Association of the PDE3A-SLCO1C1 locus with the response to anti-TNF agents in psoriasis

Abstract

Psoriasis is a prevalent autoimmune disease of the skin that causes significant psychological and physical disability. Tumor necrosis factor (TNF)-blocking agents have proven to be highly efficacious in the management of moderate-to-severe psoriasis. However, a significant percentage of patients do not respond to this treatment. Recently, variation at the PDE3A-SLCO1C1 (phosphodiesterase 3A-SoLute Carrier Organic anion transporter family member 1C1) locus has been robustly associated with anti-TNF response in rheumatoid arthritis. Using a cohort of 130 psoriasis patients treated with anti-TNF therapy, we sought to analyze the association of this locus with treatment response in psoriasis. We found a highly significant association between PDE3A-SLCO1C1 and the clinical response to TNF blockers (P=0.0031). Importantly, the allele that was previously associated with the lack of response to rheumatoid arthritis (G allele, single-nucleotide polymorphism rs3794271) was associated with a higher anti-TNF efficacy in psoriasis. The results of this study are an important step in the characterization of the pharmacogenetic profile associated with anti-TNF response in psoriasis.

Introduction

Psoriasis is a chronic inflammatory disease of the skin and is one of the most prevalent autoimmune diseases in the world.1 It is a heterogeneous disease with a complex etiology, which includes the contribution of multiple risk genes. Genetic research studies in psoriasis, particularly through genome-wide association analysis, have identified more than 40 loci associated with the susceptibility to the disease.2, 3, 4, 5, 6, 7, 8 However, little is known about the genetic factors that influence key clinical aspects of the disease such as the response to therapy. In particular, the identification of pharmacogenetic markers for the response to antitumor necrosis factor (TNF) agents would be a major advance in psoriasis translational research.

The chronic inflammatory process occurring in psoriasis skin lesions is characterized by the overexpression of multiple cytokines including tumor necrosis factor-α (TNF-α). TNF-α is also a cytokine overexpressed in other chronic inflammatory diseases such as rheumatoid arthritis, psoriatic arthritis or Crohn’s disease.9 Similar to this other group of autoimmune diseases, the blockade of the levels of TNF-α has proven to be a highly effective therapeutic approach to control the inflammatory process in psoriasis.10 There is, however, a significant percentage of anti-TNF-treated psoriasis patients (~30%) who do not show a significant clinical response.11,12 Anti-TNF agents are costly and are not exempt of secondary effects.13 Consequently, there is a need to identify new markers that can predict which patients will benefit from this particular therapy from those who will not respond.14

Genetic variation not only contributes to the increased risk of developing psoriasis but it has also been shown to influence the risk of developing different clinically relevant phenotypes.15 Using this approach, psoriasis risk locus TNFAIP3 (refs 2, 5) locus has been recently found to be associated with the response to anti-TNF therapy.16 In particular, it was found that the association was significant in the patients treated with etanercept, a TNF receptor fusion protein, but not with anti-TNF monoclonal antibodies adalimumab and infliximab. This result suggests that the genetic variation associated with treatment response is not homogeneous for all treatments and adds a new layer of complexity to the analysis of psoriasis pharmacogenetics. To date, however, no other psoriasis risk gene has been associated with anti-TNF response.

Genome-wide association studies provide a powerful approach for the analysis of the genetic risk associated with multiple traits. Genome-wide association studies can detect new candidate genes associated with treatment response without the need for prior biological knowledge. Recently, a genome-wide association studies of anti-TNF response in rheumatoid arthritis in the Danish population identified a large group of candidate regions.17 Using an independent cohort of rheumatoid arthritis patients from the Spanish population, we were able to replicate the association between PDE3A-SLCO1C1 ( phosphodiesterase 3A-SoLute Carrier Organic anion transporter family member 1C1) locus on chromosome 12p12.2 and anti-TNF response.18 Combining the evidence between the two patient cohorts, PDE3A-SLCO1C1 association was the first pharmacogenetic locus to reach the genome-wide level of significance in rheumatoid arthritis. Although the genetic basis of rheumatoid arthritis and psoriasis susceptibility is markedly different, we sought to test if the variation at this genomic region is also associated with the response to anti-TNF therapy in psoriasis.

Using a cohort of 130 patients, we have analyzed the association between the PDE3A-SLCO1C1 locus chromosome 12p12.2 and the clinical response to anti-TNF therapy in psoriasis. Additionally, we have analyzed the influence of different clinical factors on the genetic association to treatment response.

Patients and methods

Patients

A total of 130 patients with psoriasis who underwent treatment with an anti-TNF agent (etanercept, adalimumab and infliximab) were included in this study. The patients were recruited from the outpatients clinics of the dermatology departments from 11 university hospitals from Spain participating in the IMID Consortium.15 Psoriasis patients with plaque psoriasis affecting torso and/or extremities and with at least 1 year of duration were included. Patients with a single clinical localization of plaque psoriasis (i.e. scalp, face, palmoplantar), with exclusively inverse plaque psoriasis or with an inflammatory bowel disease, were excluded from the study.

