Background: Interleukin-8 (IL-8) is a potent neutrophil chemokine that has been implicated in the pathogenesis of renal inflammation in human glomerulonephritis. To explain inter-patient variations in renal inflammation during diseases such as systemic lupus erythematosus (SLE), it was postulated that the promoter region of the IL-8 gene contains polymorphic residues that influence the level of IL-8 expression in response to immune-complex deposition, and thereby affect the severity of renal injury. This study was undertaken to identify polymorphisms in the 5'-flanking region of the IL-8 gene that correlate with the severity of SLE nephritis.
Methods: A 1526 base pair segment of the IL-8 5'-flanking region was PCR amplified from the genomic DNA of 100 individuals and sequenced on an automated capillary electrophoresis system. Sequence data were compared with the published IL-8 sequence to identify polymorphisms. Allelic variations were verified by cloning and re-sequencing, and also by restriction enzyme analysis. Patients with SLE nephritis were genotyped for IL-8 polymorphisms, and associations between specific alleles and severity of SLE nephritis [based on the World Health Organization (WHO) classification] were determined.
Results: Three single nucleotide polymorphisms were identified in the IL-8 flanking region. Labeled relative to the IL-8 translational start site, these are T-845C, T-738A, and A-353T. T-845C and T-738A are novel, and found primarily in African Americans. The C for T change at position -845 was found to be 3.6 to 7.5 times more frequent in African Americans with severe (WHO Class IV) SLE nephritis, than in African American controls, or patients with less severe forms of SLE nephritis, respectively.
Conclusions: IL-8-845C might predispose African Americans with SLE nephritis to more severe renal injury, perhaps by influencing IL-8 expression. Genotyping patients with glomerulonephritis for IL-8 polymorphisms may be useful in predicting disease outcome and individualizing immunosuppressive therapy.