Intron 4 polymorphism of the endothelial nitric oxide synthase gene is associated with the development of lupus nephritis

Abstract

The objective was to investigate whether the functional polymorphism of intron 4 in the endothelial nitric oxide synthase (eNOS) gene is associated with susceptibility to systemic lupus erythematosus (SLE) and its clinical features. The 27-bp repeat polymorphism in intron 4 of the eNOS gene was determined by polymerase chain reaction in 88 SLE patients and 95 healthy control subjects. Clinical manifestations were analysed in each patient and correlated with the genotypes. The genotype distribution of the intron 4 of the eNOS did not differ between SLE patients and control subjects (aa, ab, bb genotypes 0, 15, 73 versus 2, 19, 74 controls respectively, chi-squared 2.21, 2 df, P 0.331). In the lupus patients according to the intron 4 genotypes of the eNOS, there was no clinically significant difference in age at onset, anti-dsDNA titre, C3, C4 level, SLEDAI, SLICC/ACR Damage Index, or autoantibodies such as RF, anti-Ro, La, RNP, Sm, or phospholipid antibodies. However, renal involvement was higher in patients with ab genotypes than in those with bb genotypes (53% versus 26%), but it did not reach statistical significance (P 0.062). Logistic regression showed that having the ab genotype was a significant risk factor for the development of lupus nephritis (odds ratio 3.28, 95%CI: 1.04-10.2, P 0.04). In conclusion, our data show that the eNOS ab genotypes may be associated with the development of lupus nephritis, suggesting individuals who carry the ‘a’ allele are more susceptible to lupus nephritis than those with the ‘b’ allele.

Keywords

eNOS polymorphisms systemic lupus erythematosus

Get full access to this article

View all access options for this article.

References

Bredt DS , Snyder SH. Nitric oxide: a physiologic messenger molecule . Am Rev Biochem 1994; 63: 175-195 .

Miyahara K , Kwamoto T , Sase K et al. Cloning and structural characterization of the human endothelial nitric oxide synthase gene . Eur J Biochem 1994; 223: 719-726 .

Tsukada T , Yokoyama K , Tomoko Y et al. Evidence of association of the ecNOS gene polymorphism with plasma NO metabolite levels in humans . Biochem Biophys Res Commun 1998; 245: 190-193 .

Wanchu A , Khullar M , Deodhar SD , Bambery P , Sud A. , Nitric oxide synthesis is increased in patients with systemic lupus erythematosus . Rheumatol Int 1998; 18: 41-43 .

Tan EM , Cohen AD , Fries JF et al. The 1982 revised criteria for the classification of systemic lupus erythematosus . Arthritis Rheum 1982; 25: 1271-1277 .

Bombardier C , Gladman DD , Urowitz MB , Caron D , Chang CH. Derivation of the SLEDAI. A disease acitivity index for lupus patients. The committee on prognosis studies in SLE . Arthritis Rheum 1992; 35: 630-640 .

Gladman D , Ginzler E , Goldsmith C et al. The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index for systemic lupus erythematosus . Arthritis Rheum 1996; 39: 363-369 .

Marsden PA , Heng HH , Scherer SW et al. Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene . J Biol Chem 1993; 268: 17478-17488 .

Droma Y , Hanaoka M , Ota M et al. Positive association of the endothelial nitric oxide synthase gene polymorphisms with high-altitude pulmonary edema . Circulation 2002; 106: 826-830 .

10.

Tempfer CB , Dorman K , Deter RL , O’Brien WE , Gregg AR. An endothelial nitric oxide synthase gene polymorphism is associated with preeclampsia . Hypertens Preg 2001; 20: 107-118 .

11.

Kunnas TA , Ilveskoski E , Niskkangas T et al. Association of the endothelial nitric oxide synthase gene polymorphism with risk of coronary artery disease and myocardial infarction in middle-aged men . J Mol Med 2002; 80: 605-609 .

12.

Lee YC , Cheon KT , Lee HB et al. Gene polymorphisms of endothelial nitric oxide synthase and angiotensin-converting enzyme in patients with asthma . Allergy 2000; 55: 959-963 .

13.

Weinberg JB , Granger DL , Pisetsky DS et al. The role of nitrix oxide in the pathogenesis of spontaneous murine disease . J Exp Med 1994; 179: 651-660 .

14.

Tolins JP , Palmer RMJ , Moncada S , Raij L. Role of endothelium-derived relaxing factor in regulation of renal hemodynamic responses . Am J Physiol 1990; 258: 655-662 .

15.

Baylis C , Mitruka B , Edng A. Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage . J Clin Invest 1992; 90: 278-281 .