Background/Purpose: A major finding of the GWAS era of common disease gene-mapping has been that observed associations more often involve intergenic locations than protein-coding regions.  Whilst there has been substantial interest in the potential role of ncRNA in heritable diseases, as yet to our knowledge in no common disease has a polymorphism in a ncRNA been demonstrated to cause disease, and very few examples exist in monogenic diseases. Of the 43 independent genetic associations that have been reported for ankylosing spondylitis, most occur in intergenic, intronic or other untranslated regions of the genome. Two in particular, at chromosomes 2p15 and 21q22, occur in intergenic regions with no annotated transcription.

Methods: We have used a new technique known as CaptureSeq, which utilises RNAseq on samples enriched for transcripts from a genomic region of interest allowing the detection of transcripts expressed at too low levels for detection by conventional RNAseq. Using this technique, we undertook ultra-deep transcriptional profiling in peripheral blood mononuclear cells from 5 cases carrying the protective allele and 5 carrying the susceptibility allele at the 21q22 locus.

Results: We identified two completely novel divergently transcribed long non-coding RNAs (lncRNA) expressed from this region, which were upregulated in AS cases compared with healthy controls, as well as those subjects carrying the susceptibility allele. This overexpression in PBMCs was confirmed in two independent data sets, using both RNAseq and qPCR.

To further elucidate the potential function of this novel transcript we mined the FANTOM5 Atlas of human gene expression which showed expression of the 21q22 transcripts almost exclusively in CD14+ monocytes. We confirmed this in purified CD14+ cells from our PBMC samples with no expression seen in any other cell type. Expression was also significantly enhanced by stimulation of the monocytes with microbial components.

Conclusion: This is the first example of a role for a lncRNA in AS, and one of the first in any human disease where a polymorphism influences disease by effects on an ncRNA.  Our findings strongly support a role for monocytes in AS aetiology possibly through responses to microbes. Monocyte antigen presentation has previously been implicated in AS and is strengthened by the identification of the HLA-B27-ERAP1 genetic interaction. Aberrant microbial-induced CD14+ monocyte expression of the 21q22 transcript presents a novel potential mechanism by which AS might be influenced by microbes.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-novel-monocyte-specific-transcript-underlies-the-chromosome-21q22-intergenic-genetic-association-in-ankylosing-spondylitis/