All patients received anti-TNF treatment as their first biologic therapy after having a refractory psoriasis to 1 conventional systemic therapy, including methotrexate, cyclosporine, acitretin or phototherapy. Disease activity was measured at baseline and at 12–14 weeks of treatment using the Psoriasis Area and Severity Index (PASI).19

Genotyping

Whole blood samples were obtained from all patients and genomic DNA was extracted using the Chemagic Magnetic Separation Module (Perkin-Elmer, Norwalk, CT, USA). All samples were processed and stored at the IMID-Biobank (Vall Hebron Research Institute, Barcelona, Spain) until analysis. Genotyping of the PDE3A-SLCO1C1 locus single-nucleotide polymorphism (SNP) rs3794271 was performed using the Real-Time TaqMan® PCR genotyping system (Life Technologies, Carlsbad, CA, USA). The C_27502188_10 Taqman® SNP genotyping assay was used. Reverse transcription-PCR thermal conditions were as follows: 50 °C for 2 min and 95 °C for 10 min, followed by 40 cycles of 92 °C for 15 s and 60 °C for 1 min. The PCR assay and point fluorescent readings were performed using an ABI PRISM® 7900HT sequence detection system (Life Technologies). Twenty percent (n=26) of the individuals were genotyped in duplicate to estimate the genotyping error. The regenotyping of these samples was performed using the same technological platform (i.e. Taqman Reverse Transcription-PCR) and the same DNA aliquot as the initial genotyping. All genotypes were replicated and thus we estimated a <1% genotyping error in our study.

Statistical analysis

Response to therapy was measured using the relative change in the PASI between baseline and at 12–14 weeks of anti-TNF therapy: PASI response=(PASIbaseline−PASIend point)/ PASIbaseline × 100). The PASI response measures the percentage of improvement in disease activity relative to a specified baseline.20 The use of a relative score has the added advantage that it avoids any potential bias associated with different levels of disease activity at baseline. The association of the rs3794271 SNP genetic variation with the PASI response was performed using linear regression.

Clinical variables including age, age at psoriasis onset, duration of psoriasis, gender, presence of psoriatic arthritis, body mass index (BMI), nail involvement, family history of psoriasis, severity of disease, presence of additional skin forms of psoriasis (i.e. guttate, erythrodermic and pustular psoriasis) and type of anti-TNF agent were also tested for association with the response to anti-TNF treatment. Severity of disease was determined as described previously.15 Briefly, psoriasis patients are categorized into mild or moderate-to-severe disease according to the maximum level of body surface area affection achieved from disease diagnosis to the time of recruitment in the study. Patients never reaching a body surface area of 10% were categorized into having a mild disease and patients having had 10% body surface area were included in the moderate-to-severe group. The association between each variable and the PASI response was tested using linear regression. All statistical analyses were performed using the R statistical software version 3.0.1.21

The present study was performed following the Declaration of Helsinki protocols, and all patients gave their written informed consent to participate in this study. The study was approved by the local Institutional Review Boards of each of the participating centers.

Results

A total of 130 psoriasis patients having received an anti-TNF therapy were analyzed in the present study. Table 1 summarizes the main clinical features of the patient cohort.

Table 1 Clinical characteristics of the psoriasis patient cohort

We found a highly significant association between the genetic variation at PDE3A-SLCO1C1 SNP rs3794271 and the response to anti-TNF treatment in psoriasis (P=0.0031). Compared with the genetic association in rheumatoid arthritis, the minor allele of rs3794271 SNP (G) was associated with an improvement of the clinical response to anti-TNF therapy. Patients carrying one or two copies of the minor allele G had, on average, >10% improvement in the PASI response compared with patients homozygous for the major allele A (t-test for difference in means between the two groups, P=0.00017). Table 2 shows the average PASI response according to each rs3794271 SNP genotype.

Table 2 Genotype frequencies and associated PASI response for PDE3A-SLCO1C1 rs3794271 SNP

Analyzing the association of the clinical variables as potential predictors of anti-TNF therapy, we found a significant association between nail involvement, BMI and erythrodermic psoriasis with the PASI response (P=0.021, P=0.05 and P=0.018, respectively). Patients with nail disease were found to have a lower response to anti-TNF therapy (mean±s.d. PASI response with nail involvement=76.1±25.1%, without nail involvement=85.3±17.7%). We also found that BMI was negatively correlated with the PASI response (r2=−0.17, Pcorrelation=0.05). The presence of erythrodermic psoriasis was also associated with a lower response to anti-TNF therapy (mean±s.d. PASI response with erythrodermic psoriasis=63.1±34.3%, without erythrodermic psoriasis=81.4±20.9%). No other clinical variables, including anti-TNF treatment type, showed a significant association with the clinical response. To control for the potential effect of the covariates on the observed PDE3A-SLCO1C1 association with anti-TNF response, we used a multivariate linear regression analysis. Including all significant clinical variables in the multivariate model, the association between rs3794271 SNP and the PASI response was still highly significant (P=0.00057).

