Pharmacogenomics on the Treatment Response in Patients with Psoriasis: An Updated Review

The efficacy and the safety of psoriasis medications have been proved in trials, but unideal responses and side effects are noted in clinical practice. Genetic predisposition is known to contribute to the pathogenesis of psoriasis. Hence, pharmacogenomics gives the hint of predictive treatment response individually. This review highlights the current pharmacogenetic and pharmacogenomic studies of medical therapy in psoriasis. HLA-Cw*06 status remains the most promising predictive treatment response in certain drugs. Numerous genetic variants (such as ABC transporter, DNMT3b, MTHFR, ANKLE1, IL-12B, IL-23R, MALT1, CDKAL1, IL17RA, IL1B, LY96, TLR2, etc.) are also found to be associated with treatment response for methotrexate, cyclosporin, acitretin, anti-TNF, anti-IL-12/23, anti-IL-17, anti-PDE4 agents, and topical therapy. Due to the high throughput sequencing technologies and the dramatic increase in sequencing cost, pharmacogenomic tests prior to treatment by whole exome sequencing or whole genome sequencing may be applied in clinical in the future. Further investigations are necessary to manifest potential genetic markers for psoriasis treatments.


Introduction
Psoriasis is a chronic, immune-mediated, inflammatory skin disease concomitant with other systemic complications. Environmental, behavioral, and genetic factors play a role in the etiology of the disease. Especially, genetic predisposition is thought to be a key contributor to psoriasis through involvement in immune pathophysiology [1], and about 40% of

Introduction
Psoriasis is a chronic, immune-mediated, inflammatory skin disease concomitant with other systemic complications. Environmental, behavioral, and genetic factors play a role in the etiology of the disease. Especially, genetic predisposition is thought to be a key contributor to psoriasis through involvement in immune pathophysiology [1], and about 40% of patients diagnosed with psoriasis or psoriatic arthritis have a related family history [2]. To date, almost 100 psoriasis susceptibility loci have been identified through selective candidate genes or genome-wide association studies (GWAS) [3]. The pharmacogenetic issue of psoriasis struck a chord after the immunogenetics of psoriasis were outlined gradually, and the need for personalized medicine increased when more and more anti-psoriatic drugs were available and showed variable efficacy among different drugs and individuals. This study aimed to overview the current findings of possible genetically predictive markers for treatment outcomes of psoriasis under the use of systemic and topical medicine.

