Abstract
Spondyloarthritis (SpA) represents a group of inflammatory rheumatic diseases that cluster within families and possess overlapping clinical features. The pathogenesis of SpA encompasses a complex array of genetic, immunological and environmental factors. In this article, we will briefly review the genetics of PsA, and then focus on the genes that may be potentially linked either directly or indirectly to the immunopathology of the Th-17 pathway. The most consistent and dominant genetic effect of PsV and PsA is located on chromosome 6p21.3 within the major histocompatibility complex (MHC) region, which accounts for approximately one-third of the genetic contribution of PsV and PsA. To date, 36 genes have reached genome-wide significance, accounting for approximately 22% of psoriasis (PsV) heritability. Prominent genes identified via GWAS include HLA-Cw6, IL12B, IL23R, IL23A, TNIP1, TNFAIP3, LCE3B-LCE3C, TRAF3IP2, NFkBIA, FBXL19, TYK2, IFIH1, REL, and ERAP1 . Genes identified in psoriatic arthritis (PsA) has largely echoed those in PsV and include HLA-B/C, HLA-B, IL-12B, IL-23R, TNIP1, TRAF3IP2, FBXL19, and REL . The lack of identified genetic susceptibility loci is largely attributed to the much smaller number of PsA patients and the greater clinical heterogeneity of PsA. Searching for different types of genetic variants such as small CNVs and/or insertions/deletions has also led to the identification of several genes with a function relative to PsV in particular including DEFB4 , LCE3C_LCE3B , and IL-22 gene (exon 1). The candidate genes identified in PsV/PsA have highlighted pathways of critical importance to psoriatic disease including distinct signaling pathways comprised of barrier integrity, innate immune response and adaptive immune response, mediated primarily by Th-17 and Th-1 signalling. While GWAS studies have yielded great insights into the genes that contribute to the pathogenesis of PsV and PsA, replication in large cohorts, fine-mapping and resequencing efforts, together with functional studies of genetic variants identified, are warranted to better understand susceptibility to and progression of these diseases. That searching solely for common variants by GWAS will identify only a fraction of the entire genetic burden of disease, a concerted effort is underway to search for highly penetrant but rare disease alleles in families with PsV and PsA, using next-generation sequencing and through epigenetic investigations.
Highlights
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We propose a new hybrid bio-inspired solver combining elements from Coral Reefs Optimization (CRO) and Harmony Search (HS).
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This new optimization approach is applied to the selection of input features for a Extreme Learning Regressor in the context of wind speed prediction.
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The hybrid scheme is validated in two different meteorological towers located in USA and Spain, and results are compared to those rendered by naïve versions of its constituent algorithms.
Introduction
Spondyloarthritis (SpA) represents a group of inflammatory rheumatic diseases that cluster within families, have overlapping clinical features, and share common pathogenesis, particularly with respect to the critical role of the T helper (Th)-17 axis in initiating and propagating inflammation in ankylosing spondylitis (AS) and psoriatic arthritis (PsA). In this section, we briefly review the genetics of PsA, and then focus on the genes that may be potentially linked either directly or indirectly to the immunopathology of the Th-17 pathway.
The pathogenesis of SpA encompasses a complex array of genetic, immunological, and environmental factors. Population-based studies suggest a strong genetic basis to PsA given the impressive magnitude of familial aggregation. The recurrence ratio of PsA among first-degree relatives ( λ 1 ) ranges from 30 to 55, which ranks second only behind AS, and this value is considerably higher than what is estimated in psoriasis . Additional evidence regarding the genetic basis of PsA arises from class I human leukocyte antigen (HLA) associations, non-HLA major histocompatibility complex (MHC) genes, and validated genetic associations outside the MHC region . Additionally, there is a robust genetic association for psoriasis vulgaris (PsV). Much of what has been identified regarding the genetics of PsA has originated from studies in PsV, as the genetics of PsV have been more thoroughly investigated. Genetic associations in PsV are relevant to PsA as the two diseases are interrelated epidemiologically and share similar immunopathology. Almost all patients with PsA either have or will develop PsV, and approximately 30% of patients with PsV have PsA . Therefore, PsA and PsV will undoubtedly share common genetic variants.
