Wong T Y, Poon P, Szeto C C, Chan J C, Li P K
Department of Medicine and Therapeutics, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, Hong Kong.
Kidney Int. 2000 Feb;57(2):632-8. doi: 10.1046/j.1523-1755.2000.00884.x.
Plasminogen activator inhibitor-1 (PAI-1) is a key regulator of fibrinolytic pathway and extracellular matrix (ECM) turnover. Because diabetic nephropathy is characterized by the presence of basement membrane thickening and mesangial expansion, we examined the role of PAI-1 gene polymorphisms in the development of type 2 diabetic nephropathy. Evidence also suggested that the PA/plasmin system and the renin-angiotensin system (RAS) interact together to affect the risk of fibrosis and thrombosis. Hence, we also studied the synergistic effect between PAI-1 and angiotensin-converting enzyme (ACE) gene polymorphisms.
The PAI-1 and ACE (D/I) gene polymorphisms were examined in a cohort of Chinese type 2 diabetic patients who had diabetes for an average of 14 years. These patients were sex and age matched. Group A (N = 46) consisted of patients without diabetic nephropathy (normoalbuminuric with creatinine <120 micromol/L), and group B (N = 95) was with diabetic nephropathy (with albuminuria or renal impairment, including patients on dialysis).
Patients with type 2 diabetic nephropathy had a higher frequency of PAI-1 (4G/4G) genotypes than those without nephropathy [4G/4G:4G/5G:5G/5G = 41:38:21 (%) vs. 15:65:20(%), P = 0.005]. Diabetic patients with coexistence of PAI-1 4G/4G genotype and ACE D alleles had a higher incidence of diabetic nephropathy (22 vs. 7%, P = 0.012) than those with other combinations of genotypes. Multivariate logistic regression analysis showed that PAI-1 4G/4G (P = 0.01) and the prevalence of hypertension (P < 0.0001) are independent risk factors of development of type 2 diabetic nephropathy.
These results suggest that the PAI-1 4G/4G genotype is associated with an increased risk for type 2 diabetic nephropathy in Chinese patients, which is an independent risk factor for the development of nephropathy. The PAI-1 4G/4G genotype also exhibits a synergistic effect with the ACE D allele on development of diabetic nephropathy.
纤溶酶原激活物抑制剂-1（PAI-1）是纤维蛋白溶解途径和细胞外基质（ECM）周转的关键调节因子。由于糖尿病肾病的特征是基底膜增厚和系膜扩张，我们研究了PAI-1基因多态性在2型糖尿病肾病发生发展中的作用。有证据还表明，PA/纤溶酶系统和肾素-血管紧张素系统（RAS）相互作用，共同影响纤维化和血栓形成的风险。因此，我们还研究了PAI-1与血管紧张素转换酶（ACE）基因多态性之间的协同作用。
在一组平均患糖尿病14年的中国2型糖尿病患者中检测PAI-1和ACE（D/I）基因多态性。这些患者在性别和年龄上相匹配。A组（N = 46）由无糖尿病肾病的患者组成（正常白蛋白尿，肌酐<120微摩尔/升），B组（N = 95）患有糖尿病肾病（有蛋白尿或肾功能损害，包括透析患者）。
2型糖尿病肾病患者中PAI-1（4G/4G）基因型的频率高于无肾病患者[4G/4G:4G/5G:5G/5G = 41:38:21（%）对15:65:20（%），P = 0.005]。同时存在PAI-1 4G/4G基因型和ACE D等位基因的糖尿病患者患糖尿病肾病的发生率（22%对7%，P = 0.012）高于其他基因型组合的患者。多因素逻辑回归分析显示，PAI-1 4G/4G（P = 0.01）和高血压患病率（P < 0.0001）是2型糖尿病肾病发生发展的独立危险因素。
这些结果表明，PAI-1 4G/4G基因型与中国患者2型糖尿病肾病风险增加相关，这是肾病发生发展的一个独立危险因素。PAI-1 4G/4G基因型在糖尿病肾病发生发展中还与ACE D等位基因表现出协同作用。