Pathophysiology and Immunogenetics
Regards to pathogenesis and immunogenetics of psoriasis (Figure 1), the disease results from an aberrant innate or adaptive immune response associated with T lymphocytes that leads to inflammation, angiogenesis, and epidermal hyperplasia [4]. Genetic or environmental factors can trigger immune-mediated damage for keratinocytes in psoriasis patients. The key pathomechanism of psoriasis is that dendritic cells or macrophages can secrete IL-23 and then stimulate CD4 + Th17 polarization, resulting in the secretion of cytokines, such as IL-17, IL22, TNF-α, etc. Moreover, IL-12 can activate the differentiation of CD4 + Th1 cells, which induces INF-γ, IL-2, and TNF-α synthesis; CD8 + T cells are also known to be activated and can release pro-inflammatory cytokines, including TNF-α and INF-γ. The abundant cytokines lead to epidermal overgrowth, immune overactivation, and neovascularization. Consequently, the positive feedback loop of immune reaction leads to the development and maintenance of psoriatic lesions.
The initiation of psoriasis lesion is when antigenic or auto-antigenic stimuli induced by damaged or stressed skin activate antigen-presenting cells (APCs), including dendritic cells (DCs) and macrophages. The process results in producing pro-inflammatory cytokines such as interferon (IFN)-α, tumor necrosis factor (TNF)-α, interleukin (IL)-12, IL-20, and IL-23, and initiates the early phase of cutaneous inflammation in psoriasis [5]. Genetic or environmental factors can trigger immune-mediated damage for keratinocytes in psoriasis patients. The key pathomechanism of psoriasis is that dendritic cells or macrophages can secrete IL-23 and then stimulate CD4 + Th17 polarization, resulting in the secretion of cytokines, such as IL-17, IL22, TNF-α, etc. Moreover, IL-12 can activate the differentiation of CD4 + Th1 cells, which induces INF-γ, IL-2, and TNF-α synthesis; CD8 + T cells are also known to be activated and can release pro-inflammatory cytokines, including TNF-α and INF-γ. The abundant cytokines lead to epidermal overgrowth, immune overactivation, and neovascularization. Consequently, the positive feedback loop of immune reaction leads to the development and maintenance of psoriatic lesions.
The initiation of psoriasis lesion is when antigenic or auto-antigenic stimuli induced by damaged or stressed skin activate antigen-presenting cells (APCs), including dendritic cells (DCs) and macrophages. The process results in producing pro-inflammatory cytokines such as interferon (IFN)-α, tumor necrosis factor (TNF)-α, interleukin (IL)-12, IL-20, and IL-23, and initiates the early phase of cutaneous inflammation in psoriasis [5].
The pro-inflammatory cytokines released from activated APCs promote T cell-mediated immunity through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. In addition, engagement of the T cell receptor (TCR) with major histocompatibility complex (MHC)-presenting antigen of APCs activates the calcium-calcineurin-nuclear factor of activated T cells (NFAT) pathway. Thus, these signals result in the migration, differentiation, and activation of naïve effector T cells. In particular, IL-23 stimulates CD4 + T helper 17 (Th17) polarization, which releases IL-17A/F, IL-22, and TNF-α. On the other  hand, IL-12 activates the differentiation of the Th1 subset of CD4+ cells, which induces  INF-γ, IL-2, and TNF-α synthesis [6].
The inflammatory cytokines secreted from T cells, especially IL-17A, attract many more immune cells, such as neutrophils, enhance angiogenesis, facilitate hyperproliferation of keratinocytes, and promote the further release of cytokines. Additionally, keratinocytes activated by IL-17, IL-22, and IL-20 through JAK-STAT, NF-κB, and calcium-calcineurin-NFAT pathways release C-C motif ligand 20 (CCL20), antimicrobial peptides (AMP), and cytokines; hence, they contribute to the pro-inflammatory environment and amplify the inflammatory response [7].
In brief, the over-activated innate immunity induces exaggerative T cell-mediated autoimmune activation, epidermal overgrowth, and neovascularization. Consequently, a positive feedback loop leads to the development and maintenance of psoriatic lesions. The psoriasis susceptibility genes were found to involve in the entire immunopathogenesis from antigen presentation, cytokines and receptors, signal transductions, and transcription factors to regulators of immune responses [1,8]; at the same time, whether these susceptibility genes are potential predictors of treatment response has been investigated. In the following context, we discuss the response-related genes in psoriasis treatment (Tables 1-7,  Supplementary Table S1) and present levels of evidence of the pharmacogenomic association by the PharmGKB annotation scoring system. According to PharmGKB, six levels from 1A to 4 represent high, moderate, and low to unsupported evidence, respectively.

Methotrexate
Methotrexate (MTX) is an antagonist of the enzymes dihydrofolate reductase (DHFR) and thymidylate synthase (TYMS). It is commonly used as a first-line systemic immunosuppressive therapy for moderate to severe psoriasis. However, significant variations in its efficacy and toxicity exist among individuals. Therefore, several studies have identified potential pharmacogenetic factors that can be used to predict the clinical response of MTX (Table 1).
The genes encoding the efflux transporters of MTX are ATP-binding cassette (ABC) subfamily C member 1 (ABCC1), ABCC member 2 (ABCC2), and ABC subfamily G member 2 (ABCG2). Overexpression of these genes can lead to multidrug resistance by extruding drugs out of the cell through various mechanisms [9,10]. In regard to psoriasis, a cohort study of 374 British patients found significant positive associations between methotrexate responder, two of ABCG2 (rs17731538, rs13120400), and three SNPs of ABCC1 (rs35592, rs28364006, rs2238476) with rs35592 being the most significant (PASI75 at 3 months, p = 0.008). One cohort study from Slovenia demonstrated that polymorphism of ABCC2 (rs717620) presented an insufficient response to MTX treatment (75% reduction from baseline PASI score (PASI75) at 6 months, p = 0.039) [11]. About toxicity, a British cohort study has noted that the major allele of six SNPs in ABCC1 (rs11075291, rs1967120, rs3784862, rs246240, rs3784864, and rs2238476) was significantly associated with the onset of adverse events, with rs246240 showing the strongest association (p = 0.0006) [12].

