Identification of cis-regulatory variations in the IL6R gene through the inheritance assessment of allelic transcription.

BACKGROUND: The level of circulating interleukin-6 receptor in human blood varies depending on the genetic and/or physiological causes, and has been implicated in the development of chronic inflammatory diseases.

METHOD: The cis-regulatory effects of genetic variations on the transcription of interleukin-6 receptor gene, IL6R, were studied by assessing allelic transcriptions in the immortalized lymphocytes derived from unrelated and familial samples.

RESULTS: The assays for allelic transcription in the cells from unrelated subjects demonstrated an extensive and variable range of allelic transcriptional imbalances, suggesting an operation of multiple cis-regulations with varying degrees on the locus. Analysis of the familial samples illustrated the Mendelian inheritance of allelic transcriptions, enabling us to assign each haplotype allele into one of the 3 transcriptional strengths. A comparison of the allele structures based on the transcriptional attributes highlighted 2 SNP variations, rs952146 and rs4845617, as being associated with higher allelic transcription. Consistently, lymphocytes that were homozygous for the 2 SNPs exhibited differences in their transcript levels depending on the haplotypes.

CONCLUSION: Inheritance assessment of allelic transcription of IL6R identified 2 SNPs that are associated with transcriptional variation in cis.

GENERAL SIGNIFICANCE: Our results not only demonstrate genetic variations that are associated with IL6R transcription in cis but also demonstrate an effective genetic approach for isolating cis-regulatory variations.