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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 221

Psoriasis
Psoriasis is an autoimmune disease in which the interaction between numerous environmental and
[72]
genetic factors favors the inflammation of skin cells [73,74] . Interestingly, alterations in lncRNA expression
have been identified in psoriatic patients, increasing the interest in elucidating their potential role in
[74]
psoriasis pathogenesis .
In this sense, HOTAIR harbors several psoriasis-associated SNPs that can alter the expression or function of
this lncRNA. Several studies have described an association between the SNP rs12826786 and the risk of
developing psoriasis in independent cohorts [75,76] . This lncRNA participates in nuclear factor-kappa B
(NF-κB) activation by facilitating the degradation of IκBα inhibitor, resulting in the induction of several of
NF-κB downstream genes, including IL-6 and inducible nitric oxide synthases (iNOS) . Interestingly,
[77]
NF-κB is increased in psoriatic skin, showing an implication of this pathway in the pathogenesis of
[78]
psoriasis . Furthermore, HOTAIR silencing leads to reduced transcription of NF-κB target genes by
repressing the binding of NF-κB to target promoter regions. In addition, reduction of HOTAIR in
[77]
macrophages suppresses the induction of diverse NF-κB-related genes .

Specifically, the T allele in psoriasis-associated SNP causes increased HOTAIR expression and a higher risk
of developing the disease . Collectively, association studies point that upregulated HOTAIR expression in
[79]
the presence of rs12826786 risk allele could induce the cytokines and chemokines involved in psoriasis
development, explaining the association of this SNP with psoriasis. Nevertheless, a deeper functional study
of the effect of the SNP genotype in HOTAIR-dependent proinflammatory response in psoriasis is still
needed to achieve a more complete understanding of the pathogenesis process.

Atherosclerosis
Atherosclerosis is a chronic vascular inflammatory disorder. It is not considered a disease directly caused by
the immune system, but it has a major immune component in all disease stages. For example, the
infiltration of leukocytes and the secretion of proinflammatory cytokines by immune cells are among the
primary events in early pathogenesis .
[80]

There is an intronic SNP (rs2850711) in the lncRNA LINC00305 that shows an association with
atherosclerosis [14,80] . LINC00305 has been demonstrated to have an increased expression in atherosclerotic
plaques in comparison to normal arteries. Additionally, these lncRNA levels were higher in monocytes than
in endothelial or smooth muscle cells [14,80] . In monocytes, it is in charge of promoting the expression of
inflammatory genes . Mechanistic functional analyses have demonstrated that LINC00305 modulates
[80]
NF-κB by targeting lipocalin-1 interacting membrane receptor (LIMR) and aryl-hydrocarbon receptor
repressor (AHRR). As a result, it is able to enhance monocyte inflammation and phenotypic switch of aortic
muscle cells, which are signatures of atherosclerosis . The exact mechanisms that underlie the association
[80]
between the SNP and the lncRNA in the context of the disease have not been described in detail, but it is
known that the risk allele of this SNP increases the expression of the lncRNA [14,80] . As LINC00305 function
consists of increasing inflammation, a higher inflammation is expected in patients with atherosclerosis in
the presence of the risk allele.

Several SNPs within the genomic locus of the lncRNA H19 have also been linked to some cardiovascular-
[14]
related conditions ; for example, rs217727 has been associated with an increased risk of coronary artery
disease (CAD) . H19 has been identified within adult human atherosclerotic plaques, which suggests its
[81]
implication in this disease . Regarding its mechanism of action, it is a cytoplasmatic sponge for the miRNA
[82]
family let-7 . Interestingly, impaired function of let-7 miRNAs has been linked to cardiovascular
[34]
diseases . Even if the implication of lncRNA H19 in different cardiovascular diseases has been widely
[83]