Interleukin 6 Gene Polymorphisms Are Associated with Systemic Lupus Erythematosus in Koreans

Abstract

Interleukin 6 (IL-6) gene polymorphisms are known to play a role in chronic inflammatory disorders. We searched for polymorphisms in the IL-6 gene and described their pathogenic role in Korean patients with systemic lupus erythematosus (SLE). Genomic DNA was extracted from 151 patients with SLE and 151 controls, and about 1.4 kb-sized IL-6 genes located between promoter region and exon 2 region were amplified by polymerase chain reaction. The promoter activity was analyzed by luciferase reporter assay in Hep3B cells and HeLa cells. We identified 4 single-nucleotide polymorphisms (SNP; -572 C > G, -278 A > C in the promoter, and 330 T > G, and 334 A > T in exon 2) and a -373 A(n)T(n) tract polymorphism in the IL-6 gene. The genotype frequency, -373 A(10)T(11), -278 C, and 334 T allele were significantly associated with SLE (p < 0.001, p = 0.03 and p = 0.005, respectively). Patients with SLE carrying the -572 G allele had anti-dsDNA more frequently (p = 0.007). In addition, thrombocytopenia was significantly more common in patients carrying the -278 C allele (p = 0.006). In the haplotype analysis, patients with SLE had more frequently haplotype HT3 (CA(10)T(11)ATA, dominant model, p = 0.012) that was associated with arthritis, leukopenia, anti-dsDNA, and hypocomplementemia. Promoter reporter structures carrying the -278 C allele displayed significantly higher promoter activity than the -278 A allele in Hep3B cells (p < 0.001) and HeLa cells (p < 0.001). These data suggest that IL-6 gene polymorphisms are associated with disease susceptibility and phenotype of SLE. In addition, promoter polymorphisms may be involved in regulation of IL-6 expression.