risk score based on creatinine-estimated glomerular filtration rate and its association with kidney outcomes.
    Author: Thio CHL, van der Most PJ, Nolte IM, van der Harst P, Bültmann U, Gansevoort RT, Snieder H.
    Journal: Nephrol Dial Transplant; 2018 Oct 01; 33(10):1757-1764. PubMed ID: 29294079.
    Abstract:
    BACKGROUND: Meta-analysis of cross-sectional genome-wide association studies (GWAS) on creatinine-estimated glomerular filtration rate (eGFRcrea) identified 53 single-nucleotide polymorphisms (SNPs). These SNP effects can be aggregated into a genetic risk score (GRS) for chronic kidney disease (CKD). To assess its clinical utility, we examined associations with creatinine-estimated kidney outcomes, both cross-sectionally and longitudinally. Additionally, we examined associations with cystatin C-estimated kidney outcomes to verify that a GRS based on eGFRcrea SNPs represents the genetics underlying kidney function. METHODS: In the community-based Prevention of REnal and Vascular ENdstage Disease (PREVEND) study, we assessed eGFRcrea and eGFRcysc at baseline and four follow-up examinations. The GRS comprised 53 SNPs for eGFRcrea weighted for reported effect-sizes. We adjusted for baseline demographics and renal risk factors. RESULTS: We included 3649 subjects (median age 49 years, 52% male, median follow-up 11 years, n = 85 baseline CKD, n = 154 incident CKD). At baseline, a higher GRS associated with lower eGFRcrea {adjusted B [95% confidence interval (CI)] = -2.05 (-2.45 to - 1.65) mL/min/1.73 m2, P < 0.001} and higher CKD prevalence [adjusted odds ratio (95% CI) = 1.41 (1.12-1.77), P = 0.002]. During follow-up, a higher GRS associated with higher CKD incidence [adjusted hazard ratio (95% CI) = 1.28 (1.09-1.50), P = 0.004], but no longer significantly after adjustment for baseline eGFR. No significant association with eGFRcrea decline was found. Associations with cystatin C-estimated outcomes were similar. CONCLUSIONS: The GRS robustly associated with baseline CKD and eGFR, independent of known risk factors. Associations with incident CKD were likely due to low baseline eGFR, not accelerated eGFR decline. The GRS for eGFRcrea likely represents the genetics underlying kidney function, not creatinine metabolism or underlying aetiologies. To improve the clinical utility of GWAS results for CKD, these need to specifically address eGFR decline and CKD incidence.
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