Genetic associations within the MHC region (directed genetic studies)
All genetic investigations to date have revealed that the most consistent and dominant genetic effect of PsV and PsA is located on chromosome 6p21.3 within the MHC region, accounting for approximately one-third of the genetic contribution of PsV and PsA . The genetic variants identified to date involve class I HLA alleles and, to a lesser extent, non-HLA genes within the MHC region.
The major effect in the MHC region is located within an ∼300-kb segment known as psoriasis susceptibility region 1 ( PSORS1 ). Elegant resequencing studies have confirmed that HLA-Cw*0602 is the PSORS1 risk variant in PsV . This is a reproducible finding among all type 1 PsV cohorts. Potential genotype–phenotype correlations with HLA-Cw*0602 include early age of onset, higher likelihood of familial psoriasis, guttate psoriasis, and presence of the Koebner phenomenon . The presence of HLA-Cw*0602 may also lead to improvement of psoriasis during pregnancy .
HLA-Cw*0602 is also associated with PsA; however, the magnitude of association is lower than in PsV . In fact, among PsV patients, individuals who carry the HLA-Cw*0602 allele have a delayed onset of PsA and also are less likely to develop PsA. Other HLA antigens associated with PsA include HLA-B13 , HLA-B27 , HLA – B38/39 , HLA-B57 , and HLA-DRB1*04 . The most recent case–control and family-based association study by Chandran et al. demonstrated that HLA-C*12/B*38, HLA-B*27, and HLA-C*06/B*57 are haplotypes (alleles) robustly associated with PsA .
HLA alleles have also been associated with disease expression and prognosis in PsA. The effect sizes for these associations have been modest, thus limiting its clinical utility. Peripheral polyarthritis in PsA is associated with B38 and B39 , while axial involvement is associated with HLA-B 27 . Dactylitis occurs more frequently in individuals carrying the HLA-B27 allele . With respect to the progression of PsA, HLA-B 39 alone, HLA-B 27 only in the presence of HLA-DR 7, and HLA-DQ 3 only in the absence of HLA-DR 7 and HLA-Cw*0602 are associated with a higher rate of disease progression in PsA .
Among PsV patients, pre-genome-wide association study (GWAS) candidate gene studies identified several HLA-B alleles and non-HLA genes (such as CDSN , HCR , and PSORS1C3 ), but their independence from HLA-C has not been proven . In PsA, non-HLA candidates within the MHC region have produced conflicting results. The most replicated associations have been with the tumor necrosis factor ( TNF )- α promoter polymorphisms ( TNF -238G/A and TNF -857T) and MIC alleles, particularly trinucleotide repeat polymorphism, MICA – A9 , that corresponds to MICA*002 . A recent PsA association study confirmed the previous association of the KIR2DS gene, especially KIR2DS2 , with PsA .
Genetic associations within the MHC region (directed genetic studies)
All genetic investigations to date have revealed that the most consistent and dominant genetic effect of PsV and PsA is located on chromosome 6p21.3 within the MHC region, accounting for approximately one-third of the genetic contribution of PsV and PsA . The genetic variants identified to date involve class I HLA alleles and, to a lesser extent, non-HLA genes within the MHC region.
The major effect in the MHC region is located within an ∼300-kb segment known as psoriasis susceptibility region 1 ( PSORS1 ). Elegant resequencing studies have confirmed that HLA-Cw*0602 is the PSORS1 risk variant in PsV . This is a reproducible finding among all type 1 PsV cohorts. Potential genotype–phenotype correlations with HLA-Cw*0602 include early age of onset, higher likelihood of familial psoriasis, guttate psoriasis, and presence of the Koebner phenomenon . The presence of HLA-Cw*0602 may also lead to improvement of psoriasis during pregnancy .
