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The PPARγ2 Pro12Ala variant is protective against progression of nephropathy in people with type 2 diabetes.

Lapice E, Monticelli A, Cocozza S, Pinelli M, Cocozza S, Bruzzese D, Riccardi G, Vaccaro O - J Transl Med (2015)

Bottom Line: Among others, urinary albumin excretion rate (UAER) was measured on spot sample, GFR was estimated with the CKD-EPI Equation.Baseline UAER and GFR were similar for carriers or non-carriers of the polymorphism.At follow-up no significant changes from baseline were observed for UAER or eGFR in carriers of the Pro12Ala polymorphism whereas a significant increase in UAER [17 (11.3-37.9) versus 24.5 (13.8-49.9) μg/mg, p < 0.006)] and a significant reduction in the eGFR (82.8 ± 14.5 versus 80.3 ± 17.3 ml/min/1.73, m(2) p = 0.02), were observed in non carriers of the Pro12Ala polymorphism.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Medicine and Surgery, University of Naples Federico II, Via S Pansini 5, Naples, 80131, Italy. emanuela1978@hotmail.it.

ABSTRACT

Objective: Cross-sectional studies suggest the association between diabetic nephropathy and the PPARγ2 Pro12Ala polymorphism of the peroxisome proliferator-activated receptor γ2 (PPARγ2). Prospective data are limited to microalbuminuria and no information on renal function is available to date. The present study evaluates the association between the Pro12Ala polymorphism of PPARγ2 and the progression of albuminuria and decay in glomerular filtration rate (GFR) in type 2 diabetes.

Patients and measurements: We studied 256 patients with an average 5-year follow-up. Among others, urinary albumin excretion rate (UAER) was measured on spot sample, GFR was estimated with the CKD-EPI Equation.

Results: Baseline UAER and GFR were similar for carriers or non-carriers of the polymorphism. At follow-up no significant changes from baseline were observed for UAER or eGFR in carriers of the Pro12Ala polymorphism whereas a significant increase in UAER [17 (11.3-37.9) versus 24.5 (13.8-49.9) μg/mg, p < 0.006)] and a significant reduction in the eGFR (82.8 ± 14.5 versus 80.3 ± 17.3 ml/min/1.73, m(2) p = 0.02), were observed in non carriers of the Pro12Ala polymorphism. Progression of nephropathy - defined according to a combined end point of UAER and eGFR- i.e. doubling of baseline UAER to at least 100 μg/mg, or new onset microalbuminuria, or progression from micro to macroalbuminuria, or 25% reduction of eGFR, or annualized eGFR decline >3 ml/min/year - was significantly less frequent in Ala carriers than non carriers (11.4% vs 35.8%; p < 0.01); HR adjusted for baseline age, AER, eGFR, HbA1c, diabetes duration and blood pressure was 0.32 (0.12-0.80).

Conclusions: This study found that among patients with type 2 diabetes, the PPARγ2 Pro12Ala polymorphism is protective against progression of nephropathy and decay of renal function independent of major confounders.

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Related in: MedlinePlus

Kaplan Meyer curves for progression of nephropathy (cumulative hazard) according to the Pro12Ala of PPARγ2 polymorphism.
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Fig1: Kaplan Meyer curves for progression of nephropathy (cumulative hazard) according to the Pro12Ala of PPARγ2 polymorphism.

