Anthony Nicolas1, Sehrish Fatima2, Amel Lamri3, Naima Bellili-Muñoz2, Jean-Michel Halimi4, Pierre-Jean Saulnier5, Samy Hadjadj5, Gilberto Velho2, Michel Marre6, Ronan Roussel6, Frédéric Fumeron7. 1. INSERM, Centre de Recherche des Cordeliers, Research Unit 1138, Paris, France; Univ Pierre et Marie Curie, Paris, France. 2. INSERM, Centre de Recherche des Cordeliers, Research Unit 1138, Paris, France. 3. INSERM, Centre de Recherche des Cordeliers, Research Unit 1138, Paris, France; Univ Paris Diderot, Sorbonne Paris Cité, Paris, France. 4. University Hospital of Tours, Diabetology and Nephrology Department, Tours, France. 5. Université de Poitiers, UFR Médecine Pharmacie, CIC1402, Poitiers, France; CHU de Poitiers, Service Endocrinologie, Diabétologie, Pole DUNE & Centre d'investigation Clinique, Poitiers, France; INSERM, CIC1402, Poitiers, France. 6. INSERM, Centre de Recherche des Cordeliers, Research Unit 1138, Paris, France; Univ Paris Diderot, Sorbonne Paris Cité, Paris, France; Assistance Publique Hôpitaux de Paris, Bichat Hospital, Department of Diabetology, Endocrinology and Nutrition, Paris, France. 7. INSERM, Centre de Recherche des Cordeliers, Research Unit 1138, Paris, France; Univ Paris Diderot, Sorbonne Paris Cité, Paris, France. Electronic address: frederic.fumeron@inserm.fr.
Abstract
BACKGROUND AND AIM: Sterols, bile acids and their receptors have been involved in diabetic nephropathy. The ATP-binding cassette transporters G5 and G8 (ABCG5 and ABCG8) play an important role in intestinal sterol absorption and bile acid secretion. The aim of our study was to assess the associations between two ABCG8 coding polymorphisms, T400K and D19H, and the incidence of renal events in type 2 diabetic subjects. METHODS: Participants were the 3137 French type 2 diabetic subjects with micro- or macro-albuminuria from the genetic substudy of the DIABHYCAR trial. The mean duration of follow-up was 4years. Renal events were defined as a doubling of serum creatinine concentration or end-stage renal disease at follow-up. We then used a second population (DIAB2NEPHROGENE) of 2140 type 2 diabetic patients for the purpose of validation. RESULTS: In DIABHYCAR, the 400K allele was significantly associated with a higher risk of incident renal events in a multiple adjusted model (HR: 1.75 [95% CI 1.20-2.56], P=0.003). This association was still significant after further adjustments for baseline values of estimated glomerular filtration rate and urinary albumin excretion. In the validation population, the 400K allele was associated with the prevalence of end-stage renal disease (OR=2.01 [95% CI 1.15-3.54], P=0.015). No significant association was found between the D19H polymorphism and the risk of diabetic nephropathy. CONCLUSIONS: A polymorphism of the sterol transporter ABCG8 has been associated with the prevalence of end-stage renal disease and with the incidence of new renal events in type 2 diabetic patients.
BACKGROUND AND AIM: Sterols, bile acids and their receptors have been involved in diabetic nephropathy. The ATP-binding cassette transporters G5 and G8 (ABCG5 and ABCG8) play an important role in intestinal sterol absorption and bile acid secretion. The aim of our study was to assess the associations between two ABCG8 coding polymorphisms, T400K and D19H, and the incidence of renal events in type 2 diabetic subjects. METHODS:Participants were the 3137 French type 2 diabetic subjects with micro- or macro-albuminuria from the genetic substudy of the DIABHYCAR trial. The mean duration of follow-up was 4years. Renal events were defined as a doubling of serum creatinine concentration or end-stage renal disease at follow-up. We then used a second population (DIAB2NEPHROGENE) of 2140 type 2 diabeticpatients for the purpose of validation. RESULTS: In DIABHYCAR, the 400K allele was significantly associated with a higher risk of incident renal events in a multiple adjusted model (HR: 1.75 [95% CI 1.20-2.56], P=0.003). This association was still significant after further adjustments for baseline values of estimated glomerular filtration rate and urinary albumin excretion. In the validation population, the 400K allele was associated with the prevalence of end-stage renal disease (OR=2.01 [95% CI 1.15-3.54], P=0.015). No significant association was found between the D19H polymorphism and the risk of diabetic nephropathy. CONCLUSIONS: A polymorphism of the sterol transporter ABCG8 has been associated with the prevalence of end-stage renal disease and with the incidence of new renal events in type 2 diabeticpatients.