Background and Aims: A more atherogenic plasma lipoprotein profile has been described in microalbuminuric type 2 diabetic (T2D) patients as compared to normoalbuminuric ones, and recent prospective studies have identified hyperlipidemia as an independent determinant of diabetic nephropathy. Lipoprotein lipase (LPL) is a key enzyme in the postprandial processing of triglycerides and VLDL. Among a number of common sequence variants, particular interest has been attributed to the HindIII, occurring in intron 8 of the gene encoding LPL, associated with CHD and, more recently, with the presence and severity of microalbuminuria in T2D. No studies have prospectively evaluated the progression of renal disease in hypercholesterolemic T2D patients, in relation to this specific polymorphism. Materials and Methods: We consecutively enrolled 65 micromacroalbuminuric T2D patients; 28 had hypercholesterolemia (Group A), whereas 37 (Group B) had normal cholesterol levels. Routine biochemical parameters, AER, GFR (by Cockroft-Gault formula) were measured. LPL gene polymorphism HindIII and LDL receptor gene polymorphisms NcoI and AvaII were determined on genomic DNA. After the baseline evaluation, patients were followed for four years, with repeated determinations every twelve months. Results: Group A showed a faster AER increase (ΔAER: 45 μg/min in Group A vs. 15 μg/min in Group B, p<0.03) and a faster GFR decline (Group A: from 54±16 to 44±15; Group B: from 58±13 to 52±10 ml/min/1.73m2, p<0.02). When examining the progression of AER and GFR according to the different genotypes of the three studied polymorphisms, we did not find differences in the rate of decline of kidney function by LDLR gene polymorphisms, whereas patients homozygous for the mutation +/+ in the HindIII genotype of the LPL gene showed a faster decline of GFR (from 56 to 45 ml/min/1.73m2 ) and a higher increase of AER (from 76 to 118 μg/min) in comparison with +/- or -/- patients (GFR: from 56 to 52 and from 60 to 57 ml/min/1.73m2; AER: from 85 to 97 and from 59 to 65 μg/min, respectively; both p<0.05). Regression analysis showed age, BMI and HindIII polymorphism as independent determinants of final GFR (p<0.001, p=0.010 and p=0.004, respectively), and HbA1c as determinant of final AER (p=0.034). Conclusion: Hypercholesterolemic T2D patients are prone to a more aggressive course of their renal complications, and this time-course is accelerated in subjects carrying the H+/H+ genotype of the HindIII polymorphism at the LPL locus. Our findings are consistent with a distinct genetic predisposition to develop diabetic nephropathy in these subjects.

LPL gene and progression of nephropathy in hypercholesterolemic type 2 diabetic patients.

PASSARO, Angelina;
2003

Abstract

Background and Aims: A more atherogenic plasma lipoprotein profile has been described in microalbuminuric type 2 diabetic (T2D) patients as compared to normoalbuminuric ones, and recent prospective studies have identified hyperlipidemia as an independent determinant of diabetic nephropathy. Lipoprotein lipase (LPL) is a key enzyme in the postprandial processing of triglycerides and VLDL. Among a number of common sequence variants, particular interest has been attributed to the HindIII, occurring in intron 8 of the gene encoding LPL, associated with CHD and, more recently, with the presence and severity of microalbuminuria in T2D. No studies have prospectively evaluated the progression of renal disease in hypercholesterolemic T2D patients, in relation to this specific polymorphism. Materials and Methods: We consecutively enrolled 65 micromacroalbuminuric T2D patients; 28 had hypercholesterolemia (Group A), whereas 37 (Group B) had normal cholesterol levels. Routine biochemical parameters, AER, GFR (by Cockroft-Gault formula) were measured. LPL gene polymorphism HindIII and LDL receptor gene polymorphisms NcoI and AvaII were determined on genomic DNA. After the baseline evaluation, patients were followed for four years, with repeated determinations every twelve months. Results: Group A showed a faster AER increase (ΔAER: 45 μg/min in Group A vs. 15 μg/min in Group B, p<0.03) and a faster GFR decline (Group A: from 54±16 to 44±15; Group B: from 58±13 to 52±10 ml/min/1.73m2, p<0.02). When examining the progression of AER and GFR according to the different genotypes of the three studied polymorphisms, we did not find differences in the rate of decline of kidney function by LDLR gene polymorphisms, whereas patients homozygous for the mutation +/+ in the HindIII genotype of the LPL gene showed a faster decline of GFR (from 56 to 45 ml/min/1.73m2 ) and a higher increase of AER (from 76 to 118 μg/min) in comparison with +/- or -/- patients (GFR: from 56 to 52 and from 60 to 57 ml/min/1.73m2; AER: from 85 to 97 and from 59 to 65 μg/min, respectively; both p<0.05). Regression analysis showed age, BMI and HindIII polymorphism as independent determinants of final GFR (p<0.001, p=0.010 and p=0.004, respectively), and HbA1c as determinant of final AER (p=0.034). Conclusion: Hypercholesterolemic T2D patients are prone to a more aggressive course of their renal complications, and this time-course is accelerated in subjects carrying the H+/H+ genotype of the HindIII polymorphism at the LPL locus. Our findings are consistent with a distinct genetic predisposition to develop diabetic nephropathy in these subjects.
LPL gene, nephropathy, hypercholesterolemia, type 2 diabetes.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11392/2367612
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