Genetic Variation of the Renin-Angiotensin System and Chronic Kidney Disease Progression in Black Individuals in the Atherosclerosis Risk in Communities Study

Abstract

The renin-angiotensin system (RAS) regulates BP and may affect chronic kidney disease (CKD) through induction of tissue growth and fibrosis. The angiotensinogen (AGT) promoter G(؊6) allele lowers transcription and is inversely associated with hypertension. In white individuals, the A1166C 3-UTR variant of angiotensin II type 1 receptor (AT1R) has been associated with CKD. CKD associations with these RAS genes are uncertain in high-risk black populations. A prospective populationbased study of CKD risk was conducted among 3706 black individuals without severe renal dysfunction at baseline (serum creatinine >177 mol/L [2.0 mg/dl] for men, >159 mol/L [1.8 mg/dl] for women) to examine associations with AGT and AT1R. Incident CKD progression was defined as kidney disease hospitalization or increase in serum creatinine level >35 mol/L (0.4 mg/dl) above baseline. During mean follow-up of 10.2 yr, CKD progression incidence rate (per 1000 person-years) was 8.2 (n ‫؍‬ 312 cases). Risk was lower for AGT G(؊6) carriers compared with A(؊6) (incidence 6.9 versus 9.0; log-rank P ‫؍‬ 0.03) and nonsignificantly higher among AT1R C1166 carriers. Adjusting for hypertension and major CKD risk factors, AGT G(؊6)decreased risk (relative risk 0.75; 95% confidence interval 0.57 to 0.98). AT1R C1166 increased risk only among those with hypertension (relative risk 1.65; 95% confidence interval 1.14 to 2.39). The AGT G(؊6)A polymorphism may play a role in CKD progression in black individuals, consistent with in vitro effects on AGT levels and renal remodeling but independent of BP. The AT1R C1166 allele may increase susceptibility but only in the presence of hypertension.

TCF7L2 Variants Associate with CKD Progression and Renal Function in Population-Based Cohorts

“…40,41 Albuminuria was measured as described previously. 42 In FHS, serum creatinine was measured by the modified Jaffe method and statistically calibrated as described previously 40,43 before transformation to eGFR via the MDRD equation. 24 Stage 3 CKD of higher was defined according to Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines as an eGFR Ͻ60 ml/min per 1.73 m 2 .…”

Relation between AT1R Gene Polymorphism and Long-Term Outcome in Patients with Heart Failure

“…In our study, the AT1R CC homozygous genotype was significantly associated with ischemic etiology and poorer renal function. The AT1R polymorphism is a known risk factor for coronary artery disease [11,12,13,14] and development/progression of renal failure [24,25,26]. As reported by others, worsening renal function and ischemic etiology are both associated with more advanced HF disease and an increased mortality [27, 28].…”

Chronic Kidney Disease Update

“…Forty two percent of men and 44 percent of women over the age of 85 had an MDRDestimated GFR less than 60 ml/min per 1.73 m 2 in the Nijmegen Biomedical Study, a population-based cross-sectional study conducted in the eastern part of the Netherlands. In a report from Taiwan, the prevalence of an estimated GFR <60 ml/min per 1.73 m 2 was 7 % (Hsu et al, 2006). In a population-based survey from Pakistan, Kazmi et al have reported the prevalence of CKD stages 3 and 4 to be about 21 million (Kazmi et al, 2007).…”

“…A number of genetic factors (eg, single nucleotide polymorphisms and modifier genes) may influence the immune response, inflammation, fibrosis, and atherosclerosis, possibly contributing to accelerated progression of CKD (Nordfors et al, 2005;Hsu et al, 2006). Indirect evidence in support of such factors can be found in familial clustering of all-cause ESRD, with approximately one-quarter of dialysis patients having relatives with ESRD (Freedman et al, 2005).…”