Target Analysis of Human IL6R

Human IL6R

IL6 is a pleiotropic cytokine involved in a plethora of biological functions. IL6 acts via its receptor IL6R, which is a membrane bound receptor that complexes with its ligand and initiates intracellular signaling. IL6R also exists as a soluble receptor (sIL6R) generated either by proteolytic cleavage or alternative splicing. Unlike several other soluble receptors that are antagonists, sIL6R behave agonistically. On target cells, IL6 first binds to IL6R. The complex of IL6/IL6R associates with the signal transducing subunit gp130 promoting its dimerization and the subsequent initiation of intracellular signaling called ‘classical signaling’. Since membrane bound IL6R are mainly expressed in hepatocytes, neutrophils, monocytes/macrophages and some lymphocytes, naturally occurring soluble form of the IL-6R plays a critical role in signaling in other cell types via ‘trans signaling’. It has been shown that the sIL-6R strongly sensitizes target cells. Embryonic stem cells, early hematopoietic progenitor cells, T cells, neural cells, smooth muscle cells, mesothelial cells endothelial cells and keratinocytes are responsive to IL-6 only in the presence of sIL-6R.

Circulating levels of IL6R is considered to be a prognostic markers in a variety of inflammatory and autoimmune disorders like Rheumatoid arthritis, Asthma, Crohn’s disease as well as in microbial and viral Infections. It is also considered to be a favorable biomarker for risk assessment of various cancers. A single nucleotide polymorphism in IL6R located in the proteolytic cleavage site of IL6R has been studied in association with several neoplastic as well as non-neoplastic diseases. It is therefore proposed that targeting of sIL6R rather than IL6 could be a logical therapeutic treatment in various diseases employing IL6 signaling since IL6 itself is involved in several normal physiological processes.

One of the promising treatments for rheumatoid arthritis is the drug Tocilizumab which is a monoclonal antibody targeting IL6R. This drug is found to be beneficial even in patients not responding to classical RA therapies using methotrexate and anti-TNFalpha treatment. Studies done in model organisms for various diseases also suggest that blockade of Il6R could be a meaningful approach in treating diseases where Il6 signaling is upregulated. This makes anti-IL6R therapy a potent and promising therapeutic strategy.

In this report, we analyze the IL6 gene with respect to its pharmacogenetic properties. The areas of focus include:

• Gene summary
• Orthologs and paralogs
• Alternate transcription
• Expression
• SNP analysis
• Other genetic alterations
• Promoter analysis
• Protein domains
• Disease

Table of Contents

1. Gene Summary - 4

2. Orthologs of IL6R - 6
 
3. Alternate transcription in IL6R - 12
  3A. Alternate transcription in humans - 12
  3B. Alternate transcripts of IL6R in rodents - 19

4. IL6R expression in normal tissues - 19
  4A. Human IL6R expression - 19
  4B. Mouse Il6R expression - 23

5. SNPs in IL6R - 24
  5A. IL6R SNPs in humans - 24
    Coding SNPs in IL6R - 25
    Minor allele frequency (MAF) of IL6R SNPs - 28
    IL6R SNPs that have been studied for disease association - 33
  Non-coding SNPs described in literature - 24
  5B. IL6R SNPs in mouse - 24

6. Other genetic alterations of the IL6R gene - 37
  6A.Mutations - 37
  6B.Methylation and acetylation - 39
  6C.Chromosomal aberrations - 39
  6D.miRNA targets in the IL6R gene - 39

7. Promoter - 39

8. Paralogs - 43

9. Protein family and domain - 44

10. IL6R expression in Disease - 51
  10A. IL6R expression in neoplastic disease - 54
  10B. IL6R expression in non-neoplastic diseases - 61

References - 74

Executive Summaries and Sample Pages |  Sample Appendix