ADORA2A
Adenosine receptors A2a (ADORA2a) is responsible for mediating the metabolic product of methotrexate. One SNP, rs5760410 of ADORA2A, was weakly associated with the onset of toxicity (p = 0.03) [12].
Campalani et al. analyzed 188 patients in the United Kingdom (UK) with psoriasis under methotrexate therapy and revealed that allele frequency of ATIC (rs2372536) was significantly increased in patients who discontinued methotrexate owing to intolerable side effects (p = 0.038) [14]. Another British cohort study found that two SNPs in ATIC (rs2372536 and rs4672768) were associated with the onset of MTX toxicity (p = 0.01). However, these associations did not remain significant after adjusting for folic acid supplementation [15].

DNMT3b
DNA methyltransferase 3β (DNMT3b) is a methyltransferase that is involved in de-novo DNA methylation, and its polymorphism is supposed to be associated with increased promoter activity [17]. At least one copy of the variant DNMT3b rs242913 allele has been found to be associated with an insufficient response to MTX when compared to the wildtype (p = 0.005) [11].

FOXP3
Forkhead box P3 (FOXP3) appears to function as a master regulator of the regulatory pathway in the development and function of regulatory T cells (Tregs) [18]. A study on a population of 189 southern Indian patients who had used methotrexate for 12 weeks found a significant difference in genotype frequencies of FOXP3 (rs3761548) between responders and non-responders (PASI75 at 3 months, p = 0.003) [19].

GNMT
Glycine N-methyltransferase (GNMT) is a methyltransferase that converts S-adenosylmethionine to S-adenosylhomocysteine and is also a folate-binding protein. The rs10948059 polymorphism is associated with increased expression of the GNMT gene and reduces cell sensitivity to MTX [20]. The patients with at least one variant GNMT allele were more likely to be nonresponders to MTX treatment than the reference allele (PASI75 at 6 months, p = 0.0004) [11].

HLA-Cw6
The human leukocyte antigen (HLA), known as the human MHC system, regulates the immune system by encoding cell-surface proteins. HLA-Cw6 is a psoriasis susceptibility allele that has been strongly linked to the disease. It was reported that carriers of HLA-Cw6 from southern India had a higher response rate to methotrexate (PASI75 at 3 months, p = 0.003) [19]. A Scotland cohort study with 70 HLA-tested patients demonstrated that more proportion of HLA-Cw6 positive patients was carried on beyond 12 months, as compared to the HLA-Cw6 negative group (p = 0.05) [21].

MTHFR
The Methylenetetrahydrofolate reductase (MTHFR) enzyme is responsible for catalyzing the formation of 5-methyl-tetrahydrofolic acid, which acts as a methyl donor for the synthesis of methionine from homocysteine. This enzyme is indirectly inhibited by MTX. [22] According to Zhu et al., the PASI 90 response rates to MTX were significantly higher in Han Chinese patients who had the MTHFR rs1801133 TT genotype as compared to those who had the CT and CC genotype (PASI90 at 3 months, p = 0.006). Furthermore, patients with the MTHFR rs1801131 CT genotype had lower PASI 75 response rates to MTX in Han Chinese population (PASI75 at 3 months, p = 0.014). They also had a lower risk of ALT elevation (p = 0.04) [23]. However, three studies have demonstrated that no significant association was detected between clinical outcomes in individuals with psoriasis treated with methotrexate and SNPs in the MTHFR gene [11,14,15].

