ABSTRACT The present study is part of HYPERGENES Project, focused on the definition of a comprehensive genetic-epidemiological model of complex traits like essential hypertension and of intermediate phenotypes related to hypertension. We specifically focused on the identification of genetic biomarkers related to Glomerular Filtration Rate (GFR) as index of renal function. Chronic kidney disease (CKD), defined as either kidney damage or decreased kidney function for 3 or more months (GFR < 60 ml/min per 1.73m2) affects about 6-11% of the general population. A strong relationship has been reported between renal dysfunction, hypertension and cardiovascular diseases; hypertension is present in more than 80% of patients with CKD and contributes to progression to end stage renal disease and to cardiovascular events as well. Apart from the risk conferred by traditional cardiovascular risk factors, eGFR has a strong genetic component. We therefore performed a genotype-phenotype association analysis in subjects affected by essential hypertension and in a population based cohort. The analyses have been carried on using: 1) 1,634 hypertensives from the HYPERGENES Discovery phase and 1,198 hypertensives from the HYPERGENES Validation phase; 2) 2,697 subjects from Epogh-Flemengho population based sample 3) 1,952 subjects from Epogh-Flemengho population based sample with GFR follow-up data, using the difference between the last and the first measurement as phenotype of renal function. Using a Genome wide association (GWA) approach, in the HYPERGENES Discovery sample we identified a potential novel variant associated with hypertension and renal function in STAC gene (rs4678878, p-value of 3.83x10-8). This gene is likely involved in a neuron-specific signal transduction, although its function is not yet completely clear. This result was not validated in HYPERGENES Validation and in the population based studies. The finding needs further investigation performing a fine mapping of the region. Through a candidate gene approach, we could identify some variants, mapping in genes already known as associated to renal function (PPARA, CST3-CST9 region, PRKAG2, ABCA1, NEDD4L). The identification of genetic variants affecting renal function could help to better understand not only the GFR variability in the general population but also the pathophysiology of CKD and progressive kidney function decline. Ultimately, this could lead to novel tools for diagnosis, prevention and therapy of CKD.
GENETIC BIOMARKERS OF RENAL FUNCTION / F. Rizzi ; tutor: C. Barlassina ; coordinatore: M. Clerici. - Milano : Università degli studi di Milano. DIPARTIMENTO DI FISIOPATOLOGIA MEDICO-CHIRURGICA E DEI TRAPIANTI, 2013 Feb 07. ((25. ciclo, Anno Accademico 2012.
|Titolo:||GENETIC BIOMARKERS OF RENAL FUNCTION|
|Supervisori e coordinatori interni:||CLERICI, MARIO SALVATORE|
|Data di pubblicazione:||7-feb-2013|
|Parole Chiave:||genetic biomarkers ; eGFR ; renal function ; SNPs|
|Settore Scientifico Disciplinare:||Settore MED/14 - Nefrologia|
Settore MED/03 - Genetica Medica
|Citazione:||GENETIC BIOMARKERS OF RENAL FUNCTION / F. Rizzi ; tutor: C. Barlassina ; coordinatore: M. Clerici. - Milano : Università degli studi di Milano. DIPARTIMENTO DI FISIOPATOLOGIA MEDICO-CHIRURGICA E DEI TRAPIANTI, 2013 Feb 07. ((25. ciclo, Anno Accademico 2012.|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.13130/rizzi-federica_phd2013-02-07|
|Appare nelle tipologie:||Tesi di dottorato|