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.

Analysis of urinary sphingolipids using liquid chromatography‐tandem mass spectrometry in diabetic nephropathy

“…Considering our finding that the urinary levels of Cer C22:0 and C24:0 were higher in patients with stage 3 diabetic nephropathy, these urinary ceramides might be mainly derived from the kidney. Actually, a CerS2 variant reportedly elevates the risk of an increase in albuminuria, although whether CerS2 function directly causes albuminuria remains controversial; no phenotypic abnormalities in the kidney have been reported in CerS2‐deficient mice. Further basic studies are required to show the involvement of CerS2 in the pathogenesis of diabetic nephropathy.…”

The effect of altered sphingolipid acyl chain length on various disease models

“…Mutated CerS have been reported in patients (Eckl et al, 2013;Radner et al, 2013;Mosbech et al, 2014), and several CerS gene variants associated with human diseases have been identified using highthroughput sequencing (Kirin et al, 2013;Shiffman et al, 2014;Lemaitre et al, 2015). Recent advances in understanding of the pathophysiological roles played by SL acyl chain length in various disease models may enable elucidation of the pathogenesis of specific human diseases.…”

Research Advances on the Genetic Mechanism of Diabetic Nephropathy

“…Therefore, we investigated a theory on whether these variants were also associated with the rate of increase in albuminuria among patients with diabetes [32]. Ceramidase synthase 2 is a hydrolyzing ceramide that can break the bond between fatty acid and sphingosine and then acylates dihydro-sphingosine to form dihydro-ceramide or sphingosine to form ceramide [33].…”

“…Researchers investigated 16 SNPs that were previously reported to be associated with eGFR at the genomewide level. After the estimates including age, ethnicity, sex and principal component of genetic heterogeneity were adjusted for, it was determined that one SNP (rs267734) in the CERS2 gene was associated with an annual rate of increase in albuminuria in diabetic patients, and each risk allele of rs267734 was related to a 50% increased risk of incident albuminuria [32].…”