Genetic and traditional cardiovascular risk factors of kidney disease in the Atherosclerosis Risk in Communities (ARIC) study

Many cardiovascular risk factors are involved with the development of kidney disease, including diabetes and hypertension; however, there is a significant body of evidence demonstrating that genetic risk factors play a role in the etiology of kidney disease. Kidney disease can manifest itself in both (1) the decline of kidney function, which can be monitored by rises in serum creatinine, and in (2) kidney damage, usually assessed by albuminuria as an indicator of glomerular damage resulting in the transudation of albumin into the urine. The aim of this dissertation was to determine if genetic components known to modulate lipid levels, blood pressure, and glucose transport would affect kidney disease in Caucasians and African-Americans. In addition, the effects of non-genetic CVD risk factors on kidney disease was studied focusing on whether hypertensive and high normal levels of blood pressure increase the prevalence of albuminuria and whether this association was seen in the absence of atherosclerosis.;The first study prospectively examined the effect on CKD progression of variation in the Apolipoprotein E (APOE) gene known to influence lipid metabolism and Alzheimer's Disease risk. APOE variation in both Caucasians (n = 10,661) and African Americans (n = 3859) predicts CKD progression (n = 806 cases), independent of diabetes, race, lipid, and non-lipid CKD risk factors.;The second study examined the risk of CKD progression in 3,706 African-Americans predicted by variation in angiotensinogen (AGT) and angiotensin II type 1 receptor (AT1R), two genes involved in the blood pressure regulating renin-angiotensin aldosterone system (RAAS). We determined that carriers of the AGT G(-6) allele had a lower risk of developing CKD progression (RH 0.75, 95% CI 0.57–0.98), after adjustment for major CKD risk factors.;The third study examined whether genetic variation of glucose transporter-1 (GLUT1) was associated with albuminuria at visit 4 among both Caucasians and African-Americans. Significant in vitro evidence demonstrated that increased GLUT1 protein expression may play a role in diabetic kidney disease through modulation of intracellular glucose levels in mesangial cells with subsequent extracellular matrix deposition and mesangial expansion.;The fourth study examined the association of blood pressure and albuminuria to determine if associations were consistent across levels of atherosclerosis and type 2 diabetes. After adjusting for major cardiovascular risk factors, hypertensive blood pressure levels, GFR < 60 mL/min/1.73m 2, and current smoking were all associated with albuminuria. (Abstract shortened by UMI.).