Cis-Acting Polymorphisms Affect Complex Traits through Modifications of MicroRNA Regulation Pathways
Figure 4
Impact model of mutated SMC4 in primary biliary cirrhosis.
Inflammation follows the autoimmune response leading to the activation of the MAPK-pathway via signal molecules as e.g. TNF-alpha. Transcription factors activated as downstream effect of MAPK activation lead to over-expression of DNA repair genes. The in PBC over-expressed hsa-mir-299-5p is hypothesized to target SMC4 at the seed complementary region where rs10923 is located. With the major allele, SMC4 is silenced, whereas the mutated SMC4-G cannot be bound by hsa-mir-299-5p and therefore is translated without interference. This results in the more frequent association of the Condensin I-PARP1-XRCC1 complex contributing to disturbed DNA repair in cirrhosis tissue.