SLC19A1
The Solute carrier family 19, member 1 (SLC19A1) gene encodes the reduced folate carrier (RFC) protein, which actively transports MTX into cells. Multiple point mutations have been identified in SLC19A1 to be associated with impaired MTX transport and resistance to MTX [24]. SLC19A1 (rs1051266) was associated with MTX-induced toxicity instead of efficacy in patients with psoriasis [12,14].

SLCO1B1
The encoded protein of solute carrier organic anion transporter family member 1B1 (SLO1B1) is a transmembrane receptor that transports drug compounds into cells. Genetic variations in SLCO1B1 have been linked to delayed MTX clearance and increased toxicity [25,26]. The haplotype variants have been classified into two groups based on their reported transporter activity: the high-activity group and the low-activity group. Patients with low-activity haplotypes of SLCO1B1 (SLCO1B1*5 and SLCO1B1*15) were less likely to be MTX non-responders as compared to patients with high-activity haplotypes (SLCO1B1*1a and SLCO1B1*1b) (PASI75 at 6 months, p = 0.027) [11].

TNIP1
TNFAIP3 interacting protein 1 (TNIP1), as one of the psoriasis susceptibility genes, is related to the immune response IL-23 signaling pathway. A Chinese study mentioned that in 221 patients with psoriasis, the TT genotype of TNIP1 rs10036748 showed a better response to MTX (PASI75 at 3 months, p = 0.043) [27].

TYMS
Thymidylate synthase (TS), encoded by the thymidylate synthase gene (TYMS), is a critical protein for pyrimidine synthesis and responsible for DNA synthesis and repair, which could be inhibited by MTX [28]. The association of polymorphisms of TYMS, TS levels, and MTX response was found in several diseases [29,30]. For example, polymorphism rs34743033 is a 28-base pair (bp) with double or triple tandem repeat (2R or 3R) located on the 5 untranslated region (UTR) [31]. A study performed in European adults with psoriasis found that the rs34743033 3R allele was more frequent in patients with poor therapeutic response to methotrexate, but the loss of significance was noted after the exclusion of palmoplantar pustulosis patients. In addition, this allele was significantly associated with an increased incidence of MTX-induced toxicity in patients who did not receive folic acid (p = 0.0025). Another TS polymorphism, 3 -UTR 6bp del of rs11280056, was significantly more frequent in patients with an adverse event irrespective of folic acid supplementation (p = 0.025) [14].

Acitretin
Acitretin is an oral vitamin A derivative that is used to treat psoriasis by inhibiting epidermal proliferation, inflammatory processes, and angiogenesis. Table 2 lists the genetic polymorphisms that have been associated with the response of acitretin in patients with psoriasis.

ApoE
Apolipoprotein E (ApoE) is a glycoprotein component of chylomicrons and VLDL. It has a crucial role in regulating lipid profiles and metabolism [32]. The lipid and lipoprotein abnormalities as a consequence of ApoE gene polymorphism are close to the side effects during acitretin therapy. In addition, ApoE levels have been linked with clinical improvement in psoriasis, indicating a potential role of the gene in acitretin treatment for psoriasis [33]. However, according to Campalani, E, et al., while ApoE gene polymorphisms are associated with psoriasis, they do not determine the response of the disease to acitretin [34].

ANKLE1
Ankyrin repeat and LEM domain containing 1 (ANKLE1) enables endonuclease activity and plays a role in positively regulating the response to DNA damage stimulus and protein export from the nucleus. ANKLE1 rs11086065 AG/GG was associated with an ineffective response compared to the GG genotype in 166 Chinese patients (PASI75 at 3 months, p = 0.003) [35].

ARHGEF3
Rho guanine nucleotide exchange factor 3 (ARHGEF3) activates Rho GTPase, which involve in bone cell biology. ARHGEF3 rs3821414 CT was associated with a more effective response compared to the TT genotype (PASI75 at 3 months, p = 0.01) [35].

