title: A gene variant in CERS2 is associated with rate of increase in albuminuria in patients with diabetes from ONTARGET and TRANSCEND.
abstract: 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; -1.7% 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 single nucleotide polymorphism encoding a glutamic acid to alanine change at position 115 of the ceramide synthase 2 (CERS2) encoded protein. However, it is unknown whether CERS2 function influences albuminuria. In conclusion, we found that rs267734 in CERS2 is associated with rate of increase in albuminuria among patients with diabetes and elevated risk of cardiovascular disease.
authors.affiliation: Celera, Alameda, CA, United States of America.
authors.forename: Dov
authors.initials: D
authors.lastname: Shiffman
authors.affiliation: Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Pare
authors.affiliation: Department of Nephrology, KH Elisabethinen, Linz, Austria and Department of Nephrology, Medical University of Vienna, Vienna, Austria.
authors.forename: Rainer
authors.initials: R
authors.lastname: Oberbauer
authors.affiliation: Celera, Alameda, CA, United States of America.
authors.forename: Judy Z
authors.initials: JZ
authors.lastname: Louie
authors.affiliation: Celera, Alameda, CA, United States of America.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rowland
authors.affiliation: Celera, Alameda, CA, United States of America.
authors.forename: James J
authors.initials: JJ
authors.lastname: Devlin
authors.affiliation: Department of Nephrology and Hypertension, Friedrich Alexander University, Erlangen, Germany.
authors.forename: Johannes F
authors.initials: JF
authors.lastname: Mann
authors.affiliation: Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: McQueen
mesh_terms: D000368:Aged; D000419:Albuminuria / Q000150:complications / Q000235:genetics*; D003920:Diabetes Mellitus / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000235:genetics*; D005260:Female; D005919:Glomerular Filtration Rate / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis; D016032:Randomized Controlled Trials as Topic; D051049:Sphingosine N-Acyltransferase / Q000737:chemistry / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; D025521:Tumor Suppressor Proteins; C438311:CERS2 protein, human; D051049:Sphingosine N-Acyltransferase