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44 Bioinformatics of Autoimmune Diseases
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Genetic Markers
2
in Autoimmunity
2.1 MAJOR ALLELIC CHANGES INVOLVED IN AUTOIMMUNE DISEASES
In the previous chapter, we explored several autoimmune diseases and discussed key genetic factors
involved in their development and progression. In this chapter, we take a closer look at the specic
allelic and molecular markers that signicantly inuence the onset, diagnosis, and potential treatment of these autoimmune diseases. Genetic predisposition is central to autoimmune susceptibility,
and among all genetic contributors, the human leukocyte antigen (HLA) complex stands out as the
most consistently implicated region (Matzaraki etal., 2017).
Changes in immune-related alleles represent a critical mechanism by which immune tolerance
is disrupted, paving the way for autoimmunity. Among these, single nucleotide polymorphisms
(SNPs, small variations at a single base pair) have been extensively studied for their impact on gene
function and regulation. Nowhere is this more apparent than in the major histocompatibility complex (MHC), particularly HLA class II genes like HLA-DR and HLA-DQ. Polymorphisms in these
genes affect how antigens are presented to the immune system, inuencing both T-cell development
in the thymus and peripheral immune responses. Specic alleles such as HLA-DRB104:01 in rheumatoid arthritis (RA) and HLA-DQB102:01 in celiac disease increase the likelihood that autoreactive CD4+ T cells will evade central tolerance and trigger autoimmune inammation (Raychaudhuri,
2010; Trynka etal., 2011).
However, the inuence of genetic variation extends beyond point mutations. Structural genomic
variants, especially copy number variations (CNVs), also contribute signicantly to autoimmune
risk. For instance, deletions of complement component genes C4A and C4B impair the clearance
of immune complexes and apoptotic cells, promoting an inammatory milieu rich in dangerassociated molecular patterns (DAMPs). Conversely, duplications of FCGR3B, a gene involved
in neutrophil-mediated immune complex handling, may disturb immune regulation and further
heighten susceptibility.
Gene regulation is also affected by non-coding variants, including those in promoters and
enhancers. These changes can subtly alter gene expression, tipping the immune balance toward
autoimmunity. For example, TNFA promoter variants enhance transcription of tumor necrosis
factor-alpha (TNF-α), a key inammatory cytokine involved in diseases such as Crohn’s disease,
psoriasis, and RA (Karban etal., 2004). Similarly, polymorphisms affecting CTLA4 are associated
with reduced expression of CTLA-4, weakening regulatory checkpoints and allowing autoreactive
T cells to escape immune surveillance (Ueda etal., 2003).
Splicing variants offer another mechanism by which allelic changes inuence immune function. Polymorphisms in PTPRC (encoding CD45) alter the splicing of transcripts involved in T
and B cell receptor signaling, effectively lowering the activation threshold and increasing sensitivity to self-antigens. Likewise, altered splicing of FOXP3, the transcription factor required
for regulatory T-cell (Treg) development, can impair Treg function and compromise immune
tolerance.
Beyond the HLA region, several non-HLA genes harbor variants that impact autoimmune
risk through diverse molecular mechanisms. The PTPN22 R620W variant, for instance, modies
T-cell receptor signaling and promotes the survival of autoreactive T cells (Bottini et al., 2004).
Variants in IL2RA reduce expression of the IL-2 receptor alpha chain (CD25), undermining Treg
stability (a feature common to both type 1 diabetes (T1D) and multiple sclerosis (MS)). Similarly,
45 DO I: 10 .1201/9 7810 0 36 85432-2
46 Bioinformatics of Autoimmune Diseases
TABLE 2.1
HLA Genes Associated with Autoimmune Diseases
Gene Name Chromosome Location Gene Length (bp) Associated Variant Autoimmune Diseases
HLA-A 6p21.3 ~3500 HLA-A*01:01 Coeliac disease
HLA-B 6p21.3 ~2700 HLA-B*08:01 Myasthenia gravis
HLA-B27 6p21.3 ~2700 HLA-B*27:05 Ankylosing spondylitis, reactive
arthritis, acute anterior uveitis
HLA-B51 6p21.3 ~2700 HLA-B*51:01 Behçet’s disease
HLA-C 6p21.3 ~3000 HLA-C*07:01 Psoriasis
HLA-DRB1 6p21.3 ~5000 HLA-DRB1*03:01 Type 1 diabetes, systemic lupus
erythematosus, rheumatoid arthritis
HLA-DQA1 6p21.3 ~4000 HLA-DQA1*05:01 Coeliac disease
HLA-DQB1 6p21.3 ~6000 HLA-DQB1*02:01 Coeliac disease
polymorphisms in STAT4 contribute to aberrant Th1 and Th17 responses, while IRF5 variants
amplify innate immune signaling, both contributing to the chronic inammation seen in systemic
autoimmune diseases (Graham etal., 6).
