| Abstract: | Background and objectives: Chronic inflammation may play a role in chronic kidney disease (CKD) progression. CRP gene polymorphisms are associated with serum C-reactive protein (CRP) concentrations. It is unknown if CRP polymorphisms are associated with CKD progression or modify the effectiveness of anti-hypertensive therapy in delaying CKD progression.Design, setting, participants, & measurements: We genotyped 642 participants with CKD from the African American Study of Kidney Disease and Hypertension (AASK), selecting five tag polymorphisms: rs2808630, rs1205, rs3093066, rs1417938, and rs3093058. We compared the minor allele frequencies (MAF) of single nucleotide polymorphisms (SNPs) in AASK to MAFs of African Americans from NHANES III. Among AASK participants, we evaluated the association of SNPs with CRP levels and prospectively with a composite: halving the GFR, ESRD, or death.Results: The MAF was higher for the rs2808630_G allele (P = 0.03) and lower for the rs1205_A allele (P = 0.03) in the AASK compared with NHANES III. Among AASK participants, the rs3093058_T allele predicted higher CRP concentrations (P < 0.0001) but not CKD progression. The rs2808630_GG genotype was associated with higher risk of the composite endpoint compared with the AA genotype (P = 0.002). Participants with the rs2808630_GG genotype on angiotensin converting enzyme inhibitors (ACEIs) versus β blockers had increased risk of progression (P = 0.03).Conclusion: CRP SNPs that were associated with higher levels of CRP did not predict CKD progression. The rs2808630_GG genotype was associated with higher risk of CKD progression, and in patients with this genotype, ACEIs did not slow progression.Familial clustering of chronic kidney disease (CKD) and ESRD has been reported in populations throughout the world for most types of nephropathy (1–6). This genetic predisposition to ESRD seems to be strongly associated with race (7,8). Compared with people with no family history of kidney disease, African Americans with a first-degree relative with ESRD have a nine-fold increase in the risk of ESRD compared with a three- to five-fold increase in whites (8). Recently, the candidate gene MYH9 has been identified as associated with nondiabetic ERSD in African Americans, and this association explains some of the disparity in incidence of ESRD observed between whites and African Americans (7,9). However, it is possible that additional genetic variants, such as those related to inflammatory pathways, may also be associated with ESRD.Biomarkers of inflammation, including C-reactive protein (CRP), are increased even in early stages of CKD and have been linked to the risk of CKD progression (10–15). These observations have led to studies examining the genetic basis of inflammation and identification of several candidate genes for ESRD susceptibility (16–19). Recently, several large population-based studies showed that plasma CRP levels are under genetic influence (20–25). Some of these polymorphisms have been consistently associated with CRP levels (higher levels associated with rs3093058_T and lower levels associated with rs1205_A and rs2808630_G) and the risk of cardiovascular events (rs3093058_T) in African Americans (23).CRP gene polymorphisms that affect CRP concentrations may reflect lifetime exposure to CRP more accurately than single time point measurements of serum CRP concentrations. The primary goal of this study was to characterize CRP gene polymorphisms and evaluate their association with CKD progression. We hypothesized that polymorphisms associated with higher levels of CRP would be associated with higher risk of CKD progression. Additionally, we examined whether these polymorphisms modify the renoprotective effects of angiotensin converting enzyme inhibitors (ACEIs), a drug class known to have anti-inflammatory effects (26–28). We hypothesized that patients with polymorphisms associated with higher levels of CRP would benefit most from ACEIs. |