CRB2
Crumbs cell polarity complex component 2 (CRB2) encodes proteins that are components of the Crumbs cell polarity complex, which plays a crucial role in apical-basal epithelial polarity and cellular adhesion. CRB2 rs1105223 TT/CT was also associated with acitretin efficacy compared to the CC genotype (PASI75 at 3 months, p = 0.048) [35,36].

HLA-DQA1*02:01
HLA-DQA1*0201 alleles may act as psoriasis susceptibility genes or may be closely linked to the susceptibility genes in Han Chinese [36]. Among 100 Chinese individuals, those who were positive for the DQA10201 allele demonstrated a more favorable response to acitretin compared to those who were negative for the same allele. (PASI75 at 2 months, p = 0.001) [37].

HLA-G
HLA-G is a nonclassical class I MHC molecule that plays a role in suppressing the immune system by inhibiting natural killer cells and T cells [39]. Among patients treated with acitretin, Borghi, Alessandro, et al. observed a significantly increased frequency of the 14 bp sequence deletion in the exon 8 of the HLA-G allele, functioning as a modification of mRNA stability, in responder patients, in comparison to the non-responders (PASI75 at 4 months, p = 0.008) [40].

IL-12B
Patients with the IL-12B rs3212227 genotype of TG were more responsive to acitretin in the treatment of psoriasis in 43 Chinese patients (PASI50, p = 0.035) [41].

IL-23R
Acitretin was found to improve the secondary non-response to TNFα monoclonal antibody in patients who were homozygous for the AA genotype at the SNP rs112009032 in the IL-23R gene (PASI75, p = 0.02) [41].

SFRP4
Secreted frizzled-related protein 4 (SFRP4) is a negative regulator of the Wnt signaling pathway, and the downregulation of SFRP4 is a possible mechanism contributing to the hyperplasia of the epidermis of psoriasis [42]. The GG/GT variation of SFRP4 rs1802073 has been found to be associated with a more effective response to acitretin compared to the TT genotype (PASI75 at 3 months, p = 0.007) [35,36].

VEGF
Vascular endothelial growth factor (VEGF) promotes angiogenesis in the pathophysiology of psoriasis, and the variant of the VEGF gene is supposed to affect the ability of acitretin to downregulate VEGF production [43]. The TT genotype of the VEGF rs833061 was associated with non-response to oral acitretin, whereas the TC genotype was associated with a significant response to acitretin (PASI75 at 3 months, p = 0.01) [44]. However, the result of VEGF polymorphism was not replicated in the population of southern China [45].

Cyclosporin
Cyclosporine, a calcineurin inhibitor, is commonly used to treat moderate to severe psoriasis. However, clinical studies investigating the pharmacogenetics of cyclosporine in psoriasis patients are currently lacking (Table 3).

CALM1
Calmodulin (CALM1) is known as a calcium-dependent protein and is related to cell proliferation and epidermal hyperplasia in psoriasis [48]. In 200 Greek patients, the allele T of CALM1 rs12885713 displayed a significantly better response to cyclosporin (PASI75 at 3 months, p = 0.011) [49].

MALT1
MALT1 encodes MALT1 paracaspase, a potent activator of the transcription factors NF-κB and AP-1, and hence has a role in psoriasis [50]. MALT1 rs287411 allele G was associated with the effective response compared to allele A (PASI75 at 3 months, p < 0.001) [49].

Tumor Necrosis Factor Antagonist
There are four FDA-approved TNF antagonists for plaque psoriasis, including etanercept, adalimumab, infliximab, and certolizumab pegol. According to our review of the literature, pharmacogenetic research has been mainly focused on the first three drugs. Etanercept is a recombinant fusion protein comprising two extracellular parts of the human tumor necrosis factor receptor 2 (TNFR2) coupled to a human immunoglobulin 1 (IgG1) Fc. Adalimumab is a fully human monoclonal antibody with human TNF binding Fab and human IgG1 Fc backbone, whereas infliximab is a chimeric IgG1 monoclonal antibody composed of a human constant and a murine variable region binding to TNFα [51]. Despite their unique pharmacological profile from each other, TNF antagonists act on the same pathologic mechanism to achieve therapeutic outcomes. Therefore, some pharmacogenetic researchers regarded all TNF antagonists as one category to analyze potential predictive genetic markers under a large-scale population, while some discussed each TNF antagonist separately (Table 4).