These variants do not act in isolation. Epistatic interactions, where combinations of alleles across
different loci inuence disease risk, play a vital role. For example, the combination of HLA-DRB1
shared epitope alleles and variants in PADI4 dramatically increases the risk for anti-citrullinated
protein antibodies (ACPA)-positive RA (Suzuki etal., 2003). These complex multi-locus interac-
tions emphasize the polygenic nature of autoimmunity.
Epigenetic mechanisms further modulate gene expression. DNA methylation, histone modications, and chromatin remodeling can amplify or suppress the effects of genetic variants.
Hypomethylation of interferon-stimulated genes is a consistent feature in patients with systemic
lupus erythematosus (SLE), resulting in chronic overexpression of inammatory genes (Coit etal.,
2013). Variants in CD40 can also inuence chromatin accessibility and gene expression, linking
genetic susceptibility with transcriptional dysregulation.
Understanding these mechanisms has driven the development of targeted therapies. Drugs such
as abatacept (a CTLA-4-Ig fusion protein) and JAK inhibitors have shown success in restoring
immune balance by addressing specic molecular defects. Similarly, interferon-blocking agents
like anifrolumab are now used to treat SLE patients with hyperactive interferon signatures (Furie
etal., 2020).
In summary, the landscape of allelic and epigenetic variation in immune system genes reveals a
delicate balance in immune regulation. Disruption of this balance, even by subtle genetic changes,
can have profound pathological consequences. Tables 2.1 and 2.2 summarize the key genes associ-
ated with autoimmune diseases. The rst table lists HLA genes, while the second focuses on nonHLA genes. Each table includes the gene name, chromosomal location, gene length, associated
variant, and the corresponding autoimmune disorder.
2.2 MUTATION ASSOCIATED WITH AUTOIMMUNE DISEASES
Mutations associated with autoimmune diseases exhibit considerable diversity in both type and biological consequence, inuencing gene function, protein expression, and the regulation of immune
responses. A comprehensive discussion of mutation discovery, annotation, and functional analysis
is presented in Chapter 6. The following overview summarizes the principal types of genetic mutations identied in genes implicated in autoimmune pathogenesis:
47 Genetic Markers in Autoimmunity
TABLE 2.2
Non-HLA Genes Associated with Autoimmune Diseases
Gene Chromosome Gene
Name Location Length (bp) Associated Variant Autoimmune Diseases
PTPN22 1p13.2 ~58,000 R620W RA, T1D, SLE, Hashimoto’s thyroiditis, Graves’
disease, Addison’s disease, myasthenia gravis,
vitiligo, systemic sclerosis, juvenile arthritis,
psoriatic arthritis
AIRE 21q22.3 ~12,000 Various mutations Autoimmune polyendocrinopathy-candidiasis-
ectodermal dystrophy
FOXP3 Xp11.23 ~12,000 Various mutations Immune dysregulation, polyendocrinopathy,
enteropathy, X-linked syndrome (IPEX)
CTLA4 2q33.2 ~6200 Polymorphisms Type 1 diabetes, Graves’ disease
IL2RA 10p15.1 ~51,600 rs2104286 Multiple sclerosis, type 1 diabetes
STAT4 2q32.2–q32.3 ~123,000 rs7574865 Rheumatoid arthritis, systemic lupus
erythematosus
TNFAIP3 6q23.3 ~23,000 rs2230926 RA, SLE
NOD2 16q12.1 ~40,000 R702W, G908R, 1007fs Crohn’s disease
TYK2 19p13.2 ~33,000 rs34536443 Multiple sclerosis, SLE
IL23R 1p31.3 ~100,000 rs11209026 Psoriasis, ankylosing spondylitis
2.2.1 SINGLE NUCLEOTIDE POLYMORPHISMS
SNPs are the most prevalent form of genetic variation in the human genome. They involve a change
at a single nucleotide position (such as a substitution of adenine (A) with guanine (G)) and can occur
anywhere within the genome. While the majority of SNPs are benign and do not affect gene function, some have signicant biological consequences. These functional SNPs can inuence protein
structure, gene expression, or regulatory elements, and in doing so, they play a crucial role in disease susceptibility, particularly in autoimmune conditions.
