Polymorphisms of the UCP2 Gene Are Associated with Glomerular Filtration Rate in Type 2 Diabetic Patients and with Decreased UCP2 Gene Expression in Human Kidney

Abstract

Introduction: Uncoupling protein 2 (UCP2) reduces production of reactive oxygen species (ROS) by mitochondria. ROS overproduction is one of the major contributors to the pathogenesis of chronic diabetic complications, such as diabetic kidney disease (DKD). Thus, deleterious polymorphisms in the UCP2 gene are candidate risk factors for DKD. In this study, we investigated whether UCP2 -866G/A, Ala55Val and Ins/Del polymorphisms were associated with DKD in patients with type 2 diabetes mellitus (T2DM), and whether they had an effect on UCP2 gene expression in human kidney tissue biopsies.

Materials and methods: In a case-control study, frequencies of the UCP2 -866G/A, Ala55Val and Ins/Del polymorphisms as well as frequencies of the haplotypes constituted by them were analyzed in 287 T2DM patients with DKD and 281 T2DM patients without this complication. In a cross-sectional study, UCP2 gene expression was evaluated in 42 kidney biopsy samples stratified according to the presence of the UCP2 mutated -866A/55Val/Ins haplotype.

Results: In the T2DM group, multivariate logistic regression analysis showed that the -866A/55Val/Ins haplotype was an independent risk factor for DKD (OR = 2.136, 95% CI 1.036-4.404), although neither genotype nor allele frequencies of the individual polymorphisms differed between case and control groups. Interestingly, T2DM patients carrying the mutated haplotype showed decreased estimated glomerular filtration rate (eGFR) when compared to subjects with the reference haplotype (adjusted P= 0.035). In kidney biopsy samples, UCP2 expression was significantly decreased in UCP2 mutated haplotype carriers when compared to kidneys from patients with the reference haplotype (0.32 ± 1.20 vs. 1.85 ± 1.16 n fold change; adjusted P< 0.000001).

Discussion: Data reported here suggest that the UCP2 -866A/55Val/Ins haplotype is associated with an increased risk for DKD and with a lower eGFR in T2DM patients. Furthermore, this mutated haplotype was associated with decreased UCP2 gene expression in human kidneys.

Fig 1. Estimated glomerular filtration rate (eGFR) in T2DM patients according UCP2 polymorphisms and mutated UCP2 haplotype.

A) eGFR in patients stratified according to the presence of the A allele of the -866G/A polymorphism (dominant model). B) eGFR in patients stratified according to the presence of the Val allele of the Ala55Val polymorphism (dominant model). C) eGFR in patients according to the presence of the Ins allele of the Ins/Del polymorphism (dominant model). D) eGFR in patients according to the presence of the UCP2 mutated haplotype (-866A/55Val/Ins; dominant model). P values were obtained using Student’s t-tests. Data are presented as mean (95% CI).

Fig 2. UCP2 gene expression in human kidney biopsies according the presence of the UCP2 mutated haplotype.

A) UCP2 gene expression in subjects homozygous for the reference haplotype (-866G/55Ala/Del), heterozygous (reference/mutated haplotypes) or homozygous for the mutated haplotype (-866A/55Val/Ins). P value was obtained using One-Way ANOVA test. * P = 0.001 (post-hoc Tukey’s test). ** P = 0.02 (post-hoc Tukey’s test). B) UCP2 gene expression in patients stratified according to the presence of the UCP2 mutated haplotype (dominant model). P value was obtained using Student’s t-tests. Data are presented as mean (95% CI) of UCP2 gene expression in logarithmic scale.