Objective Myeloperoxidase (MPO) is an enzyme that is highly expressed in neutrophil leukocytes and monocytes. It is involved in the production of free radicals generating hypochlorous acid (HOCL), a potent oxidant resulting in tissue and DNA damage. A functional G to A single nucleotide polymorphism (SNP) has been identified at position 2463 of the promoter region of the MPO gene on chromosome 17, which has been associated with vasculitis, multiple sclerosis, and renal disease. The A allele is associated with a lower MPO expression. We hypothesized that the 2463 G/A MPO gene polymorphism is a risk factor for the development/progression of systemic lupus erythematosus (SLE) and lupus nephritis (LN).
Methods DNA from 229 SLE patients and their age- and gender-matched 277 controls from the Carolina Lupus (CLU) Study cohort, 58 patients from the Sea Island Lupus Cohort, and 51 African American patients from the Lupus Multiplex Registry Cohort were tested for the 2463 G/A MPO gene polymorphism by polymerase chain reaction. Among the SLE patients, 95 had biopsy-proven lupus nephritis. A linear regression model was used to examine relationships between the 2463 G/A MPO polymorphism and case/control status, demographic characteristics, and LN. 3-Chlorotyrosine results from the interaction of reactive oxygen species with tyrosine. We further determined if the polymorphism impacted production of reactive oxygen species in African American lupus patients. We assessed levels of 3-chlorotyrosine in serum from 4 GG and 4 AA patients by high-performance liquid chromatography (HPLC).
Results Allele distribution was different (p = .03) between patients and controls. However, in the multivariate model, examining factors associated with having SLE, as is well known race was statistically significant (blacks carry a higher risk of developing SLE, OR = 4.8, CI 3.2-7.1) accounting for the allele frequency differences between patients and controls. MPO polymorphism was not a significant risk factor for developing SLE when factoring in ethnicity. In the model examining predictors of LN, male gender (p = .004) and black race (p = .0001) were identified as significant risk factors. The presence of the genotype AA was a risk factor for developing LN in black patients (OR = 2.72). Serum 3-chlorotyrosine levels were 10-fold higher in the GG patients compared to AA patients by HPLC.
Conclusion The 2463 AA MPO gene polymorphism is a risk factor for developing LN in black patients. The 2463G/A polymorphisms are not linked with the development of SLE but do profoundly affect myeloperoxidase activity in vivo.
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