Genetic Polymorphisms of Interleukin-6 in Systemic Lupus Erythematosus

BACKGROUNDS: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by polyclonal B-cell activation and elevated production of pathogenic autoantibodies. Interleukin-6 (IL-6) is a multifunctional cytokine that mediates inflammatory and immune responses, and IL-6 gene polymorphisms are known to play a part in chronic inflammatory and autoimmune disorders. We have identified single nucleotide polymorphisms (SNPs) in the IL-6 gene, determined their frequency in Korean populations, and elucidated their difference between SLE patients and controls. MATERIALS AND METHODS: Blood samples were collected from Korean SLE patients (n=151) and normal healthy controls (n=151) from the rheumatology clinic at the Ajou University Hospital. All of patients fulfilled the American College of Rheumatology (ACR) classification criteria for SLE. Genomic DNA was extracted and approximately 1.4 kb-sized IL-6 genes located between promoter region and exon2 region were amplified by polymerase chain reaction (PCR). We identified possible polymorphisms in the IL-6 gene and that were genotyped by direct sequencing. Also IL-6 genes located variable number of tandem repeat (VNTR) of 3′flanking region were amplified by PCR and that were genotyped by Genescan analysis. The effect of -276 A>C polymorphism on the promoter activity was analyzed by luciferase reporter assay in Hep3B cell and HeLa cell. Statistical analyses were undertaken using SPSS ver.11.5 P values of <0.05 were considered to be significant. RESULTS: We have identified six SNPs (-572 C>G, -373 AnTn, -276 A>C, -174 A>C in the promoter region, and 331 T>G and 334 A>T in the exon2 region) including three novel SNPs (-276 A>C, 331 T>G and 334 A>T), in the IL-6 gene. There was significant difference in the -373 A10T11 polymorphism (p<0.001) -276 A>C polymorphism (p=0.041), 334 A>T polymorphism (p=0.001) between SLE and normal controls, and no association in other SNPs. Another interesting finding was that there was no C allele of -174 G>C polymorphisms in Koreans. Also genotype of -373 AnTn and major allele of -572 C>G was differented from other ethnic groups. The -572 C>G polymorphism was statistically significantly associated with anti-ds DNA (p=0.007). The -276 A>C polymorphism was statistically significantly associated with thrombocytopenia (p=0.006). We have identified fifteen size VNTR polymorphisms in the 3′flanking region. VNTR I (642 bp) allele was associated with susceptibility of SLE, however VNTR N (652 bp)decreased susceptibility of SLE. Also, VNTR I allele was statistically significantly associated with leukopenia (p=0.048), thrombocytopenia (p=0.020) and C-reactive protein (p=0.019), and VNTR G allele was statistically significantly associated with lymphopenia (p<0.001) and hypocomplementemia (p=0.040). When the carrying of the -174 C, -373 A10T11 and VNTR I (642 bp) alleles were supposed that these alleles were significantly higher disease susceptibility of SLE. Promoter reporter construct carrying the -276 C allele displayed significantly higher promoter activity than that with the -276 A allele (p<0.001) CONCLUSIONS: These data suggest that genetic polymorphisms within IL-6 gene may be associated with disease susceptibility and phenotype of SLE in Koreans. Specially -276 A>C polymorphism within IL-6 promoter region may involve in regulation of IL-6 expression.

Author dc:creator

• 전, 자영

Contributors dc:contributor

• 서, 창희
• 대학원 의학과
• 106874

• 전신성 홍반성 루푸스
• interleukin-6 유전자
• 단일염기다형성
• Systemic lupus erythematosus
• single nucleotide polymorphism
• variablenumberoftandem repeat

Language dc:language

ko

Identifier

http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000005853
000000005853

OAI identifier oai:identifier

oai:repository.ajou.ac.kr:201003/1843