Endothelial nitric oxide synthase gene haplotype association with systemic lupus erythematosus

Endothelial nitric oxide synthase (eNOS) catalyses the production of nitric oxide, which has been shown to participate in the pathogenesis of systemic lupus erythematosus (SLE). eNOS gene polymorphism may have an effect on eNOS gene expression, eNOS protein synthesis and enzymatic activity. We investigated the influence of eNOS gene polymorphisms on susceptibility to SLE. eNOS T-786C, G894T and intron 4 27-base pair tandem repeat (VNTR4) polymorphisms were investigated in 152 SLE patients and 184 controls using RFLP-PCR, direct sequencing and fragment analysis. Allele, genotype and haplotype frequency comparisons, Hardy-Weinberg equilibrium and linkage disequilibrium (LD) analysis were performed. No significant association was detected between SLE and single-nucleotide polymorphisms (SNPs) T-786C and G894T. VNTR4 allele 4b was associated with susceptibility to SLE (OR 1.89, p = 0.023), as was the genotype 4bb (OR 2.41, p = 0.007). However, allele 4a was protective (OR 0.53, p = 0.023), as was genotype 4ab (OR 0.41, p = 0.007). T-786C and VNTR4 were in high LD (r(2) = 0.34). Haplotypes T4bC and C4aG of the three tested polymorphisms had a susceptibility effect on SLE (OR 1.89 and 4.23 at p = 0.005 and 0.001, respectively), while haplotypes T4aG and C4bG had a protective effect (OR 0.06 and 0.11 at p = 0.000001 and 0.0005, respectively). The novel finding in our study is that individual eNOS polymorphisms probably do not exert a major influence on susceptibility to SLE, but they have significant effects when combined within a specific haplotype. Lupus (2011) 20, 700-708.