In autoimmune diseases, SNPs contribute to disease risk by affecting genes involved in immune
regulation, inammation, and self-tolerance. These small genetic variations can disturb the delicate balance between immune activation and regulation, resulting in an inappropriate immune
responsedirected against the body’s own tissues. Notably, many disease-associated SNPs are found
in genes that govern cytokine signaling, immune cell function, and antigen presentation (Graham
etal., 2007).
One of the most widely studied SNPs is PTPN22 R620W (also known as C1858T, rs2476601),
located in the PTPN22 gene, which encodes the lymphoid tyrosine phosphatase (LYP). This enzyme
plays a central role in downregulating T-cell receptor signaling. The R620W variant causes an
amino acid substitution from arginine (R) to tryptophan (W), weakening the interaction between
LYP and the kinase Csk. As a result, T-cell regulation becomes impaired, and autoreactive T cells
are more likely to escape immune checkpoints, an effect that has been strongly linked to several
autoimmune diseases (Bottini etal., 2004; Rawlings etal., 2012).
Similarly, SNPs within the HLA region (particularly HLA-DRB1 and HLA-DQB1) are among
the most signicant genetic risk factors for autoimmunity. These genes encode proteins that are
essential for presenting antigens to T cells. Variants in these regions can alter the peptide-binding
preferences of HLA molecules, increasing the likelihood of presenting self-peptides in a proinammatory context, thereby triggering autoimmune responses. Associations between HLA class
II SNPs and diseases such as MS, T1D, and celiac disease are well established (Matzaraki etal.,
2017).
48 Bioinformatics of Autoimmune Diseases
FIGURE 2.1 PTPN22 R620W single nucleotide polymorphism.
Figure 2.1 illustrates the PTPN22 R620W polymorphism in which a cytosine (C) is replaced by
a thymine (T) at nucleotide position 1858 (from arginine (R) to tryptophan (W) at protein position
620), resulting in a codon change from CGG (arginine) to TGG (tryptophan). This single nucleotide
substitution leads to a missense mutation that disrupts normal LYP function. Specically, the variant impairs the binding between LYP and the Csk kinase, undermining inhibitory signals in Tcells
and promoting autoimmune reactivity. The gure highlights this molecular alteration and its downstream effects on immune regulation.
Another signicant single SNP linked to autoimmune disease is IL23R rs11209026, which has
been strongly associated with conditions such as psoriasis and ankylosing spondylitis. The IL23R
gene encodes the receptor for interleukin-23, a cytokine critical to the differentiation and maintenance of Th17 cells, a subset of pro-inammatory T helper cells. The rs11209026 variant alters
IL-23 receptor function, enhancing Th17-mediated inammatory responses and contributing to the
development and chronicity of autoimmune pathology (Duerr etal., 2006).
Beyond IL23R, SNPs in several cytokine genes have been linked to autoimmune susceptibility. For instance, variants in the TNF, IL-10, and IL2RA genes can alter cytokine production and
immune modulation. IL-10, in particular, encodes an anti-inammatory cytokine essential for
immune tolerance. Certain SNPs in IL-10 reduce its expression, leading to unrestrained inammation. This impaired anti-inammatory control has been implicated in diseases such as inammatory
bowel disease (IBD) and RA (Glocker etal., 2009; Sands etal., 2007).
