The Association Between Uncoupling Protein-2 Polymorphism And The Metabolic Disorder In Peritoneal Dialysis Patients

The association between uncoupling protein2 polymorphism and the metabolic disorder in the peritoneal dialysis patientsBackgroundPeritoneal dialysis (PD) as one of real replacement therapy in end stage real disease (ESRD), is with advantage of stable hemodynamic effect and can realize the treatment at home, and receipted by more and more patents. But we have observed that some peritoneal dialysis patients present metabolic disorder, such as insulin resistance (IR), dyslipidemia, adiposity and so on. Moreover, many aspects of metabolic disorder exist in some patients. Every aspect of metabolic may increase the risk of cardiovascular disease, and so many risks exit in one, the synergistic reaction has a larger effect than a simple sum of every risk. This has been one of the cardiovascular risk factors in peritoneal dialysis. And cardiovascular incident is one of the main reasons of the death in peritoneal dialysis.At present additional glucose absorption from the peritoneal dialysis fluid is thought to be one of the most important causes of metabolic disorder in peritoneal dialysis patients. Although every peritoneal dialysis patient has many glucose absorbed from peritoneal dialysis fluid, not everyone shows metabolic disorder. We suppose that genetic predisposition is one of the determinants of metabolic disorder in peritoneal patients except for the overload of glucose. Uncoupling protein (UCP) is a iron channel protein discovered recently, and is proposed to catalyze a mitochondrial inner-membrane H+ leak that bypasses ATP synthase, and induce energy released in heat, play part in many pathological and physiological process. UCP2 is a member of uncoupling protein family, and its pathological and physiological feature is associated with material energy metabolism. UCP2 might play a role in energy balance, body fat distribution, and etc. Its expressing level is related to oxidative stress and insulin secretion. Genetic variation in CUP2 may have effects on the development of obesity, isletβcell dysfunction and type 2 diabetes. ObjectiveTo study the UCP2 gene variants in peritoneal dialysis patients, which is including the 45bp ins/del in the 3'-untranscribed region of exon-8, ptomoter-866G/A and Ala55Val of exon-4. Compare the differences between patents with different UCP2 polymorphisms on obesity, insulin resistances, serum lipid, adipocytokines, and investigate the effect of UCP2 polymorphism on metabolic disorder in peritoneal dialysis patients.Methods116 PD patients were enrolled who were from PD centre of Huashan Hospital with regular follow up more than 6 months. Genotyping of polymorphisms of UCP2 gene in the 3'-untranscribed region of exon-8, ptomoter-866G/A and Ala55Val of exon-4. All the patients were divided into different groups by the polymorphisms to examine the somatometric measurement which was including body mass index (BMI), triceps skinfold thickness (TSF) and abdominal circumference, HOMA-IR, the plasma lipid profile, CRP, ferritin, peritoneal glucose absorption, and adipocytokines.1. Measure weight under fasting state and height, and calculate BMI=weight (kg)/hight2(m2); measure abdominal circumference and TSF.2. Insulin resistance was assessed by HOMA-IR, HOMA-IR= Plasma insulin (mU/L)* plasma glucose (mmol/L)/22.5.3. Assay serum lipid profile which was including cholesterol (CHO), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), and ferritin, C reactive protein(CRP). Assay adiponectin, leptin, resistin by ABC-ELISA method.4. Peritoneal glucose absorption, Kt/V and creatinine clearance (Ccr) of peritoneal dialysis and residual kidney were estimated in these PD patients.Results1.116 PD patients were enrolled, with 60 male and 56 female. The average age was 62.6638±14.9695, and the median of dialysis duration was 12±12 months. 2. According to the polymorphism of 45bp ins/del in the 3'-untranscribed region of exon-8 in UCP2 gene, the patients were divided into DD group and DI/II group. DD group patients had higher triglyceride level than DI/II group (2vs1.48, P<0.05), and its IR was significantly higher than DI/Ⅱgroup (3.12vs2.3778, P<0.01). The rest of the indicators there was no significant difference.3. According to UCP2-866 G/A polymorphism, the patients were divided into AA/AG group and GG group. GG patients had higher triglyceride levels (2.47vs1.52, P<0.05).Logistic regression analysis showed that:The triglyceride elevating risk in GG group was higher than AA/AG group (OR=2.72, P<0.01). Even if the dialysate glucose effect on triglyceride levels was corrected, the difference was still significant (OR=2.441, P=0.031).4. According to the exon 4 Ala55Val polymorphism, the patients were divided into AA/AV group and VV group. VV group had its TG level significantly higher than AA/AV group (2.06vs1.47, P<0.01), and dialysate glucose uptake was significantly increased (96.734vs82.6881, P<0.01). And compared to AA/AV group, VV group had itsIR (3.0933vs2.6027, P<0.05), ferritin (226.5vs221, P<0.05) increased and adiponectin decreased (9.66vsl4.39, P<0.05).Logistic regression analysis showed that:VV group of patients had the 2.745 times higher risk of triglyceride elevating than AA/AV group, P=0.01. Even if the effect of dialysate glucose uptake on the trglyceride level was excluded, the difference was still significant, OR=2.441, P =0.03.5. DDGGVV type patients were enrolled into disadvantage group, while the patients who contained no or only a disadvantage homozygous gene were enrolled into advantage group. Advantage group occurred 2 new onset diabetes patients in 45 patients, while 6 patients in 27 patients in disadvantage group. This had significantly difference (P=0.02). The use of statin drug in advantage group was 33.3%, but 59.3% in disadvantage, having statistical significance (P=0.031).IR in disadvantage group was significantly increased (3.9271vs2.432, P<0.01). And its TG level was significantly higher than advantage group (2.68vsl.4, P<0.01). Moreover, disadvantage group had a significantly increased glucose uptake (108.9939vs83.6698, P<0.01), and had higher CHO (5.3641vs4.6527, P<0.05), CRP (5.77vsl.72, P<0.05), ferritin (270vs209, P<0.05), leptin (2.8583vs2.0542, P<0.05).Logistic regression analysis showed that:The risk of insulin resistance in disadvantage group is 3.75-fold higher than advantage group, P=0.01. Even if the effect of dialysate glucose uptake was amended, the difference was still significant, OR=3.084, P=0.031. And in the same time, disadvantage group also had 6.562 times higher risk of triglyceride elevating than advantage group, P=0.001. Even if the effect of dialysate glucose uptake was corrected, and the significant difference still existed, OR=5.97, P=0.002.ConclusionThe polymorphism of UCP2 gene in the 3'-untranscribed region of exon-8, ptomoter-866G/A and Ala55Val of exon-4 sites is associated with the metabolic disorder in PD patients. DD type, GG type and VV type patients in the context of overload glucose were more susceptible to metabolic disorders, representing insulin resistance, abnormal lipid metabolism. DDGGVV type patients have obvious metabolic disorder, and are at higher risks of insulin resistance and high triglyceride.