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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 223

Rheumatoid arthritis
Rheumatoid arthritis (RA) is a chronic and systemic autoimmune disease characterized by erosive and
[92]
polyarthritis as the main clinical manifestations . The presence or absence of autoantibodies like anti-
cyclic citrullinated peptide (CCP) and rheumatoid factor (RF) have been suggested to be adequate to classify
[93]
different RA subtypes . Due to its complex pathogenesis and subtle clinical features, early diagnosis of RA
is challenging to achieve. Hence, there is still a need for early diagnosis, selection of appropriate therapeutic
agents, and implementation of effective clinical management strategies .
[94]
There are various studies describing RA-associated SNPs within lncRNA genes, speculating that they act as
genetic regulators in the development of RA. More specifically, the association between several SNPs
located within the lncRNA FAM211A-AS1 and RF-positive RA has been described in a Chinese
population . In silico analyses have suggested that these polymorphisms are localized in regulatory
[95]
elements (promoters, enhancers…). Hence, these SNPs could alter the binding of the transcription factors
to these regions, potentially altering the expression of FAM211A-AS1 lncRNA and nearby genes . Indeed,
[95]
these SNPs were identified to be eQTLs for FAM211A-AS1 and its nearby genes .
[95]
Within the last years, many different lncRNAs, including MALAT1 , UCA1 (urothelial carcinoma
[96]
associated 1) , ENST00000456270 , and the above-mentioned FAM211A-AS1 , have emerged as
[99]
[98]
[97]
potential players in the pathogenesis of RA, as they have been found to be dysregulated in RA patients .
[95]
However, to date, no studies have reported mechanistic evidence between SNPs located within these
lncRNAs and the genetic predisposition to RA. Hence, further functional studies are required to progress
from association and bioinformatic analyses to the clarification of the precise molecular mechanisms altered
by these SNPs in the context of RA pathogenesis.

Systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is an immune-related disorder characterized by aberrant immune
responses that lead to a loss of self-antigen tolerance and excessive production of autoantibodies. SLE
primarily affects females of reproductive age and nearly 50% of SLE patients experience life-threatening
[100]
complications . Although an imbalance of CD4+ T cells is known to be implicated in the pathogenesis of
SLE , the exact underlying mechanisms remain unclear as the pathogenesis of SLE involves a complex
[100]
interplay of genetic, environmental, and hormonal factors.

Dysregulation of some lncRNAs has been reported in SLE patients . In particular, IL21 antisense RNA 1
[101]
(IL21-AS1) levels are decreased and positively correlated with IL-2 gene expression in these patients.
Moreover, IL21-AS1 expression is positively correlated with the proportion of activated T follicular
[102]
regulatory (Tfr) cells in SLE patients . Interestingly, defective IL-2 production has been observed in SLE
patients, resulting in reduced Tfr cell numbers . Additionally, IL21-AS1 expression is also negatively
[103]
correlated with disease activity in SLE, suggesting that a reduced expression of this lncRNA may contribute
to SLE development .
[102]
In the context of SLE, around 90% of the associated polymorphisms are located in non-coding regions,
too . Notably, a meta-analysis study has identified the SNP rs62324212, situated in the enhancer region of
[104]
IL21-AS1 , and suggests a potential association between the risk allele of rs62324212 (A) and SLE
[102]
susceptibility . However, the relationship among rs62324212, IL21-AS1, and SLE remains poorly
[102]
understood. Consequently, more functional studies would shed light on deciphering how the presence of a
SNP within the sequence of a lncRNA affects its functionality and how this contributes to the pathogenesis
of the disorder.