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

doi:10.1016/S0002-9343(02)01069-0

The American Journal of Medicine

Volume 112, Issue 7, May 2002, Pages 540-544

https://doi.org/10.1016/S0002-9343(02)01069-0 Get 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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In addition to these HLA associations, candidate gene studies have shown associations with polymorphisms in genes relevant to the 3 key “compartments” of SSc: the immune, connective tissue, and vascular systems. Positive associations with polymorphisms found in candidate genes governing vascular function have included endothelial nitric oxide synthase (eNOS), angiotensin-converting enzyme (ACE),8 and the endothelin receptor (ETR) B.9 Disease-associated polymorphisms in genes involved in the connective tissue system include connective tissue growth factor (CTGF),10 fibrillin-111 and secreted protein acidic and rich in cysteine (SPARC).12 However, none of these associations have been replicated across multiple populations.
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2009, Genomic and Personalized Medicine, Two-Vol Set

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

Abstract

Purpose

Subjects and methods

Results

Conclusion

Section snippets

Methods

Results

Discussion

Rheum Dis Clin North Am

Am J Cardiol

Lancet

FEBS Lett

J Biol Chem

FEBS Lett

Induction of angiotensin converting enzyme in the neointima after vascular injurypossible role in restenosis

J Clin Invest

The effects of angiotensin metabolites on the regulation of coagulation and fibrinolysis in cultured rat aortic endothelial cells

Thromb Haemost

Fibrinolytic balance, the renin-angiotensin system and atherosclerotic disease

Eur Heart J

Angiotensin receptors in pulmonary arterial and aortic endothelial cells

Am J Physiol

Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells. A potential link between the renin-angiotensin system and thrombosis

J Clin Invest

Captopril administration reduces thrombus formation and surface expression of platelet glycoprotein IIb/IIIa in early postmyocardial infarction stage

Arterioscler Thromb Vasc Biol

PCR detection of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene (DCP1) (dipeptidyl carboxypeptidase 1)

Nucleic Acids Res

An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels

J Clin Invest

Contribution of nitric oxide to metabolic coronary vasodilation in the human heart

Circulation

Nitric oxidean endogenous modulator of leukocyte adhesion

Proc Natl Acad Sci USA

Nitric oxide reversibly inhibits the migration of cultured vascular smooth muscle cells

Circ Res

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