SNPs also affect genes involved in intracellular signaling pathways. One prominent example is
STAT4, a transcription factor that modulates immune cell activation in response to cytokines. The
STAT4 rs7574865 polymorphism is associated with SLE and RA, largely due to its role in amplifying T-cell responses and promoting chronic inammation (Remmers etal., 2007). Another key gene
is TYK2, which encodes a tyrosine kinase involved in cytokine receptor signaling. TYK2 SNPs are
implicated in MS, lupus, and psoriasis, where they inuence the production of inammatory mediators such as interferons and interleukins (Dendrou etal., 2016).
Importantly, the pathogenic potential of SNPs often emerges in the context of environmental
triggers such as infections, diet, or stress. This gene–environment interaction is central to autoimmune disease development, as genetic predisposition alone is rarely sufcient to cause disease.
Instead, SNPs shape immune system sensitivity to external stimuli, modulating individual disease
risk (Zhernakova etal., 2009).
Understanding the functional consequences of autoimmune-related SNPs has profound implications for precision medicine. Identifying SNPs that inuence immune pathways can lead to improved
risk prediction, earlier diagnosis, and the development of targeted therapeutics. For instance, IL-23
inhibitors such as ustekinumab are used in the treatment of psoriasis, directly targeting pathways
49 Genetic Markers in Autoimmunity
TABLE 2.3
The List of SNPs that Highlight the Genetic Factors Contributing to Autoimmune Diseases
SNP (rsID) Gene Impact Associated Autoimmune Disease(s)
rs2104286 IL2RA Affects IL-2 receptor function, inuencing T-cell Multiple sclerosis, type 1 diabetes
regulation.
rs2248374 ERAP2 Alters antigen processing, affecting immune Crohn’s disease, ankylosing spondylitis,
response. psoriasis
rs12044852 CD58 Modulates cell adhesion and immune activation. Multiple sclerosis
rs1414273 CD58 Inuences microRNA processing, affecting CD58 Multiple sclerosis
expression.
rs17486481 ERAP2 Introduces premature stop codons, likely leading to Crohn’s disease, ankylosing spondylitis,
nonsense-mediated decay. psoriasis
rs1335532 CD58 Associated with decreased susceptibility to Multiple sclerosis
multiple sclerosis.
rs12722489 IL2RA Associated with susceptibility to multiple sclerosis. Multiple sclerosis
rs17486481 ERAP2 Associated with severe inammatory conditions. Crohn’s disease, ankylosing spondylitis,
psoriasis
rs16947 C2orf74 Associated with susceptibility to ankylosing Ankylosing spondylitis
spondylitis.
rs16947 C2orf74 Associated with susceptibility to Crohn’s disease. Crohn’s disease
rs16947 C2orf74 Associated with susceptibility to other autoimmune Autoimmune disorders
conditions.
dysregulated by IL23R polymorphisms. Likewise, TNF inhibitors are widely used in RA and
Crohn’s disease, supported by genetic insights into TNF pathway variants (Danese etal., 2015).
To standardize the tracking of these genetic variants, researchers rely on the dbSNP database,
maintained by the National Center for Biotechnology Information (NCBI). Each SNP is cataloged
with a unique reference SNP ID (rsID), such as rs2104286, which allows for consistent cross-study
referencing. The use of rsIDs ensures that disease-associated variants can be reliably monitored
across genomic annotations and research platforms. This system facilitates the integration of
genetics into autoimmune disease research, supporting both mechanistic studies and therapeutic
development.
Table 2.3 summarizes several well-characterized SNPs linked to autoimmune diseases, high-
lighting their molecular impacts and the specic conditions they inuence. While the table includes
some of the most extensively studied variants, it represents only a subset of the broader spectrum of
autoimmune-associated polymorphisms. With ongoing advances in genome-wide association studies (GWAS) and next-generation sequencing, this catalog continues to expand. These discoveries are
deepening our understanding of autoimmune pathogenesis and informing the future of individualized care.
