#3949 NPY GENE POLYMORPHISMS ARE STRONGLY LINKED TO CKD PROGRESSION: A MENDELIAN RANDOMIZATION STUDY

Abstract Background and Aims Neuropeptide Y (NPY) is a 36 amino-acid neuropeptide that regulates various physiological processes in both the central and peripheral nervous systems, including cardiovascular and metabolic control. We showed that high plasma NPY predicts CKD progression (NDT 2018;33:1805-1812) in a cohort of 735 patients with stage G2-5 CKD. Whether this association is causal in nature is undetermined. Method In the same cohort of the previous study, we tested the relationship between NPY gene variability, as assessed by six single nucleotide polymorphisms (SNPs) representative of the gene haploblock structure which explained about 80% of gene variability, and the incidence rate of renal events (dialysis/transplantation/eGFR reduction >30%) over a median follow up of 36 months (inter-quartile range 35-37 months). Results Three variants [rs16131 (TT, n = 563; CT+CC, n = 172), rs16140 (CG+GG, n = 413; CC, n = 322), rs16148 (CT+CC, n = 456; TT, n = 279)] coherently associated to the incidence rate of renal events (HR ranging from 1.36 to 1.57, P≤0.029). A dose response relationship was found between the number of risk variants and renal events, the HR for this outcome being highest in patients with three risk genotypes (HR: 1.66, 95% 1.05-2.61). In a multivariate model adjusting for traditional risk factors (age, gender, smoking, diabetes, cholesterol, systolic BP and background cardiovascular comorbidities) and factors peculiar to CKD (haemoglobin, eGFR, albumin, phosphate, and C-reactive protein), the association remained highly significant (P for trend = 0.001). In a separate analysis including the three variants simultaneously, only the rs16131 variant maintained an independent association with the risk for renal events (HR: 1.58, 95% CI 1.11-2.24, P = 0.01). Conclusion This Mendelian randomization study based on three gene variants is fully in line with findings indicating that high plasma NPY predicts a high risk for renal events and lends support to the hypothesis that NPY is causally involved in CKD progression. Establishing the functional significance of the rs16131 variant is a clinical research priority. Drugs antagonizing circulating NPY or its receptors, indeed, might favourably impact on CKD progression.