Tissue specific genetic regulation of Interleukin 6

Abstract

Interleukin 6 (IL6) is associated with arterial disease development, progression and surgical outcome. Raised levels of IL6 may play a causal role in disease development or may be the effect of pathology. An IL6 single nucleotide polymorphism (SNP) G- 174C has been identified and reported to associate with IL6 expression. However, conflicting results have emerged and both the relationship between IL6 and vascular disease and the precise effect of SNP G-174C in vivo in humans remains obscure.
The aim of this study was to establish the effect of SNP G-174C in humans, in vivo in different tissues. Varicose vein surgery patients donated adipose tissue, skeletal muscle, vein and blood samples. Patients were genotyped for SNP G-174C. A new pre-mRNA assay was developed, using gel electrophoresis, restriction digest and fluorescence quantification, to measure the ratio of heterozygous allelic pre-mRNA transcription. IL6 mRNA expression in different tissues was also measured using relative real time PCR (RT-PCR) to assess effect of tissue type on expression profiles. mRNA expression within tissues was compared between G-174C genotypes, to further quantifying the association of SNP G-174C with transcript levels.
The pre-mRNA assay showed higher expression for the C-allele, though not statistically significant. The pre-mRNA assay needed to detect low levels of intron retaining allelic pre-mRNA isoforms. Replicates and controls for residual genomic DNA were used to monitor assay precision. Adipose tissue gave the greatest precision in the pre-mRNA assay. In the RT PCR assay adipose tissue expressed significantly more IL6 mRNA than all other tissues examined. In vein and leukocytes subjects with the CC genotype expressed significantly higher levels of IL6 mRNA than subjects with GC or GG genotypes. There was a trend towards higher expression for the CC genotype in all tissue types. A significant though weak correlation between IL6 mRNA expression and age was demonstrated for vein and leukocytes.
Adipose tissue may be an important source of IL6 compared to other tissues. This may be relevant for obesity associated diseases. Subjects with G-174C genotype CC showed a trend towards higher IL6 RNA expression. Further studies are necessary to clarify the effect of genotype on IL6 expression.

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