HLA-Cw*0602 is also associated with PsA; however, the magnitude of association is lower than in PsV . In fact, among PsV patients, individuals who carry the HLA-Cw*0602 allele have a delayed onset of PsA and also are less likely to develop PsA. Other HLA antigens associated with PsA include HLA-B13 , HLA-B27 , HLA – B38/39 , HLA-B57 , and HLA-DRB1*04 . The most recent case–control and family-based association study by Chandran et al. demonstrated that HLA-C*12/B*38, HLA-B*27, and HLA-C*06/B*57 are haplotypes (alleles) robustly associated with PsA .
HLA alleles have also been associated with disease expression and prognosis in PsA. The effect sizes for these associations have been modest, thus limiting its clinical utility. Peripheral polyarthritis in PsA is associated with B38 and B39 , while axial involvement is associated with HLA-B 27 . Dactylitis occurs more frequently in individuals carrying the HLA-B27 allele . With respect to the progression of PsA, HLA-B 39 alone, HLA-B 27 only in the presence of HLA-DR 7, and HLA-DQ 3 only in the absence of HLA-DR 7 and HLA-Cw*0602 are associated with a higher rate of disease progression in PsA .
Among PsV patients, pre-genome-wide association study (GWAS) candidate gene studies identified several HLA-B alleles and non-HLA genes (such as CDSN , HCR , and PSORS1C3 ), but their independence from HLA-C has not been proven . In PsA, non-HLA candidates within the MHC region have produced conflicting results. The most replicated associations have been with the tumor necrosis factor ( TNF )- α promoter polymorphisms ( TNF -238G/A and TNF -857T) and MIC alleles, particularly trinucleotide repeat polymorphism, MICA – A9 , that corresponds to MICA*002 . A recent PsA association study confirmed the previous association of the KIR2DS gene, especially KIR2DS2 , with PsA .
Genome-wide strategies
Hypothesis-free association-based studies involve genome-wide linkage studies and GWASs. A number of genome-wide linkage studies were completed between 2005 and 2009. Linkage methods were initially used for the identification of susceptibility determinants across the entire genome. The immediate appeal of linkage studies is the ability to identify novel genes, which may not have been initially considered as potential targets. However, the genome-wide linkage studies in complex rheumatic diseases have traditionally been underpowered, and have sparse marker (microsatellite) coverage and relatively small sample sizes, and very few loci identified by linkage studies have been replicated. The most consistently replicated locus resides within the MHC region at chromosome 6 p 21.3 referred to as PSORS1 . It is estimated that this region accounts for one-third to one-half of the genetic susceptibility to PsV. Nine other prominent regions of linkage were identified from all the genome-wide linkage scans, designated PSORS2 – PSORS10 (as reviewed by Duffin et al.) . These regions have not been consistently replicated but selected loci do contain potential candidate genes of interest in the pathogenesis of PsV/PsA. For instance, a region that contains a gene that regulates the production of type 1 interferon (IFN) is noted in PSORS3 (4 q 34); a gene that encodes S-100 proteins that are involved in chemotaxis resides within PSORS4 (1 q 21); the JUNB gene, which is an essential component of the AP-1 transcription factor, was identified within PSORS 6 (19 p 13); and a gene that contains an important cytokine in PsV, interleukin 15 (IL-15), is located within PSORS9 (4 q 31) . Only a single genome-wide linkage study has been completed in PsA, and a suggestive linkage was noted on chromosome 16 q . In this Icelandic study, a significant logarithm of odds (LOD) score was only achieved, when the linkage analysis was conditioned on paternal transmission .
