1. Figure 3 Example of how a noncoding regulatory rheumatoid
arthritis-associated single nucleotide polymorphism might result in a rheumatoid arthritis phenotype
Figure 3 | Example of how a noncoding regulatory rheumatoid arthritis-associated single nucleotide polymorphism might result in a rheumatoid arthritis phenotype. The hypothetical noncoding single nucleotide polymorphism (SNP) with risk allele A and non-risk allele G lies near the peak summit of the open chromatin marks in a non-MHC region (for example, H3K4me3 histone peaks or DNase-hypersensitive sites) in some disease-relevant cell types (such as stimulated CD4+ T cells) and, unexpectedly, in a cell type unrelated to rheumatoid arthritis (such as hepatocytes). Transcriptional factors in these cell types bind to the variation region in an allele-specific manner, resulting in allele-specific expression. On the other hand, no allele-specific effects are seen in other cell types, such as neurons or pancreatic islet β cells, because of the closed chromatin structure and/or absence of transcription factors. Altered gene expression in relevant tissues causes the rheumatoid arthritis (RA)-risk effect that contributes to intermediate phenotypes associated with RA, and eventually increases RA risk. Allele-specific expression in irrelevant tissues could be connected with non-RA phenotypes (for example, pleiotropic effects of the UBE2L3 SNP rs (r2 = 0.78 in Europeans and r2 = 0.94 in Asians with the RA-associated SNP rs ) associated with allele-specific expression of UBE2L3 in blood52 and liver97, and with cholesterol level97). ACPA, anti-citrullinated protein autoantibody; RF, rheumatoid factor.
Kim, K. et al. (2016) Update on the genetic architecture of rheumatoid arthritis
Nat. Rev. Rheumatol. doi: /nrrheum