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 >or=25%. RESULTS After 11 years between creatinine measurements, the eGFR declined by >or=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.