Since 2007, single-nucleotide polymorphism (SNP)-based GWASs have revolutionized the identification of genomic regions associated with complex diseases. GWASs have identified approximately 2000 robust associations with >300 complex diseases and traits . The number of candidate genes identified is much greater than for linkage-based studies or candidate gene association studies. In PsV, three large GWAS studies have been published, predominantly in cohorts of European ancestry. To date, 36 genes have reached genome-wide significance among Caucasians, accounting for approximately 22% of its estimated heritability ( Table 1 ). Prominent genes identified via GWASs include HLA-Cw6 , IL-12B , IL-23R , IL-23A , TNF-induced protein 3 (TNFAIP3)-interacting protein 1 ( TNIP1 ), TNFAIP3 , LCE3B-LCE3C , TRAF3IP2 , NFκBIA , FBXL19 , TYK2 , IFIH1 , REL , and endoplasmic reticulum aminopeptidase 1 ( ERAP1 ) .
| Gene/Locus | Chr. | Ethnic ancestry | Psoriatic disease | Signaling pathways affected | |
|---|---|---|---|---|---|
| PsV | PsA | ||||
| Th-17 Cell Differentiation | |||||
| IL-6 | 7p21 | European | X | IL-6 pathway | |
| IL-1RN | 2q14.2 | European | X | IL-1 pathway | |
| IL-12β | 5q31.1–q33.1 | European | X | X | IL-23 pathway |
| IL-23A | 12q13.3 | European | X | X | IL-23 pathway |
| IL-23R | 1p31.3 | European | X | X | IL-23 pathway |
| TYK2 | 19p13.2 | European | X | IL-23 pathway | |
| STAT3 | 17q21.31 | European | X | X | IL-23 pathway |
| SOCS1 | 16p13.13 | European | X | IL-23 pathway | |
| ETS1 | 11q23.3 | European | X | IL-23 pathway | |
| Th-17 Effector Signaling | |||||
| IL-17RD | 3p14.3 | European | X | IL-17 pathway | |
| IL-22 | 12q15 | Asian | X | IL-22 pathway | |
| IL-2/IL-21 | 4q27 | European | X | X | IL-21 pathway |
| Crosstalk with Innate Immune Response (TNF-α and NFκB) | |||||
| TNF-α | 6p21.3 | European | X | X | TNF-induced NFκB-dependent gene expression |
| TNIP1 | 5q32–q33.1 | European | X | X | TNF-induced NFκB-dependent gene expression |
| TNFAIP3 | 6q23 | European | X | NFκB activation | |
| CARD14 | 17q25 | European | X | NFκB activation | |
| REL | 2p13–p12 | European | X | X | Essential part of NFκB complex |
| CARM1 | 19p13.2 | European | X | Transcriptional coactivator of NFκB | |
| NFκBIA | 14q13 | European | X | Interferes with nuclear localization signals | |
| FBXL19 | 16p11.2 | European | X | X | Inhibits NFκB signaling |
| UBE2L3 | 22q11.21 | European | X | Ubiquitination of NFκB | |
Relatively small GWASs have also been completed in multiple PsA cohorts with two larger GWAS studies yet to be published . Genes identified in PsA have largely echoed those in PsV and include HLA-B/C , HLA-B , IL-12B , IL-23R , TNIP1 , TRAF3IP2 , FBXL19 , and REL . The relative lack of genome-wide significant genes in PsA as compared with PsV is likely attributed to the much smaller number of PsA patients who have been studied. The greater clinical heterogeneity of PsA may also contribute to the lack of genome-wide significance. The candidate genes identified in PsV/PsA have highlighted pathways of critical importance to psoriatic disease including distinct signaling pathways comprising barrier integrity, innate immune response, and adaptive immune response, mediated primarily by Th-17 and Th-1 signaling.
Genes altering signaling pathways involved in antigen presentation
Immunopathology . Antigen presentation is a critical event in inciting SpA. Disruption of antigen presentation and alternation of CD8 T cell signaling can result in inappropriate targeting and destruction of cells, thereby contributing to SpA pathogenesis.