2.2.2 INSERTION AND DELETION MUTATIONS
Insertion and deletion mutations, collectively referred to as indels, are genetic alterations involv-
ing the addition or removal of nucleotide sequences within the genome. The functional impact of
these mutations largely depends on their location, length, and whether they disrupt the reading
frame of the gene. When the number of inserted or deleted nucleotides is not divisible by three, a
frameshift mutation occurs. This alters the downstream codon alignment and typically introduces a
premature stop codon, often resulting in a truncated, nonfunctional protein. Frameshift mutations
50 Bioinformatics of Autoimmune Diseases
are particularly disruptive when they occur within coding regions, as they can severely compromise
protein integrity and biological function (Cooper & Hausman, 2013).
In contrast, in-frame indels, where the nucleotide change is divisible by three, do not shift the
reading frame but still alter the amino acid sequence. These mutations may insert or delete one or
more codons, potentially affecting protein structure, stability, or activity. Even when occurring outside of coding regions (such as in regulatory elements, splicing junctions, or promoter sequences),
indels can signicantly inuence gene expression levels or messenger RNA (mRNA) processing,
with cascading effects on cellular function.
In the context of autoimmune diseases, indel mutations play a key role in disrupting immune tolerance and triggering inappropriate immune responses. These mutations often affect genes involved
in innate immunity, antigen presentation, and cytokine signaling. A prominent example is the
NOD2 1007fs (3020insC) mutation, which involves the insertion of a single cytosine nucleotide that
causes a frameshift and results in a truncated NOD2 protein. NOD2 is essential for sensing muramyl dipeptide (MDP), a component of bacterial peptidoglycan, and initiating immune responses
in the intestinal mucosa. Loss-of-function (LOF) mutations in this gene impair microbial recognition and dampen regulatory immune signals, predisposing individuals to exaggerated inammatory
responses (Hugot etal., 2001).
The NOD2 1007fs variant has been strongly associated with Crohn’s disease, a form of IBD
characterized by chronic gastrointestinal inammation. This mutation exemplies how a single
indel event can disrupt immune homeostasis and contribute to autoimmune pathology, particularly
when combined with environmental triggers and other genetic risk factors (Lesage etal., 2002).
As genomic sequencing technologies evolve, the role of indels in autoimmune disorders is
being explored more comprehensively. Their functional consequences, especially in regulatory or
immune-related genes, underscore the importance of structural variants in shaping disease susceptibility and progression.
Figure 2.2 illustrates how the insertion of a single cytosine at nucleotide position 3020 in the
NOD2 gene (designated as 3020insC or 1007fs) results in a frameshift mutation that profoundly
alters the resulting protein sequence. Under normal conditions, the codon CTC at this position
encodes the amino acid leucine (Leu1007). The insertion of an additional cytosine within this codon
disrupts the triplet reading frame, leading to a misreading of all downstream codons. This shift
produces a series of incorrect amino acids that do not resemble the native protein structure. The
aberrant translation persists for a short stretch until a premature stop codon is encountered, resulting
in early termination of the polypeptide chain. The truncated NOD2 protein consequently lacks its
critical C-terminal leucine-rich repeat (LRR) domain, which is essential for recognizing bacterial
FIGURE 2.2 NOD2 1007fs (3020insC).
51 Genetic Markers in Autoimmunity
MDP. This loss of function compromises innate immune responses and contributes signicantly
to the increased susceptibility to Crohn’s disease observed in individuals harboring this mutation.
Another notable example of indel mutations in autoimmune disease is the CTLA4 3′ UTR deletion, which affects the post-transcriptional regulation of the CTLA4 gene. CTLA4 encodes a critical
immune checkpoint receptor that plays a key role in downregulating T-cell activity. Deletions in
this regulatory region have been associated with reduced CTLA4 expression, resulting in overactive
immune responses and increased susceptibility to autoimmune disorders (Ueda etal., 2003). This
highlights how even non-coding deletions can disrupt immune homeostasis and promote pathogenic
aut oi mm un ity.
Other signicant indels include deletions in the LCE3B and LCE3C genes, which encode proteins involved in the maintenance of epidermal barrier integrity. These deletions have been strongly
associated with psoriasis, emphasizing the relationship between barrier dysfunction and immune
activation in chronic inammatory skin diseases (de Cid etal., 2009).