Mentions: The genotype distribution was in Hardy Weinberg equilibrium, 212 participants (82.8%) were Pro/Pro homozygotes, 44 (17.2%) Pro/Ala heterozygotes, no homozygotes for the Ala variant were found. The characteristics of the study participants were similar in the two genotype groups. Age at onset of diabetes was 52.1 ± 9.6 and 53.6 ± 7.4 respectively in carriers or non carriers of the ala allele. Attained age, BMI, gender distribution, diabetes duration, glycated haemoglobin, blood pressure; UAER, eGFR and the proportion of people with micro/macroalbuminuria or GFR < 60 ml/min/ 1.73 m2, were comparable in the two genotype groups as was the proportion of current smokers, the proportion of people with retinopathy and the proportion of patients on antihypertensive medications (Table 1). As for antidiabetic treatment the proportion of people treated with diet, oral agents or insulin was similar in the two genotype groups. No one was treated with glitazones. The median follow-up was 5 years (IQR 3–7), similar in the two genotype groups. During the study period UAER remained stable in the Ala carriers [15.9 (IQR 9.4-26.3) versus 18.9 (IQR 11.9-30.7) μg/mg)], whereas a significant increase was observed in people with the ProPro genotype [17.0 (IQR 11.3-37.9 μg/mg) versus 24.5 (IQR 13.8-49.9) μg/mg], p = 0.006 (Table 2). The estimated GFR remained unchanged in Ala carriers (85.3 ± 12 vs 85.2 ± 13 ml/min/ 1.73 m2, p = ns) and declined slightly, but significantly, in the Pro/Pro group (82.8 ± 14.5 vs 80.3 ± 17.3 ml/min/ 1.73 m2, p =0.02) (Table 2). On average glucose control and blood pressure remained stable overtime in both genotype groups (Table 2). The proportion of patients with progression of nephropathy was significantly lower in patients carriers of the Ala polymorphism (11.4% vs 35.8%; p = 0.002, log rank test). The Cox regression analysis, performed with progression of nephropathy as the outcome variable and genotype, baseline age, UAER, eGFR, glycated haemoglobin, diabetes duration and blood pressure as predictor variables, confirmed a significant association of the Pro12Ala polymorphism with a lower risk of progression of nephropathy independent of established risk factors (HR = 0.32; 95% CI; 0.13-0.81 for12Ala carriers vs non carriers). A different model which included blockers of the renin angiotensin system instead of blood pressure provided similar results (HR = 0.30; 95% CI; 0.12-0.80). The Kaplan–Meier curve for progression of nephropathy in the two genotype groups is given in Figure 1.Table 1


The PPARγ2 Pro12Ala variant is protective against progression of nephropathy in people with type 2 diabetes.

Lapice E, Monticelli A, Cocozza S, Pinelli M, Cocozza S, Bruzzese D, Riccardi G, Vaccaro O - J Transl Med (2015)

Kaplan Meyer curves for progression of nephropathy (cumulative hazard) according to the Pro12Ala of PPARγ2 polymorphism.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4358785&req=5

Fig1: Kaplan Meyer curves for progression of nephropathy (cumulative hazard) according to the Pro12Ala of PPARγ2 polymorphism.
Mentions: The genotype distribution was in Hardy Weinberg equilibrium, 212 participants (82.8%) were Pro/Pro homozygotes, 44 (17.2%) Pro/Ala heterozygotes, no homozygotes for the Ala variant were found. The characteristics of the study participants were similar in the two genotype groups. Age at onset of diabetes was 52.1 ± 9.6 and 53.6 ± 7.4 respectively in carriers or non carriers of the ala allele. Attained age, BMI, gender distribution, diabetes duration, glycated haemoglobin, blood pressure; UAER, eGFR and the proportion of people with micro/macroalbuminuria or GFR < 60 ml/min/ 1.73 m2, were comparable in the two genotype groups as was the proportion of current smokers, the proportion of people with retinopathy and the proportion of patients on antihypertensive medications (Table 1). As for antidiabetic treatment the proportion of people treated with diet, oral agents or insulin was similar in the two genotype groups. No one was treated with glitazones. The median follow-up was 5 years (IQR 3–7), similar in the two genotype groups. During the study period UAER remained stable in the Ala carriers [15.9 (IQR 9.4-26.3) versus 18.9 (IQR 11.9-30.7) μg/mg)], whereas a significant increase was observed in people with the ProPro genotype [17.0 (IQR 11.3-37.9 μg/mg) versus 24.5 (IQR 13.8-49.9) μg/mg], p = 0.006 (Table 2). The estimated GFR remained unchanged in Ala carriers (85.3 ± 12 vs 85.2 ± 13 ml/min/ 1.73 m2, p = ns) and declined slightly, but significantly, in the Pro/Pro group (82.8 ± 14.5 vs 80.3 ± 17.3 ml/min/ 1.73 m2, p =0.02) (Table 2). On average glucose control and blood pressure remained stable overtime in both genotype groups (Table 2). The proportion of patients with progression of nephropathy was significantly lower in patients carriers of the Ala polymorphism (11.4% vs 35.8%; p = 0.002, log rank test). The Cox regression analysis, performed with progression of nephropathy as the outcome variable and genotype, baseline age, UAER, eGFR, glycated haemoglobin, diabetes duration and blood pressure as predictor variables, confirmed a significant association of the Pro12Ala polymorphism with a lower risk of progression of nephropathy independent of established risk factors (HR = 0.32; 95% CI; 0.13-0.81 for12Ala carriers vs non carriers). A different model which included blockers of the renin angiotensin system instead of blood pressure provided similar results (HR = 0.30; 95% CI; 0.12-0.80). The Kaplan–Meier curve for progression of nephropathy in the two genotype groups is given in Figure 1.Table 1

