Genetic Polymorphisms and the Risk of Accelerated Renal Function Decline in Women

BACKGROUND: Reduced glomerular filtration rate is an important predictor of cardiovascular disease and death. Genetic polymorphisms, particularly in genes involved in the renin-angiotensin system (RAS), may influence the rate of renal function decline. METHODOLOGY/PRINCIPAL FINDINGS: We examined the relation between specific single nucleotide polymorphisms (SNPs), including those in the RAS, apolipoprotein E and alpha-adducin, and renal function decline assessed by estimated glomerular filtration rate (eGFR) over an 11-year period in 2578 Caucasian participants of the Nurses' Health Study. Logistic regression was used to examine the associations between genotype and risk of eGFR decline of ≥25%. RESULTS: After 11 years between creatinine measurements, the eGFR declined by ≥25% in 423 of 2578 (16%) women. The angiotensinogen (AGT) A-20C polymorphism was associated with a higher risk of renal function decline when two risk alleles were present than if one or no alleles were present (CC vs AA and AC) OR 1.83 (95% CI 1.02–3.26; p = 0.04). The angiotensin II type 1 receptor (AT(1)R) A1166C polymorphism was marginally associated with a higher risk of renal function decline when two risk alleles were present (CC vs AA, OR = 1.41; 95% CI 0.98–2.01; p = 0.06). The alpha-adducin G460W polymorphism was associated with a lower risk of renal function decline when any number of risk alleles were present (WG vs GG, OR = 0.78, 95% CI 0.61–0.99, p = 0.04; WW vs GG, OR = 0.46; 95% CI 0.20–1.07, p = 0.07). Linear regression analysis with change in eGFR as the outcome showed a larger decline of 3.5 (95% CI 0.5 to 6.4, p = 0.02) ml/min/1.73 m(2) in AGT A-20C CC homozygotes. No other polymorphisms were significantly associated with renal function decline or absolute change in eGFR over the study period. CONCLUSIONS: Genetic variants in the angiotensinogen, angiotensin II type 1 receptor and alpha-adducin genes may contribute to loss of renal function in the general female Caucasian population.