Clinical study
High prevalence of polymorphisms of angiotensin-converting enzyme (I/D) and endothelial nitric oxide synthase (Glu298Asp) in patients with systemic sclerosis

https://doi.org/10.1016/S0002-9343(02)01069-0Get rights and content

Abstract

Purpose

Systemic sclerosis is characterized by progressive microvascular occlusion and fibrosis and by an imbalance in the fibrinolytic system. In vivo and in vitro studies suggest that the renin-angiotensin system partly regulates vascular fibrinolytic balance. Angiotensin II increases the production and secretion of plasminogen activator inhibitor-1, while angiotensin-converting enzyme (ACE) contributes to reduced production of tissue plasminogen activator and endothelial nitric oxide synthesis by bradykinin degradation. The aim of our study was to investigate the effects of ACE insertion/deletion (I/D) and endothelial nitric oxide synthase (eNOS) Glu298Asp (G894→T) and T–786→C polymorphisms in patients with systemic sclerosis.

Subjects and methods

We studied 73 consecutive patients (47 with limited and 26 with diffuse cutaneous systemic sclerosis) and 112 control subjects. ACE I/D and eNOS polymorphisms were genotyped by polymerase chain reaction–restriction fragment length polymorphism analysis.

Results

The ACE I/D and the eNOS G894→T polymorphisms were more common in patients than in controls (for the ACE D allele: odds ratio [OR] = 3.4; 95% confidence interval [CI]: 1.5 to 7.9; P = 0.003; for the eNOS T allele: OR = 1.9; 95% CI: 1.0 to 3.4; P = 0.04). There was no association between the eNOS T–786→C polymorphism and systemic sclerosis.

Conclusion

Our findings of an increased risk of systemic sclerosis in ACE D and eNOS 894T allele carriers suggest that these polymorphisms may contribute to the pathogenesis of the disease.

Section snippets

Methods

We investigated 73 consecutive Italian patients (62 women, 11 men) with systemic sclerosis who had been referred to the Section of Rheumatology of the Department of Internal Medicine of the University of Florence, Italy. The median age was 62 years (range, 24 to 79 years). The diagnosis of systemic sclerosis was established according to the criteria of the American College of Rheumatology (23). One hundred and twelve control subjects of the same ethnicity, with no history of cardiovascular

Results

The ACE D and eNOS 894T alleles, but not the eNOS –786C allele, were significantly more common in patients with systemic sclerosis than in controls (Table 1). The ACE D allele was associated with about a threefold increase in the risk of systemic sclerosis (OR [DD + ID vs. II] = 3.4; 95% CI: 1.5 to 7.9; P = 0.003), and the eNOS 894T allele with about a doubling in the risk (OR [TT + GT vs. GG] = 1.9; 95% CI: 1.0 to 3.4; P = 0.04).

Forty-one (56%) of 73 patients had both the ACE D and eNOS 894T

Discussion

We found that the ACE D allele and the eNOS 894T allele were associated with an increased risk of systemic sclerosis, but not with the disease subset and clinical features. This suggests the possibility that these alleles affect the incidence, but not the progression and evolution, of the disease.

The ACE D allele affects plasma ACE levels (10), perhaps because the I allele may have a “silencer” effect (27), thereby regulating the production of angiotensin II and the degradation of bradykinin.

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