| Summary: | Prostaglandin E2 (PGE2) is a major actor mediating renal injury. We aimed to determine genetic variability in the genes coding for its receptors (<i>PTGER1-4</i>) and study associations with nephrosclerosis risk and clinical outcomes. We identified 96 tag-SNPs capturing global variability in <i>PTGER1-4</i> and screened 1209 nephrosclerosis patients and controls. The effect of these variants was evaluated by multivariate regression analyses. Two <i>PTGER3</i> SNPs, rs11209730 and rs10399704, remained significant in a backward elimination regression model with other non-genetic variables (OR = 1.45 (1.07–1.95), <i>p</i> = 0.016 and OR = 0.71 (0.51–0.99), <i>p</i> = 0.041, respectively). In the nephrosclerosis patients, a proximal region of <i>PTGER3</i> was tagged as relevant for eGFR (<i>p</i> values for identified SNPs ranged from 0.0003 to 0.038). Two consecutive <i>PTGER3</i> SNPs, rs2284362 and rs2284363, significantly decreased systolic (<i>p</i> = 0.005 and <i>p</i> = 0.0005), diastolic (<i>p</i> = 0.039 and <i>p</i> = 0.005), and pulse pressure values (<i>p</i> = 0.038 and 0.014). Patients were followed for a median of 47 months (7–54) to evaluate cardiovascular (CV) risk. Cox regression analysis showed that carriers of the <i>PTGER1</i>rs2241360 T variant had better CV event-free survival than wild-type individuals (<i>p</i> = 0.029). In addition, <i>PTGER3</i>rs7533733 GG carriers had lower event-free survival than AA/AG patients (<i>p</i> = 0.011). Our results indicate that genetic variability in PGE2 receptors, particularly EP3, may be clinically relevant for nephrosclerosis and its associated CV risk.
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