Indels affecting the complement system also contribute signicantly to autoimmune disease susceptibility. CNVs in C4A and C4B, key components of the classical complement pathway, inuence
the body’s ability to clear immune complexes. In particular, C4A deciency has been linked to
impaired clearance, resulting in persistent immune stimulation, increased production of autoantibodies, and heightened risk for SLE (Yang etal., 2007). Similarly, deletions in FCGR3B, a gene that
encodes a receptor important for neutrophil-mediated clearance of immune complexes, are associated with RA and SLE, due to the accumulation of inammatory debris and unresolved immune
responses (Aitman etal., 2006).
In addition to structural variants in coding genes, regulatory indels can impact cytokine signaling.
For instance, deletions in IL10RA and IL10RB, which encode receptors for the anti-inammatory
cytokine interleukin-10, can compromise the body’s ability to suppress inammatory responses.
These rare but impactful deletions are particularly associated with very early-onset IBD, where the
failure to regulate mucosal immunity leads to severe and chronic gut inammation (Glocker etal.,
2009).
Together, these examples underscore the profound effects that indel mutations can have on
immune function. Their contributions to immune dysregulation, defective cytokine signaling, and
impaired antigen clearance make them important targets for precision medicine approaches. For
example, the CTLA4-Ig fusion protein abatacept is used to mimic the natural inhibitory signal
of CTLA4, helping to restore immune balance in diseases linked to CTLA4 pathway dysfunction
(Bluestone etal., 2015). Similarly, therapeutic strategies targeting IL-10 signaling are under devel-
opment for patients with genetic defects in this pathway.
To support the identication and classication of structural variants, the NCBI dbVar data-
base serves as a comprehensive resource for larger genomic alterations, including indels, duplications, and inversions. Each variant is assigned a unique accession number (e.g., esv2676147 for the
FCGR3B deletion), enabling researchers to track disease-associated mutations across populations
and studies. For example, C4A deletions (esv2676146) in SLE and LCE3B/C deletions (esv2676148)
in psoriasis are cataloged in dbVar and reect the growing understanding of structural genomic
variation in autoimmunity. A summary of key indel variants, including their effects and associated
diseases, is presented in Table 2.4.
2.2.3 COPY NUMBER VARIATIONS
CN Vs are structural genetic alterations in which segments of DNA (typically larger than 50 base
pairs) are duplicated or deleted, resulting in variable numbers of gene copies across individuals.
Unlike SNPs, which affect a single base, CNVs can signicantly impact gene dosage, altering
gene expression, protein production, and immune responses. These changes can either enhance or
dampen immune activity, playing a central role in autoimmune disease by disturbing immune tolerance, antigen processing, and inammatory signaling networks.
52 Bioinformatics of Autoimmune Diseases
TABLE 2.4
Notable Indel Mutations Linked to Autoimmune Conditions
Variant Type of Associated Autoimmune
Reference ID Gene Mutation Impact Disease(s)
rs1143679 ITGAM Insertion Alters integrin function, affecting Systemic lupus erythematosus
leukocyte adhesion and migration. (SLE)
rs17849502 NOD2 Insertion Impairs bacterial recognition, leading to Crohn’s disease
defective immune responses.
esv2676147 FCGR3B Deletion Reduces receptor expression, impairing Systemic lupus erythematosus
immune complex clearance. (SLE), rheumatoid arthritis
esv2676146 C4A Deletion Decreases complement protein Systemic lupus erythematosus
production, affecting immune complex (SLE)
clearance.
esv2676148 LCE3B/C Deletion Disrupts skin barrier proteins, leading to Psoriasis
increased susceptibility to skin
inammation.
In autoimmune disorders, CNVs often disrupt genes critical for complement activation, immune
receptor function, and cytokine signaling. One of the most well-characterized examples is the C4A
and C4B CNV, in which reduced gene copy number of C4A is strongly associated with SLE. The
C4 proteins are essential for clearing apoptotic cells and immune complexes; when C4A copies are
decient, the impaired clearance results in prolonged immune activation and autoantibody production, a hallmark of SLE (Yang etal., 2007).
Similarly, deletions in FCGR3B, which encodes an Fc-gamma receptor responsible for immune
complex clearance by neutrophils, are associated with both SLE and RA. Reduced FCGR3B copy
number leads to defective clearance of immune complexes, promoting sustained inammation and
tissue damage (Aitman etal., 2006). These ndings underscore how CNVs can destabilize immune
homeostasis and exacerbate autoimmunity.
