PAI-1基因和纤维蛋白原β链基因多态性与狼疮性肾炎肾小球微血栓的关系

目的 探讨纤溶酶原活化剂抑制物－1（plasminogen activator inhibitor-1,PAI-1）基因和纤维蛋白原β链基因多态性与狼生肾炎（lupus nephritis,LN）肾小球微血栓形成之间的相关性。方法 选取101例LN患者，依据肾活检组织肾小球微栓的有无，将患者分为两组：LN伴血栓（LN＋T）组46例；不伴血栓(LN-T)且55例。应用聚合酶链反应－限制性片段长度多态性和聚合酶链反应－序列长度多态性技术分别分析两修选基因的基因型，正常对照组为128名健康成人。结果 （1）PAI－1基因4G／4G基因型和4G等位基因与LN＋T组显著相关；LN中4G／4G型患者发生肾小球Pan内血栓的相对风险率的比值比（odds ratio,OR）为2.96,95%可信区间（confidence interval,CI）：1.26-6.92；92）纤维蛋白原β链基因G／A＋A／A基因型和A型等位基因与LN＋T组显著相关；LN中A型等位基因携带者发生肾小球Pan内血栓的相对风险率为OR＝2.44，95％CI：0.98－5.59；（3）LN患者若同时兼有上述两的血栓易感基因型，其发生肾小球微血栓的相对风险率明显增加，OR＝4.5,95%CI:1.34-15.12；血栓易感基因型的混合病因分值（45.98%）也高于各自单独的病因分值（PAI－1基因4G／4G型为31.67%、纤维蛋白原β链基因G／A＋A／A基因型为28.23%）。结论 LN肾小球微血栓的形成与PAI－1基因和纤维蛋白原β基因多态性有关，两基因的易栓基因型在LN肾小球微血栓这一病理表型的形成上具有协同效应。

Genetic variations in plasminogen activator inhibitor-1 gene and β fibrinogen gene associated with glomerular microthrombosis in lupus nephritis and the gene dosage effect

OBJECTIVE: To explore the relationship of plasminogen activator inhibitor-1 (PAI-1) gene -675 4G/5G and beta fibrinogen gene -455 G/A variations to glomerular microthrombosis(T) in lupus nephritis(LN). METHODS: One hundred and one patients with biopsy proven LN were divided into two groups according to the presence or absence of glomerular microthrombus, i.e. group LN+T(n=46) and group LN-T(n=55). The genotypes of PAI-1 gene and beta fibrinogen gene were profiled by polymerase chain reaction-sequence length polymorphism (PCR-SLP) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) respectively. Clinical baseline data at the time of renal biopsy were collected. Normal controls consisted of 128 unrelated healthy adults. The etiologic fractions (EF) were calculated for estimating the contribution of risk genotypes of the two candidate genes to an increase in susceptibility to glomerular microthrombosis in LN patients. RESULTS: Both the 4G/4G genotype and the 4G allele of PAI-1 gene occurred more frequently in group LN+T (47.83% and 0.685) than in group LN-T (23.64% and 0.507)(P<0.05) and normal controls (28.13% and 0.570) (P<0.05). The PAI-1 4G/4G genotype was significantly associated with microthrombosis (OR=2.96, 95%CI:1.26-6.92). Besides, the prevalence of the genotypes carrying the A allele of beta fibrinogen gene, i.e. G/A and A/A, as well as the prevalence of the A allele per se, was increased in group LN+T (47.83% and 0.261) versus group LN-T (27.27% and 0.145)(P<0.05). LN patients carrying the A allele had a high risk of glomerular thrombosis(OR=2.44, 95%CI:0.98-5.59). In addition, the presence of the PAI-1 4G/4G genotype together with the A allele of the beta fibrinogen gene was found to be a greater risk factor (OR=4.5, 95%CI: 1.34-15.12) for glomerular thrombosis in LN than the 4G/4G genotype or the A allele alone. The pooled EF (45.98%) for the risk genotypes of both PAI-1 gene and beta fibrinogen gene was also higher than that for the risk genotypes of either gene (31.67% and 28.23%). CONCLUSION: The above findings indicated that genetic variations in PAI-1 and beta fibrinogen loci might represent risk factors for glomerular microthrombosis in LN. They may have synergetic impact and present gene dosage effect on the susceptibility to this pathological subphenotype.