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Page 220 Bergara-Muguruza et al. J Transl Genet Genom 2023;7:213-229 https://dx.doi.org/10.20517/jtgg.2023.14

[13]
In the particular case of rs917997 SNP, the risk allele T disrupts the secondary structure of lnc13 and
reduces the binding to hnRNDP and chromatin, leading to an increased expression of CeD-related
[61]
proinflammatory genes . This work functionally described how the associated SNP enhances the
predisposition to develop CeD.

Moreover, this polymorphism has also been associated with several autoimmune diseases, including
[62]
[63]
inflammatory bowel disease , rheumatoid arthritis , and T1D . This suggests that the function of the
[64]
lncRNA may differ depending on the cell type and the impact of this SNP may vary across different
diseases .
[13]
Type 1 diabetes
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the destruction of insulin-
producing pancreatic β-cells by the immune system. The initial stages of the disease involve the infiltration
of immune cells into pancreatic islets, resulting in the generation of a proinflammatory microenvironment
that facilitates the destruction of β-cells . The reciprocal interaction between β-cells and the infiltrating
[65]
immune cells induces the production of proinflammatory chemokines and cytokines, resulting in increased
[66]
inflammation of the pancreatic islets . Multiple studies have implicated lncRNAs in the regulation of
innate antiviral immune responses, chemokines associated with innate immunity and other inflammatory
[67]
genes ; hence, it is plausible that lncRNAs are also involved in T1D pathogenesis.
[68]
Indeed, while the T allele of rs917997 SNP in the above-mentioned lnc13 is the risk allele for CeD, the C
allele is associated with an increased risk in T1D . The study of this lncRNA in the context of T1D showed
[69]
a totally different function in pancreatic β-cells. In particular, lnc13 was described to be a key participant in
the activation of the proinflammatory STAT1 pathway. Upon viral infection, which is considered a potential
[70]
environmental trigger in T1D , nuclear export of lnc13 occurs. Within the cytoplasm, this lncRNA
stabilizes the STAT1 mRNA molecule by facilitating the binding of PCBP2 protein to the 3′-untranslated
region of STAT1. This stabilization results in an activation of the STAT1 proinflammatory pathway, thereby
increasing a proinflammatory environment and consequent β-cell destruction. This critical regulatory role
of lnc13 in T1D-associated dysfunction and death of the pancreatic β-cells highlights its involvement in the
disease pathogenesis . Notably, pancreatic islets carrying the T1D risk genotype of rs917997 exhibit
[69]
increased STAT1 expression levels compared to the protective genotype. It has been proposed that the
secondary structure disruption by the risk allele promotes the formation of the lnc13, PCBP2 and STAT1
mRNA complex .
[69]

Another example of a T1D-related SNP in a lncRNA that influences disease pathogenesis is illustrated by
the SNP rs9585056 located in an exonic region of the lncRNA ARGI (Antiviral Response Gene Inducer).
This lncRNA is highly expressed in the nuclei of pancreatic β cells after viral infections and is able to bind
the transcription factor CCCTC-binding factor (CTCF) to interact with promoter and enhancer regions of
[71]
the interferon beta (IFNβ) and some interferon-stimulated genes (ISGs), promoting their expression . The
risk allele of this SNP (G) has been predicted to provoke changes in the secondary structure of ARGI,
inducing a hyperactivation of the type I IFN response in pancreatic β cells, a common characteristic in
pancreatic tissue of T1D patients .
[71]

The identification of the mentioned SNPs in lncRNAs and their mechanistic association with T1D
represents significant advances in understanding the processes in disease development, providing valuable
insights into T1D pathogenesis, and suggesting potential therapeutic targets for future approaches.