Nonspecific TNF Antagonist Better Response of Efficacy
In 144 Spanish patients, carriers of the CT/CC allele in MAP3K1 rs96844 and the CT/TT allele in HLA-C rs12191877 achieved a better PASI75 response at 3 months. The study also found significantly better results for carriers of MAP3K1 polymorphism and CT/TT in CDKAL1 rs6908425 at 6 months [52]. Another study enrolled 70 patients in Spain implicated that patients harboring high-affinity alleles, FCGR2A-H131R (rs1801274) and FCGR 3A-V158F(rs396991), contribute to better mean BSA improvement but not PASI improvement at 6-8 weeks after anti-TNF treatment of psoriasis [53]. The result between FCGR 3A-V158F(rs396991) and response to anti-TNFα therapy (PASI75 at 6 months, p = 0.005), especially etanercept (PASI75 at 6 months, p = 0.01), was replicated in 100 Caucasian patients from Greece, while FCGR2A-H131R (rs1801274) was found to be no association [54]. A study conducted in 199 Greek patients found an association between carriers of CT/CC in HLA-C rs10484554 and a good response to anti-TNF agents (PASI 75 at 6 months, p = 0.0032), especially adalimumab (p = 0.0007) [55].

Poor Response of Efficacy
In 144 Spanish patients, four SNPs were associated with the inability to achieve PASI75 at three months, including AG/GG allele in PGLYRP4-24 rs2916205, CC allele in ZNF816A rs9304742, AA allele in CTNNA2 rs11126740, and AG/GG allele in IL12B rs2546890. Additionally, the results for polymorphisms in the IL12B gene were replicated at six months and one year. The study also obtained significant results for the FCGR2A and HTR2A polymorphism at 6 months [52]. Notably, the result of the FCGR2A polymorphism showed variability between studies [52][53][54]. In 376 Danish patients, five SNPs, which are IL1B (rs1143623, rs1143627), LY96 (rs11465996), and TLR2 (rs11938228, rs4696480), were all associated with nonresponse to treatment [58]. One study found a higher frequency of G-carriers of the TNFRSF1B rs1061622 among non-responders (PASI < 50) compared to cases achieving PASI75 to TNF blockers in 90 Caucasians from Spain [59].

Toxicity
Among the 161 Caucasian patients, the polymorphism rs10782001 in FBXL19 and rs11209026 in IL23R may contribute to an increased risk of the secondary development of psoriasiform reactions owing to TNF blocking. In addition, in 70 Spanish patients, the copy number variation (CNV) harboring three genes (ARNT2, LOC101929586, and MIR5572) was related to the occurrence of paradoxical psoriasiform reactions at 3 and 6 months (p = 0.006) [60]. In contrast, the presence of rs3087243 in CTLA4, rs651630 in SLC12A8, or rs1800453 in TAP1 was related to protection against psoriasiform lesions [61]. Interestingly, the IL23R rs11209026 polymorphism was reported as having a protective role reported in classical psoriasis.

FCGR3A
This gene encodes a receptor for the Fc portion of immunoglobulin G, where the TNF antagonist binds specifically. In 100 psoriasis patients in Greece, the study showed an association with FCGR3A-V158F (rs396991) and better response to etanercept (PASI75 at 6 months, p = 0.01) [54].

TNFAIP3
TNFα induced protein 3 (TNFAIP3) plays a protective role against the harmful effects of inflammation and is involved in immune regulation [64]. Rs610604 in TNFAIP3 showed associations with good responses to etanercept (PASI75 at 6 months, p = 0.007) [55].