Bottom Line: Among others, urinary albumin excretion rate (UAER) was measured on spot sample, GFR was estimated with the CKD-EPI Equation.Baseline UAER and GFR were similar for carriers or non-carriers of the polymorphism.At follow-up no significant changes from baseline were observed for UAER or eGFR in carriers of the Pro12Ala polymorphism whereas a significant increase in UAER [17 (11.3-37.9) versus 24.5 (13.8-49.9) μg/mg, p < 0.006)] and a significant reduction in the eGFR (82.8 ± 14.5 versus 80.3 ± 17.3 ml/min/1.73, m(2) p = 0.02), were observed in non carriers of the Pro12Ala polymorphism.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Medicine and Surgery, University of Naples Federico II, Via S Pansini 5, Naples, 80131, Italy. emanuela1978@hotmail.it.

ABSTRACT

Objective: Cross-sectional studies suggest the association between diabetic nephropathy and the PPARγ2 Pro12Ala polymorphism of the peroxisome proliferator-activated receptor γ2 (PPARγ2). Prospective data are limited to microalbuminuria and no information on renal function is available to date. The present study evaluates the association between the Pro12Ala polymorphism of PPARγ2 and the progression of albuminuria and decay in glomerular filtration rate (GFR) in type 2 diabetes.

Patients and measurements: We studied 256 patients with an average 5-year follow-up. Among others, urinary albumin excretion rate (UAER) was measured on spot sample, GFR was estimated with the CKD-EPI Equation.

Results: Baseline UAER and GFR were similar for carriers or non-carriers of the polymorphism. At follow-up no significant changes from baseline were observed for UAER or eGFR in carriers of the Pro12Ala polymorphism whereas a significant increase in UAER [17 (11.3-37.9) versus 24.5 (13.8-49.9) μg/mg, p < 0.006)] and a significant reduction in the eGFR (82.8 ± 14.5 versus 80.3 ± 17.3 ml/min/1.73, m(2) p = 0.02), were observed in non carriers of the Pro12Ala polymorphism. Progression of nephropathy - defined according to a combined end point of UAER and eGFR- i.e. doubling of baseline UAER to at least 100 μg/mg, or new onset microalbuminuria, or progression from micro to macroalbuminuria, or 25% reduction of eGFR, or annualized eGFR decline >3 ml/min/year - was significantly less frequent in Ala carriers than non carriers (11.4% vs 35.8%; p < 0.01); HR adjusted for baseline age, AER, eGFR, HbA1c, diabetes duration and blood pressure was 0.32 (0.12-0.80).

Conclusions: This study found that among patients with type 2 diabetes, the PPARγ2 Pro12Ala polymorphism is protective against progression of nephropathy and decay of renal function independent of major confounders.

Show MeSH
Related in: MedlinePlus