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Bergara-Muguruza et al. J Transl Genet Genom 2023;7:213-229 https://dx.doi.org/10.20517/jtgg.2023.14 Page 219

[49]
inhibition results in a failure of remyelination and the progression of the disease . The underlying
mechanisms by which GAS5 inhibits the polarization of M2 microglia have not been elucidated yet, but the
authors suggest that during the course of MS, mTOR is activated in T-cells, and given that GAS5 is
[50]
regulated by this signaling pathway , lncRNA expression is increased under these conditions. Another
suggested mechanism involves GAS5 exerting a negative effect on neuronal survival by interacting with
[51]
miR-137, a critical regulator involved in various aspects of brain function . GAS5 competes endogenously
with this miRNA and inactivates its function, resulting in the release of its target Notch1. The modulation of
[52]
this signaling pathway has been reported to decrease neuronal survival .
Moreover, rs2067079 SNP is located within a region that functions as either an active promoter or enhancer
and displays a prominent characteristic of expression quantitative trait locus (e-QTL) in multiple tissues,
[53]
suggesting its potential influence on the expression levels of numerous target genes . Furthermore, this
[53]
SNP affects GAS5 secondary structure and stability, potentially affecting its function .
Interestingly, another investigation reported elevated levels of circulating GAS5 in Egyptian MS patients’
sera ; hence, serum exosomal GAS5 has been proposed as a potential novel biomarker for MS, showing a
[54]
correlation with EDSS (expanded disability status scale) scores in most of their patients, indicating its
involvement in disease severity .
[54]

While significant efforts are currently underway within this field, further investigations are required to gain
a comprehensive understanding of the mechanism by which GAS5 is implicated in the development of this
disease and the influence exerted by the SNP rs2067079 on its function. Nevertheless, the presence of this
lncRNA in non-invasive samples, such as serum, and the fact that it promotes disease progression indicate
its potential not only as a biomarker but also as a therapeutic target.

Celiac disease
Celiac disease (CeD) is a chronic immune-mediated disorder characterized by an inappropriate immune
response in genetically susceptible individuals due to the consumption of gluten proteins from wheat,
barley, and rye. The small intestine is the primary organ affected by this disease . The major genetic factor
[55]
involved in CeD development is the Major Histocompatibility Complex (MHC) region, which accounts for
approximately 40% of the genetic risk associated with the disease . In addition, through various GWAS
[56]
and Immunochip projects, 39 non-HLA loci have been identified as associated with the genetic risk of CeD.
However, only 3 of the CeD-associated SNPs are linked to protein-altering variants located in exonic
[57]
regions , making it difficult to elucidate the role of the associated variants. Within the last years, some
lncRNAs have been implicated in CeD pathogenesis [58,59] . However, the precise contribution of these
lncRNAs to the disease development remains poorly understood.

Several association studies have linked lncRNAs and CeD risk, for example, the intronic SNP rs6962966
located in MAGI2 and the SNP rs3130838 in HCG14 , among others. However, there is only one
[59]
[60]
functionally described lncRNA named lnc13, which harbors the CeD-associated SNP rs917997. This
lncRNA has been observed to be downregulated in small intestinal biopsy samples from CeD patients
compared to healthy controls . In basal conditions, lnc13 interacts with the nuclear RNA binding protein
[61]
hnRNPD (Heterogeneous Nuclear Ribonucleoprotein D) and HDAC1 (Histone Deacetylase 1)
transcriptional repressor , repressing the expression of some inflammatory genes, including STAT1,
[61]
IL1RA, TRAF2 and MYD88, described to be altered in CeD. Upon exposure to inflammatory stimuli, lnc13
undergoes degradation, leading to the activation of these proinflammatory genes .
[61]