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

Abstract

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.