Genetic Pathology . Variations within five genes encoding proteins crucial for antigen presentation have been identified in GWASs investigating susceptibility to PsV including HLA-B , HLA-C , ERAP1 , ERAP2 , and MICA . The main function of the product of ERAP1 is to trim peptides in the endoplasmic reticulum for MHC class I presentation , and ERAP1 interacts with HLA-C . ERAP2 trims peptides in the ER before their MHC class I presentation and forms heterodimers with ERAP1 . Secondary analyses of recent GWASs have convincingly demonstrated the gene–gene interactions of ERAP1 and HLA-Cw6 in PsV .
The following seven genes ( RUNX3 , ETS1 , TNFRSF9 , IRF4 , MBD2 , TAGAP , and B3GNT2 ) identified in PsV GWAS encode proteins important for T cell function and proper antigen presentation . RUNX3 , TNFRSF9 , and MBD2 encode proteins involved in the generation of CD8 T cells , while ETS1 , IRF4 , TAGAP , and B3GNT2 encode proteins involved in the activation and differentiation of CD8 T cells .
Genes involved in innate immunity
Activation of the innate immune response secondary to the disruption of barrier integrity (possibly by genetic variation) represents the initial physiological trigger, which sets in motion an inflammatory cascade initiating PsV/PsA pathogenesis. The resultant inflammatory milieu and related downstream cellular signaling tip the immune balance towards autoimmunity. IFNs and TNF-α appear to represent the predominant cytokines involved in triggering the innate immune response in PsV and PsA as evidenced by their release from dendritic cells in damaged skin and synovial fluid, respectively . Interestingly, both cytokines signal via the immediate-early response transcription factor, nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), which represents one of the most important transcriptional regulators of the innate immune response.
IFN signaling
Immunopathology . IFN signaling is an important early mediator of inflammation producing proinflammatory cytokines (e.g., TNF-α and IL-1) and regulating effector cells in the innate immune response . IFNs are a family of proteins consisting of three major types: type I (IFN-α, IFN-β, IFN-ε, and IFN-ω), type II (IFN-γ), and type III (IFN-λ1, IFN-λ2, and IFN-λ3) .
Genetic Pathology . Genetic variation in this pathway may cause accumulation of proinflammatory cytokines contributing to psoriatic disease. To date, variations within eight genes encoding proteins crucial for IFN signaling have been identified in GWASs investigating susceptibility to PsV including ELMO1 , TYK2 , SOCS1 , IFIH1 , RNF114 , IRF4 , DDX58 , and IFNLR1 . By contrast, only a single genetic locus involved in IFN signaling, TYK2 , has reached genome-wide significance in PsA . ELMO1 is a protein-coding gene, which is essential for IFN-α induction by plasmacytoid dendritic cells . TYK2 encodes a tyrosine kinase involved in the initiation of IFN-α signaling, and SOCS1 is a member of the suppressor of cytokine signaling family of proteins and interacts with TYK2 in cytokine signaling . The RNA helicase encoded by IFIH1 initiates a transduction cascade that stimulates several cytokines including IFNs . RNF114 encodes a protein, which regulates a positive feedback loop enhancing the production of type I IFNs . IRF4 , which codes for interferon regulatory factor (IRF)-4, is important in the regulation of IFNs and IFN-inducible genes. It also negatively regulates Toll-like-receptor (TLR) signaling that is central to the activation of the innate immune system . DDX58 encodes for a DEAD box protein that is involved in initiating the cascade of events leading to the activation of transcription factors (IRFs and NFκB), followed by the activation of IFN genes . The protein encoded by IFNLR1 belongs to the class II cytokine receptor family, which interacts with three closely related cytokines, including IL-28A, IL-28B, and IL-29 . Collectively, the genetic loci revealed by GWASs support a role of IFNs in the pathogenesis of psoriatic disease. The discrepancy regarding the number of loci involved between psoriasis and PsA is a reflection of the limited number of studies for the latter.
