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Endothelial Nitric Oxide Synthase Gene Polymorphism Is Associated with Systemic Lupus Erythematosus

NORMA C. SERRANO, CAROLINA PÁEZ, PAULA A. CORREA, and JUAN-MANUEL ANAYA

ABSTRACT.

Objective. In systemic lupus erythematosus (SLE), endothelial nitric oxide synthase (eNOS) gene locus has been found to be suggestive of linkage with disease, nitric oxide (NO) is produced in significant amounts, and endothelial cell dysfunction is observed. eNOS gene polymorphism may affect both the synthesis of eNOS protein and its enzymatic activity. We examined the influence of eNOS gene polymorphisms on susceptibility to SLE.

Methods. Genomic DNA from 88 Northwestern Colombian women with SLE, as well as 199 controls matched for sex, age, and ethnicity, was genotyped for the –786T®C polymorphism in the promoter region, the intron 4 variable number of tandem repeats, and the Glu298Asp polymorphism in exon 7 of the eNOS gene by polymerase chain reaction and restriction fragment length polymorphism techniques. Haplotype and allele frequency comparisons, a Hardy-Weinberg equilibrium test, and linkage disequilibrium (LD) analysis were performed.

Results. The intron 4b allele was associated with SLE (OR 2.2, 95% CI 1.29–3.60, p_c = 0.005) as was the 4bb genotype (OR 2.9, 95% CI 1.61–5.33, p_c = 0.0009), while the 4a allele was protective (OR 0.4, 95% CI 0.26–0.76, p_c = 0.005), as was the 4ab genotype (OR 0.29, 95% CI 0.15–0.56, p_c < 0.0001). In controls, all loci were in linkage disequilibrium (p < 0.02). In patients, intron 4 was in Hardy-Weinberg disequilibrium, due to an excess of homozygotes (p = 0.01).

Conclusion. eNOS polymorphism influences SLE predisposition. Since intron 4bb genotype is responsible for higher levels of eNOS synthesis and intron 4 ab genotype is associated with lower synthesis, our results might provide insight into the elevated levels of NO observed in SLE patients. (J Rheumatol 2004;31:2163-8)

Key Indexing Terms:

SYSTEMIC LUPUS ERYTHEMATOSUS
ENDOTHELIAL NITRIC OXIDE SYNTHASE
POLYMORPHISM
LUPUS NEPHRITIS
AUTOANTIBODIES
GENETICS

From the School of Medicine, Universidad Autónoma de Bucaramanga (UNAB), Bucaramanga; the Cellular Biology and Immunogenetics Unit, Corporación para Investigaciones Biológicas (CIB), Medellín; Rheumatology Unit, Clínica Universitaria Bolivariana, School of Medicine, Universidad Pontificia Bolivariana (UPB), Medellín, Colombia.

Supported by Universidad Autónoma de Bucaramanga (#2101), Bucaramanga, and Corporación para Investigaciones Biológicas, Medellín, Colombia.

N.C. Serrano, MD, MSc, Associate Professor, School of Medicine, UNAB; C. Paez, MD, Assistant Researcher, UNAB; P.A. Correa, MSc, Assistant Researcher, Cellular Biology and Immunogenetics Unit, CIB, Assistant Professor, School of Medicine, UPB; J-M. Anaya, MD, Associate Researcher, Cellular Biology and Immunogenetics Unit, CIB, Professor of Medicine, School of Medicine, UPB.

Address reprint requests to Dr. J-M. Anaya, Corporación para Investigaciones Biológicas, Cra. 72-A No 78-B-141, Medellín, Colombia. E-mail address: janaya@cib.org.co

Submitted January 22, 2004; revision accepted June 9, 2004.