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Page 222 Bergara-Muguruza et al. J Transl Genet Genom 2023;7:213-229 https://dx.doi.org/10.20517/jtgg.2023.14

described, the contribution of the GWAS-identified SNPs that are thought to confer disease predisposition
[14]
in the pathogenesis process is unclear and more studies are required.
Some other studies have identified SNPs within the atherosclerosis-related lncRNA antisense non-coding
RNA in the INK4 locus (ANRIL). ANRIL is located in the gene cluster of the CDKN2A/B gene, close to the
CAD risk region, and that is why ANRIL is known to play an important role in regulating this locus .
[84]
Mechanistically, ANRIL recruits polycomb group proteins that epigenetically modify chromatin,
consequently inhibiting gene expression in cis. Moreover, ANRIL can also have trans-regulation functions
[84]
by binding Alu elements, E2F transcription factor 1, or CTCF, among others . It has been identified that
the simultaneous presence of the T allele of the rs10811656 SNP and the G allele of rs10757278 increases
ANRIL expression and disrupts its binding site with STAT1. In addition, carrying the risk allele for the SNPs
[85]
rs10757274, rs2383206, rs2383207, rs10757278 is linked to more severe atherosclerotic plaques . Another
study demonstrated that carrying the A allele for the SNP rs7865618 is strongly associated with a higher
[86]
expression of a certain transcript of ANRIL . Altogether, it has been seen that the expression of diverse
ANRIL transcripts can be influenced by the SNP genotype, affecting both cis- and trans-gene regulation .
[86]
In summary, the multiple involvement of lncRNAs in the molecular mechanisms of atherosclerosis
pathogenesis emphasizes their promising role as novel targets for potential therapeutic strategies.

Inflammatory bowel disease
Inflammatory Bowel Disease (IBD) comprises a group of disorders characterized by chronic inflammation
of the gastrointestinal tract. Typically, it has been classified into two subgroups: Chron’s disease (CD),
which causes inflammation through the entire gastrointestinal tract, and ulcerative colitis (UC), which
exclusively affects the mucosal layer of the colon . The causes of IBD remain unclear, but it has been
[87]
suggested that it may result from an inappropriate inflammatory response to intestinal microorganisms and
foreign antigens in genetically susceptible individuals . Several interleukins and cytokines have been
[88]
reported to mediate the inflammatory process that takes place in this disorder, including interferon-gamma
(IFN-γ). IFN-γ is mainly synthesized by T- and NK-cells and is involved in Th1 responses and bacterial
[14]
defense .

Of interest, there is an intronic SNP (rs7134599) in the genomic sequence of the lncRNA interferon gamma
antisense 1 (IFNG-AS1), and several GWAS studies have observed a correlation between this SNP and IBD
susceptibility [14,87,88] . IFNG-AS1 overlaps with the locus of IFN-γ and is highly expressed in CD4 and CD8 T
cells, B cells, and NK cells in the colon. Indeed, it has been demonstrated to be elevated in UC patients, even
[87]
higher in active UC compared to non-inflamed ones . This lncRNA was demonstrated to promote the
[87,89] [90]
expression of IFN-γ in cis . A mechanism that has been suggested to explain this regulation is that
IFNG-AS may bind to the MLL/SET1 histone methylation complex and enhance transcription activating
[87,91]
methylation on the histones surrounding the gene of IFN-γ .
[87]
However, it is unclear how rs7134599 genetically predisposes to IBD , nor how it alters the function of
IFNG-AS1 to promote pathogenesis, as there are many association studies but not enough functional studies
to clarify the current mechanistic gaps of the SNP implication. One of the strongest hypotheses is that the
SNP could regulate the splicing of the lncRNA, which may contribute to its high levels observed in IBD
patients . In this way, the expression of IFN-γ would be enhanced, creating the characteristic inflammatory
[87]
environment of this condition. Nevertheless, further studies are of special necessity to establish a
mechanistic link between the SNP and the lncRNA functionality, as well as the involvement in the
pathogenesis.