HLA
The rs9260313 in the HLA-A gene was found to be associated with more favorable responses to adalimumab (PASI75 at 6 months, p = 0.05) [55]. Among 169 Spanish patients, HLA-Cw06 positivity had a better response to adalimumab. (PASI75 at 6 months, p = 0.018) [68].

IL17F
IL-17F, activated by IL23/Th17, is recognized as having a critical role in the pathogenesis of psoriasis. In a cohort study in Spain, carriers of TC genotype in IL-17F rs763780 were associated with a lack of response to adalimumab (n = 67, PASI75 at weeks 24-28, p = 0.0044) while interestingly, with better response to infliximab (n = 37, PASI at weeks 12-16, p = 0.023; PASI at weeks 24-28, p = 0.02).

NFKBIZ
The nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, zeta (NFKBIZ) gene encodes an atypical inhibitor of nuclear factor κB (IκB) protein, involved in inflammatory signaling of psoriasis [69]. Among 169 Spanish patients, the deletion of NFKBIZ rs3217713 had a better response to adalimumab (PASI75 at 6 months, p = 0.015) [68].

TNF, TNFRSF1B
None of the genotyped SNPs of TNF, TNFRSF1A, and TNFRSF1B genes were associated with responsiveness to treatment with infliximab or adalimumab [66].

IL-12/IL-23 Antagonist
Ustekinumab, as an IL12/IL23 antagonist, targets the p40 subunit that is shared by IL-12 and IL-23, whereas guselkumab, tildrakizumab, and risankizumab target the p19 subunit of IL-23. These four drugs are efficacious in treating moderate to severe plaque psoriasis [71]. While ustekinumab is the earliest commercially available drug among IL23 antagonists, relatively abundant studies of the association between the response and gene status have been conducted. In contrast, there is limited research on the genetic predictors of clinical response to guselkumab, tildrakizumab, and risankizumab (Table 5).

Ustekinumab (UTK) Better Response of Efficacy
In a Spanish study enrolled 69 patients, good responders at 4 months were associated with CC genotype in ADAM33 rs2787094 (p = 0.015), CG/CC genotype in HTR2A rs6311 (p = 0.037), GT/TT genotype in IL-13 rs848 (p = 0.037), CC genotype in NFKBIA rs2145623 (p = 0.024), and CT/CC genotype in TNFR1 rs191190 [72]. Rs151823 and rs26653 in the ERAP1 gene showed associations with a favorable response to anti-IL-12/23 therapy among 22 patients from the UK. [55] Several studies exhibited that the presence of the HLA-Cw*06 or Cw*06:02 allele may serve as a predictor of faster response and better response to ustekinumab in Italian, Dutch, Belgian, American, and Chinese patients [72][73][74][75][76][77]. A recent meta-analysis study confirmed that HLA-C*06:02positive patients had higher response rates (PASI76 at 6 months, p < 0.001) [78]. In addition, the presence of the GG genotype on the IL12B rs6887695 SNP and the absence of the AA genotype on the IL12B rs3212227 or the GG genotype on the IL6 rs1800795 SNP significantly increased the probability of therapeutic success in HLA-Cw6-positive patients [77]. Rs10484554 in the HLA-Cw gene did not show an association with a good response to ustekinumab in a Greek population [55]. Patients with heterozygous genotype (CT) in the IL12B rs3213094 showed better PASI improvement to ustekinumab than the reference genotype (CC) (∆PASI at 3 months, p = 0.017), but the result was not replicated with regard to PASI75 [63]. The genetic polymorphism of TIRAP rs8177374 and TLR5 rs5744174 were associated with a better response in the Danish population (PASI75 at 3 months, p = 0.0051 and p = 0.0012, respectively) [58].

IL-17 Antagonist
Secukinumab and ixekizumab are human monoclonal antibodies that bind to the protein interleukin IL-17A, while brodalumab is a human monoclonal antibody of IL17R, which means a pan inhibitor of IL-17A, IL-17F, and IL-25. The three IL-17 antagonists are currently used in the treatment of moderate-to-severe psoriasis ( Table 6).

