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Study Uncovers Ties between Atherosclerosis Risk SNPs and Circular Non-Coding RNA Levels

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – The levels of certain circular, non-coding RNAs may have unappreciated ties to human disease risk, according to a paper appearing online last night in PLoS Genetics.

A University of North Carolina at Chapel Hill research team investigating a long non-coding RNA known as "Antisense Non-coding RNA in the INK4 Locus" (ANRIL) garnered evidence suggesting ANRIL — which is found in a chromosome 9 SNP locus previously implicated in atherosclerotic vascular disease risk — occurs in both linear and circular forms.

Because their results suggest some atherosclerosis risk SNPs can influence both ANRIL splicing and the expression of other nearby genes, the researchers explained, they believe these risk SNPs may throw off the balance between linear and circular forms of ANRIL, leading to changes in the levels of proteins influencing processes such as cellular proliferation.

"[I]t is the first time that one of these odd circular RNAs has been linked to an actual human disease," senior author Ned Sharpless, associate director of the UNC's Lineberger Comprehensive Cancer Center, said in a statement. "We showed this correlates with risk of heart attack and stroke, but believe this finding has significance for several other common diseases associated with human aging," he added.

Although several SNPs in the 9p21.3 locus on chromosome 9 have been linked to atherosclerosis in past studies, he and his co-authors explained, functional explanations for these associations have been elusive.

To explore this in more detail, the researchers focused in on ANRIL, a ncRNA that's found in the region and thought to exist in multiple isoforms.

Using a combination of RNA ligase mediated 3' and 5' rapid amplification of cDNA ends, PCR, and RNA-sequencing, the team looked at the sorts of ANRIL isoforms that were found in normal and cancerous cell lines and primary human peripheral blood T-lymphocytes.

They then incorporated these findings with RNA sequencing data from Genbank and ENCODE databases and with insights from their subsequent experiments, which included Taqman gene expression analyses of 106 primary human blood T-lymphocyte samples and targeted Roche 454 and Illumina Genome Analyzer II sequencing of the atherosclerosis risk region using pooled DNA from five Asian and European individuals.

Together, their findings indicate that some ANRIL isoforms curb the activity of tumor suppressors coded by genes in the INK4/ARF locus. On the other hand, they explained, ANRIL splicing also seems to produce circular forms of ANRIL that are less repressive, leading to higher levels of the cell division-regulating proteins.

The balance between these linear and circular forms of the RNA, in turn, appears to relate to the specific polymorphisms present in the atherosclerosis risk region.

"Next-generation DNA sequencing and splice prediction algorithms identified polymorphisms within the [atherosclerotic vascular disease] risk interval that may regulate ANRIL splicing and circular ANRIL (cANRIL) production," the researchers explained.

Moreover, individuals carrying SNPs expected to put them at elevated risk of atherosclerosis tended to have lower levels of circular isoforms, consistent with the notion that atherosclerosis risk SNPs influence ANRIL splicing and, consequently, levels of proteins coded by other genes in the region.

"We believe that people carrying the atherosclerosis-associated genetic variants splice the long RNAs less efficiently and make fewer circular RNAs," first author Christin Burd, a post-doctoral researcher in Sharpless' UNC lab, said in a statement. "As a result, they also have lower levels of the INK4/ARF gene products," he added, "which usually limit abnormal proliferation of the cells that form atherosclerotic plaques."

Still, the researchers emphasized, more research is needed to understand this process — and to determine whether variants affecting ANRIL splicing play a role in other diseases that have been linked to SNPs in the same chromosome 9 locus.

"We believe this work has implications beyond [atherosclerotic vascular disease]," the team concluded, "as altered ANRIL splicing could influence INK4/ARF expression, explaining the association of other nearby 9p21 SNPs with a variety of non-[atherosclerotic vascular disease] phenotypes in humans, including longevity, type II diabetes, endometriosis and several tumor types."

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