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Abstract Number: 2102

A Tissue-Specific Lincrna in the TRAF1-C5 Risk Locus As a Putative Cis-Regulator, Bridging Genetics and Disease

Tobias Messemaker1, Rute Marques1, Tom Huizinga1, Alwin Adriaans1, Aleida Bakker1, Arend Berendsen1, Nina Daha2, R E M Toes1, Harald Mikkers3 and Fina Kurreeman1, 1Rheumatology, Leiden University Medical Center, Leiden, Netherlands, 2Leiden University Medical Center, Leiden, Netherlands, 3Molecular Cell Biology, Leiden University Medical Center, Leiden, Netherlands

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Genetics and rheumatoid arthritis (RA)

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Session Information

Session Title: Genetics, Genomics and Proteomics

Session Type: Abstract Submissions (ACR)

Background/Purpose

In the last decade genome wide association studies (GWAS) have identified genetic polymorphisms that associate with Rheumatoid arthritis (RA). However, the way these genetic regions contribute to disease remains ill defined. We previously identified the TRAF1-C5 locus as a predisposing risk factor to the development of RA. In the present study we investigated functional consequences of this risk locus.

Methods

We finemapped likely causal variants by querying Eqtl datasets and identified a strong signal between TRAF1 and C5. We measured by RT-PCR the intergenic region in different tissue panels. We performed knockdown of the intergenic region using shRNA.

Results

Using expression quantitative trait loci (eQTL) datasets, we observed an association between the risk allele and expression of TRAF1 and C5 at the mRNA level in various blood-related cell types. As part of an underlying mechanism we identified a novel large non-coding RNA intergenic of TRAF1 and C5 (C5T1-lincRNA). The lincRNA is transcribed in the same orientation as TRAF1 and C5 by RNA polymerase II, is highly transcribed in liver, and its expression is rapidly induced in different immune cells by specific immune stimuli. Expression of C5T1-lincRNA correlated with either C5 or TRAF1 expression in a tissue specific manner. In addition, knockdown of the intergenic transcript in a hepatocyte cell line resulted in decreased C5 levels.

Conclusion

Together our data support the involvement of a novel lincRNA in regulating C5 and TRAF1 expression. We propose that this lincRNA, which is fully located within the associated region, is responsible for the RA associated altered RNA levels of TRAF1 and C5 and plays a role in RA susceptibility.


Disclosure:

T. Messemaker,
None;

R. Marques,
None;

T. Huizinga,
None;

A. Adriaans,
None;

A. Bakker,
None;

A. Berendsen,
None;

N. Daha,
None;

R. E. M. Toes,
None;

H. Mikkers,
None;

F. Kurreeman,
None.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-tissue-specific-lincrna-in-the-traf1-c5-risk-locus-as-a-putative-cis-regulator-bridging-genetics-and-disease/

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