| ObjectiveThe level of serum uric acid is correlated with hypertension, diabetes and insulin resistance, but whether HUA was an independent risk factor of these diseases is not clear. There are glucose-uric acid coupled transporters in renal tubular cells, suggests that the level of serum uric acid might be associated with blood glucose. However, the connection between persistented higher blood glucose and the uric acid level remains to be elucidated in type 2 diabetes mellitus (T2DM). We conducted a prospective cohort study to reveal the relationship between serum uric acid and hypertension. Meanwhile, we tested the correlation among uric acid, blood glucose, and glycated hemoglobin (GHbAlc) in patients with T2DM. We carried out association studies among single nucleotide polymorphism (SNPs) of glucose-uric acid transporter genes and serum uric acid levels.The prevalence of diabetes increased damatically in the world, the latest research results showed that the prevalence rate of diabetes was 11.6% in Chinese adults. The interaction of genetic and environmental factors contributed to the epidemic of diabetes, deciphering the genetic background of diabetes is important to understand its etiology. In order to find genes associated with T2DM in Han Chinese population, we conducted association studies among SNPs of candidate genes of T2DM in our study.Microvascular complications of diabetes (MVCD), mainly consists of diabetic nephropathy (DN) and diabetic retinopathy (DR), are major causes of morbidity and mortality of diabetes mellitus. DN is the major reason for end stage renal failure in diabetes patients. DR, on the other hand, is a major cause of blindness in adults. Both DN and DR have strong familial aggragations. Although hyperglycemia was considered as the major reason of MVCD, the susceptibility of MVCD varies in different patients:prolonged diabetes history and poorly controlled plasma glucose are not necessary to be the indicator of MVCD. It suggests that genetic factors also play an important role in the development of MVCD. We conducted association studies among SNPs of candidate genes and MVCD. to find MVCD related gene polymorphisms in Han Chinese population.MethodsWe selected 7032 individuals in a cohort of 6 years follow-up physical examinations to study the relationship between uric acid and hypertension. Subjects are divided into four groups according to the quartiles of uric acid, the first group <P25 (<293μmol/L), the second group P25～(293μmol/L～), the third group P50～ (346μmol/L～), and the fourth group≥P75 (≥405μmol/L). Cox proportional hazards model is used to analyze the risk factors of hypertension. A Kaplan-Meier survival analysis was used to compare cumulative incidences of hypertension among different uric acid levels.A total of 2250 unrelated Han Chinese T2DM patients in Tianjin are recruited. We chose 4220 people in the physical examination cohort in 2011, subjects were divided into two groups based on the fasting blood glucose levels:the group with abnormal blood glucose (>6.1mmol/L) and the normal blood glucose group (≤6.1mmol/L). Correlation analyses were performed to test correlations among uric acid, plasma glucose, and GHbAlc in T2DM patients, the abnormal blood glucose group, and the normal blood glucose group, respectively. We carried out association studies among SNPs of glucose-uric acid transporter genes and serum uric acid levels.We employed candidate gene case-control association studies for T2DM:all 2250 T2DM patients were used as cases,909 individuals (>57 years old) with normal blood glucose were used as controls. A total of 33 SNPs of 22 candidate genes were genotyped for this study.We also conducted case-control association studies for MVCD candidate genes: 2250 T2DM patients were divided into four groups:DN (836), DR (504), Proliferative diabetic retinopathy (PDR) (106), and MVCD (1116) (including DN, DR and PDR). Two control groups were chosen for this study:the first group of controls were 266patients with>10 years T2DM history, without DR or DN (266); the second control group consisted of patients with>10 years T2DM history, without DR or DN (266), and 909 individuals (>57 years old) with normal blood glucose.,ResultsWe had collected clinical data for a total of 7032 individuals (men 75.7%, women 24.3%) in the physical examination cohort from 2006 to 2011. The Cox regression analysis showed that comparing with the lowest quartiles (<293μmol/L), other three groups (293μmol/L～,346μmol/L～, and ≥405μmol/L) yielded OR values for hypertension of 1.200 (1.086～1.328),1.354(1.224～1.498), and 1.526 (1.373～ 1.695), respectively. Kaplan-Meier analyses showed higher prevalence of hypertension with the increased of serum uric acid levels. The results suggest that serum uric acid is an independent risk factor for hypertension.A total of 2250 unrelated Han Chinese T2DM patients (men 54.1%, women 45.9%) were recruited in this study. The HUA prevalence in T2DM subjects was 17.25%(men14.82%, women 20.06%). The serum uric acid levels were negatively correlated with GHbAlc and P2hG in T2DM subjects, correlation coefficients were-0.109 and -0.178, respectively; Serum uric acid levels were negatively correlated with GHbAlc and FPG in abnormal glucose subjects but positively correlated with GHbA1c and FPG in normal glucose subjects. A multi-variable analysis disclosed that the serum uric acid level was negatively correlated with GHbAlc (P=0.007, (OR=0.872,95%CI:0.790～0.963). Genetic association studies showed that two glucose-uric acid transporter genes, ABCG2 and SLC2A9, were significantly associated with uric acid:rs7660895 and rs1014290 of the SLC2A9 gene, rs2231142 of the ABCG2 gene were significantly associated with plasma uric acid levels (P<0.05). The CC genotype of rs2231142, the AA genotype of rs7660895, and the CC genotype of rs1014290 had lower uric acid levels than their counterpart alleles.In our association studies for T2DM, we used 2250 T2DM patients as cases,909 individuals (>57 years old) with normal blood glucose as controls.Candidate genes association study showed that the TOX gene rs1526167 SNP (P=2.85×10-9, OR=1.440,95%CI:1.276～1.624) and the CDKN2A/B gene rs10811661 SNP (P=4.09×10-/, OR=1.364,95%CI:1.209～1.538) were associated with T2DM.Among 2250 T2DM patients, DN, DR, PDR, and MVCD patients were selected as cases. In order to eliminate the influence of T2DM, patients with>10 years T2DM history, without DR or DN were chosen as controls (266). Candidate genes association study found that TOX and CDKN2A/B gene polymorphisms were associated with DN. DR. PDR and MVCD. When patients with>10 vears T2DM history, without DR or DN (266) and 909 individuals (>57 years old) with normal blood glucose were used as controls, TOX and CDKN2A/B gene polymorphisms were also associated with DN, DR, PDR, and MVCD. In addition, IGF2BP2, SMAD3, ESR1, CDKAL1, SLC2A9, and SLC30A8 gene polymorphisms showed nominal associations with the incidence of MVCD (P< 0.05).Conclusion Serum uric acid is an independent risk factor for hypertension. The serum uric acid level is negatively correlated with GHbAlc in T2DM subjects and abnormal glucose subjects, but positively correlated with GHbAlc in normal glucose subjects. Under a high blood glucose circumstance, the reverse transporting of uric acid and glucose in renal tubule might be activated to stabilize the blood glucose level. Association studies showed that SLC2A9 and ABCG2 gene polymorphisms were associated with plasma uric acid levels in T2DM patients. In our study, we found a genome-wide level association (P<5x10-8) between a TOX gene polymorphism and T2DM. We also found that CDKN2A/B gene SNPs were associated with T2DM. TOX and CDKN2A/B gene region polymorphisms were associated with MVCD, even after the substraction of genetic backgrounds of T2DM. |
PDF Full Text Request