Role of the endothelin-1 gene locus for Renal impairment in the general nondiabetic population

• Published in: Journal of the American Society of Nephrology Vol. 14; no. 10; pp. 2596 - 2602
• Main Authors: PINTO-SIETSMA, Sara-Joan, HERRMANN, Stefan-Martin, SCHMIDT-PETERSEN, Klaus, TIANHUA NIU, HILLEGE, Hans L, JANSSEN, Wilbert M. T, DE ZEEUW, Dick, DE JONG, Paul, KREUTZ, Reinhold
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.10.2003
• Subjects: Adult; Aged; Albuminuria - epidemiology; Albuminuria - genetics; Biological and medical sciences; Case-Control Studies; Cohort Studies; Endothelin-1 - genetics; Female; Glomerular Filtration Rate; Haplotypes; Humans; Kidney Failure, Chronic - epidemiology; Kidney Failure, Chronic - genetics; Male; Medical sciences; Middle Aged; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Polymorphism, Single Nucleotide; Renal failure; Risk Factors; Kidney disease; Human; Chronic; Urinary system disease; Renal function; Gene; Renal failure; Exploration; Endothelin 1; Genetic determinism
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1097/01.asn.0000089827.03201.8e

A decreased GFR in the range of mild renal insufficiency and an increased urinary albumin excretion (UAE) rate in the range of microalbuminuria are important cardiovascular risk factors. Endothelin-1 (ET-1) has been suggested to be a major disease promoting factor in renal disease. The role of the ET-1 gene locus (EDN1) for renal function in the general nondiabetic population was evaluated. To explore the overall relevance of EDN1, two suitable single-nucleotide polymorphisms, EDN1 K198N and EDN1 T-1370G, were selected, and haplotype analysis was performed. Determined were genotypes in 7291 nondiabetic subjects from the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. Genetic analysis was related to UAE and GFR as continuous variables and to microalbuminuria and diminished filtration as dichotomous traits. In a logistic regression analysis, no significant higher risk for increased UAE, microalbuminuria, decreased GFR, or diminished filtration could be observed for either single-nucleotide polymorphism separately. Haplotype analysis revealed that individuals with the homozygous G-N haplotype (compound EDN1 -1370GG/198NN genotype) have a lower GFR than the remaining subjects (P < 0.05) and exhibit a significant higher risk for the presence of a diminished filtration (relative risk, 2.4; 95% confidence interval, 1.07 to 5.33; P < 0.05). Further analysis demonstrated no association between this haplotype and UAE or plasma ET-1 levels. Although a functional relevance of the EDN1 G-N haplotype itself remains unclear, the data demonstrate that genetic variation at the EDN1 locus has a significant effect on glomerular filtration but not on UAE in the general nondiabetic population.