IL-17
No associations were found between the five genetic variants of IL-17 (rs2275913, rs8193037, rs3819025, rs7747909, and rs3748067) and ∆PASI, PASI75, or PASI90 after 12 and 24 weeks of anti-IL-17A agents, including SCK and IXE in European [84]. The lack of pharmacogenetic data for BDL was noted during the review.

Topical Agents
Globally used topical therapies for psoriasis include retinoids, vitamin D analogs, corticosteroids, and coal tar. Lack of evidence emphasizes the association between treatment response and pharmacogenetics of corticosteroids, retinoids, and coal tar. The link between VDR genes, encoding the nuclear hormone receptor for vitamin D3, and the response to calcipotriol has been discussed but remained controversial in different populations [86][87][88][89][90][91]. Lindioil is another topical medicine refined from Chinese herbs and is effective in treating plaque psoriasis [92]. It has been reported that HLA-Cw*06:02 positivity showed a better response (PASI75 at 3 months, p = 0.033) while HLA-Cw*01:02 positivity showed a poor response in 72 patients (PASI 75 at 2.5 months, p = 0.019) [93].

Discussion
Psoriasis has been proven to be genetically affected over half a century [94][95][96]. With the breakthrough of the technique of genetic analysis, more and more psoriasis susceptibility genes have been widely detected and analyzed as predictive markers of treatment response when unexplained and unsatisfied treatment responses and side effects have been recorded [97][98][99][100]. In addition, several reviews have highlighted the findings of pharmacogenomics in psoriasis in the last ten years [97,98,[101][102][103]. In the review, regarding efficacy, carriers of HLA-Cw*06 positivity implied a more favorable response in the treatment of methotrexate and ustekinumab. HLA-Cw6 status was not indicative of treatment response to adalimumab, etanercept, and secukinumab. Polymorphism of ABCB1 rs1045642 may indicate poor responses in Greek and Russian. However, there are some limitations in the current review. First, the relevant data of anti-IL17 agents were lacking, which reflects that it is relatively novel to the market and shows outstanding responses irrespective of genotype. Further genetic analysis of acitretin, cyclosporin, and apremilast is worth exploring. Secondly, the majority of the included pharmacogenomic studies of psoriasis were from Europe and America. This implies the limited application to Asians and Africans. It may reflect that Europe and America have more clinical trial studies or drug options, resulting in interest in studying treatment responses for psoriasis than in other areas [101]. In addition, the accessibility of gene-analysis resources may affect the development of pharmacogenomic studies. Thirdly, the protocol to identify the related gene varies between studies. A generalized and standardized method would facilitate the utilization and replication of the pharmacogenomic studies. Fourthly, pharmGKB is a comprehensive resource that curates knowledge about the impact of genetic variation on drug responses for clinicians [102]. The level of evidence of the pharmacogenetic results in this database mostly remains low (level three) due to conflicted results, small cases, or a single study. Whereas biomarkers must show a relatively strong effect in order to be of use in clinical decision-making, replicated large cohort studies of each medical therapy are required in different ethnic groups. The use of the global polygenic risk score allowed for the prediction of onset psoriasis in Chinese and Russians [85,101]. The establishment of the polygenic score for psoriasis treatment response may be developed in the future. In addition, tofacitinib, a kind of Janus kinase (JAK) inhibitor, was approved by FDA for psoriatic arthritis in 2017.
Although no indication of psoriasis alone is approved, pharmacogenetic research of JAK inhibitor is expected considering its potential cardiovascular and cancer risk in patients with rheumatoid arthritis [104].

Conclusions
This review article updates the current pharmacogenomic studies of treatment outcomes for psoriasis. A standardized protocol could be established for utilization and comparison worldwide. Currently, high-throughput whole exome sequencing (WES) or whole genome sequencing (WGS) can rapidly obtain comprehensive genetic information for individuals [105][106][107]. Genetic basic research promotes the progress of personalized medicine. Its development contributes to the precision of the effective treatment individually, providing alternatives when treatment fails, preventing adverse effects, and reducing the economic burden of treating psoriasis.