TNF-α signaling
Immunopathology . TNF-α is similar to IFNs with respect to both being key effectors of innate immune responses. TNF-α induces the production of inflammatory chemokines resulting in the accumulation of proinflammatory leukocytes, including neutrophils, monocytes, and activated T cells . Of relevance to PsA, TNF-α also stimulates bone loss by mobilizing osteoclast precursors from the bone marrow and by reducing bone formation by inhibiting osteoblast differentiation and function . TNF-α binds to TNFR1 or TNFR2, which activates two separate intracellular signaling pathways leading to gene transcription through NFκB activation .
Genetic Pathology . Given that TNF-α is a key effector of innate immune responses and is tightly linked to NFκB-mediated transcription, alterations in TNF-α signaling by genetic alteration may initiate the transcription of numerous target genes contributing to psoriasis or PsA pathogenesis. Although GWASs failed to detect any association signals for TNF-α genetic variants with psoriasis or PsA, a meta-analysis, which consisted of 2159 and 2360 psoriasis and PsA patients, respectively, investigated the effect of TNF-α genetic variants on susceptibility to psoriasis and PsA . The meta-analysis revealed a significant association between TNF-α -238A/G and TNF-α -857T/C polymorphism and PsA susceptibility . By contrast, the variant genotypes and alleles of TNF-α -308A/G proved to be protective against PsV, whereas TNF-α -238A/G was found to have a risk association .
NFκB signaling
Immunopathology . The NFκB complex is activated upon liberation from inhibitor of kappa B kinase (IκB), secondary to cytokine stimulation, most notably, TNF-α and IL-17. This activation leads to phosphorylation, ubiquitination, and finally degradation of the cytosolic IκB protein, which forms a complex with NFκB . Unbound NFκB can enter the nucleus to initiate the transcription of multiple genes, which encode proteins that control inflammatory processes including proinflammatory cytokines . The importance of NFκB signaling is supported by studies confirming the presence of altered NFκB activity in psoriatic disease .
Genetic Pathology . A role of the NFκB pathway in PsV and PsA is suggested by findings from GWASs. Variations within ten genes encoding proteins crucial for NFκB signaling and transcription have been identified in GWASs investigating susceptibility to PsV, including TNFAIP3 , TNIP1 , TYK2 , REL , NFκBIA , CARD14 , CARM1 , NOS2 , UBE2L3 , and FBXL19 . Likewise, several genetic loci involved in NFκB signaling, TNIP1 , REL , FBXL19 , and TYK2 , have reached genome-wide significance in PsA . TNFAIP3 encodes TNFAIP3 or Act1, and its ubiquitination in response to NFκB activation negatively regulates the subsequent NFκB activation . Interestingly, Act1 is known to contribute to both skin inflammation and bone destruction . The product of TNIP1 interacts with TNFAIP3 to inhibit TNF-induced NFκB-dependent gene expression . REL genes encode a subunit of the NFκB complex that is essential for proper signaling and the product of NFκBIA interferes with nuclear localization signals by inhibiting the activity of dimeric NFκB–REL complexes . CARD14 encodes a member of the family of caspase recruitment domain-containing scaffold proteins and mediates the recruitment and activation of the NFκB pathway . CARM1 is a transcriptional coactivator of NFκB and functions as a promoter-specific regulator of NFκB recruitment to chromatin . NFκB can induce transcription of NOS2 , which encodes an inducible form of nitric oxide synthase known as an effector of the innate immune system . On the other hand, UBE2L3 encodes an enzyme involved in the ubiquitination of NFκB precursor p105 . The product of FBXL19 reversibly inhibits NFκB signaling, and the expression of FBXL19 is significantly elevated in psoriatic compared with normal skin . Collectively, the genetic loci revealed by GWASs support a role of NFκB in the pathogenesis of psoriatic disease.
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