A Gene Variant in CERS2 Is Associated with Rate of Increase in Albuminuria in Patients with Diabetes from ONTARGET and TRANSCEND

Although albuminuria and subsequent advanced stage chronic kidney disease are common among patients with diabetes, the rate of increase in albuminuria varies among patients. Since genetic variants associated with estimated glomerular filtration rate (eGFR) were identified in cross sectional studies, we asked whether these variants were also associated with rate of increase in albuminuria among patients with diabetes from ONTARGET and TRANSCEND—randomized controlled trials of ramipril, telmisartan, both, or placebo. For 16 genetic variants associated with eGFR at a genome-wide level, we evaluated the association with annual rate of increase in albuminuria estimated from urine albumin:creatinine ratio (uACR). One of the variants (rs267734) was associated with rate of increase in albuminuria. The annual rate of increase in albuminuria among risk homozygotes (69 % of the study population) was 11.3 % (95%CI; 7.5 % to 15.3%), compared with 5.0 % (95%CI; 3.3 % to 6.8%) for heterozygotes (27 % of the population), and 1.7 % (95%CI; 21.7 % to 5.3%) for non-risk homozygotes (4 % of the population); P = 0.0015 for the difference between annual rates in the three genotype groups. These estimates were adjusted for age, sex, ethnicity, and principal component of genetic heterogeneity. Among patients without albuminuria at baseline (uACR,30 mg/g), each risk allele was associated with 50 % increased risk of incident albuminuria (OR = 1.50; 95%CI 1.15 to 1.95; P = 0.003) after further adjustment for traditional risk factors including baseline uACR and eGFR. The rs267734 variant is in almost perfect linkage-disequilibrium (r2 = 0.94) with rs267738, a singl