Beyond the complement system, CNVs also inuence skin immunity and barrier function, as seen
in psoriasis. For instance, an increased copy number of the DEFB4 gene (coding for β-defensin2,
an antimicrobial peptide with immunostimulatory properties) has been linked to enhanced local
inammation and lesion formation in psoriasis (Hollox etal., 2008). In contrast, deletions of LCE3B
and LCE3C, which encode proteins essential for the structural integrity of the skin barrier, increase
susceptibility to psoriasis by allowing microbial and environmental triggers to breach the skin and
activate immune responses (de Cid etal., 2009).
CNVs also affect genes in the Th17 cytokine axis, which plays a central role in chronic inammation. For example, CNVs inuencing IL17F, IL22, and IL23R expression have been implicated
in Crohn’s disease, psoriasis, and MS, altering the differentiation and function of Th17 cells and
thereby modulating disease activity.
With the rise of GWAS and next-generation sequencing technologies, CNVs have become increasingly recognized as important contributors to autoimmune susceptibility. Their large-scale impact
on immune-related gene networks makes them key targets for research and therapeutic development. As shown in Table 2.5, several notable CNVs have been linked to specic autoimmune disor-
ders, offering valuable insights into disease pathogenesis and opportunities for precision medicine.
2.2.4 SPLICING MUTATIONS
Splicing mutations are genetic alterations that interfere with the normal process of RNA splicing,
a crucial step in gene expression during which non-coding introns are removed and coding exons
53 Genetic Markers in Autoimmunity
TABLE 2.5
Examples of CNVs Associated with Autoimmune Conditions
Associated Autoimmune
Gene(s) Type of CNV Impact Disease(s)
FCGR3B Deletion Reduces expression of Fc-gamma receptor IIIb, Systemic lupus erythematosus
impairing immune complex clearance. (SLE), rheumatoid arthritis
C4A/C4B Deletion Decreases complement component C4, leading Systemic lupus erythematosus (SLE)
to impaired immune complex clearance.
DEFB4 Duplication
LCE3B/LCE3C Deletion Disrupts skin barrier proteins, increasing Psoriasis
Increases β-defensin production, enhancing
antimicrobial activity and inammation.
susceptibility to skin inammation.
Psoriasis, Crohn’s disease
are joined to form mature mRNA. This process is tightly regulated by highly conserved nucleotide
sequences located at the exon–intron boundaries, including the 5′ donor site, the 3′ acceptor site, and
the intronic branch point. Mutations within these regions (or in associated regulatory elements) can
disrupt accurate splicing, leading to the generation of abnormal RNA transcripts and, subsequently,
dysfunctional proteins.
Most splicing mutations arise from point mutations, insertions, or deletions at or near the canonical splice sites or within cis-regulatory elements that govern splicing efciency. These disruptions
can weaken or entirely abolish the original splice sites, often resulting in exon skipping, intron
retention, or the activation of cryptic splice sites located elsewhere in the transcript. In addition to
mutations at the core splice sites, alterations in exonic or intronic splicing enhancers and silencers
can also affect splicing delity by altering the binding of splicing factors, such as serine-/argininerich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs), which help guide the
spliceosome machinery.
In some cases, mutations introduce entirely new splice sites, giving rise to aberrant transcripts
that may encode truncated proteins or gain-of-function (GOF) variants with novel, often pathogenic, properties. This type of aberrant splicing can have severe implications in the context of disease, including cancer, neurodegeneration, and autoimmune conditions.
As illustrated in Figure 2.3, two common outcomes of splicing disruption are exon skipping and
intron retention. Under normal conditions, exons are spliced together while introns are precisely
excised, resulting in a mature mRNA transcript that faithfully encodes the functional protein. In
exon skipping, however, one or more internal exons are excluded from the nal transcript. This
omission can lead to the loss of critical functional domains in the resulting protein or cause frameshifts that produce truncated polypeptides. On the other hand, intron retention involves the inclusion
FIGURE 2.3 An example of the impact of splicing mutations.
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