Finally, to evaluate the trend of the association of rs3794271 genotype and treatment response according to anti-TNF treatment type, we performed a stratified analysis (Supplementary Table S1). We found a significant association of the SNP with PASI response with the group of etanercept-treated patients (P=0.012) and a trend in infliximab-treated patients (P=0.14).

Discussion

Psoriasis is a highly heterogeneous disease characterized by a wide variety of phenotypic manifestations and degrees of severity. In those cases with highest severity and that are refractory to other systemic therapies, anti-TNF agents are a powerful and highly effective therapeutic option. However, in 20–40% of psoriasis patients, TNF blockade is not sufficient to control the disease activity in the skin. Consequently, there is a high need to identify markers that can help predict the type of response to anti-TNF agents in psoriasis. In the present study, we have found a significant association between PDE3A-SLCO1C1 locus with the response to anti-TNF agents in psoriasis. The results of this study are an important step in the personalization of anti-TNF therapy in psoriasis and provide new important clues on the clinical and molecular features that differentiate anti-TNF-responsive patients from non-responders.

PDE3A-SLCO1C1 locus SNP rs3794271 lies in the fourth intron of the SLCO1C1 gene. Extensive genotype data of this locus on chromosome 12p12.2 indicates that this SNP lies in a linkage disequilibrium region that includes both the 3′-terminal region of PDE3A gene and the promoter and 5′ region of SLCO1C1 gene.18 Therefore, the genetic variant causing the association could be related to any of the two genes. As none of the coding variants at the PDE3A or SLCO1C1 genes is in strong linkage disequilibrium with rs3794271 SNP, it is likely that the genetic variation associated with anti-TNF response in psoriasis participates in a genetic regulatory process. Using recent expression quantitative trait loci data generated by the sequencing of the transcriptome of lymphoblastoid cell lines,22 we did not find any significant evidence of cis or trans gene expression regulation for this SNP (data not shown). It is likely, however, that the regulatory functionality of the PDE3A-SLCO1C1 locus associated with the response to anti-TNF therapy in psoriasis is cell-type-specific and will only be identified in the cells relevant to the disease. Consequently, future functional experiments on specific skin and immune cell types should clarify the specific role of this genetic region in the response to anti-TNF therapy.

There is biological evidence supporting the role of both PDE3A and SLCO1C1 genes in drug response. PDE3A belongs to a large family of cyclic nucleotide phosphodiesterases that catalyze the hydrolysis of cAMP and cGMP into the inactive forms 5′-AMP and 5′-GMP, respectively. Phosphodiesterases participate in multiple intercellular signaling processes that affect multiple cell subtypes and biological functions. Phosphodiesterase 4D is strongly associated with the immune and inflammatory activity, and, importantly, therapies targeting this protein have shown to be efficacious in the treatment of psoriasis.23 SLCO1C1 gene belongs to the organic anion-transporting polypeptide family of cell membrane transporters. This group of proteins has been associated with the active transport of different organic molecules, toxins and drugs. Members of this family have been shown to be constitutively expressed in human keratinocytes.24 Importantly, there is sound evidence demonstrating that polymorphisms in SLCO1B1, a member of the organic anion-transporting polypeptide family, have strong pharmacogenetic effects on different types of drugs including methotrexate, a treatment for psoriasis and a drug that is generally coadministered with anti-TNF agents to reduce immunogenicity.25 Deep sequencing of the PDE3A-SLCO1C1 genomic region in anti-TNF responder and non-responder psoriasis patients will help to determine the precise DNA variation associated with treatment response, and, subsequently, perform functional studies to determine the biological activity associated with this genomic region.

In the present study, we have also found that the presence of nail involvement, increased BMI and the erythrodermic phenotype are bad prognosis factors for the response to anti-TNF agents in psoriasis. There is increasing evidence that BMI has a strong influence in different aspects of psoriasis epidemiology.26, 27 Importantly, there is evidence that overweight is associated with a loss of efficacy of anti-TNF agents.28 The present manuscript confirms this finding and supports the importance of an adequate management of obesity in the treatment of psoriasis. To our knowledge, our study provides the first evidence that nail involvement and the erythrodermic phenotype are bad prognosis factors for anti-TNF treatment. Finally, including the associated clinical variables as covariates, we found that PDE3A-SLCO1C1 association with the PASI response is still strong. This result demonstrates that the newly identified genetic association between PDE3A-SLCO1C1 and anti-TNF response in psoriasis is little influenced by clinical variability.

The minor allele of the PDE3A-SLCO1C1 locus SNP rs3794271 (G) was associated with a significant reduction of the disease activity in the psoriasis skin, whereas it was associated with a worse response to anti-TNF agents in rheumatoid arthritis. In rheumatoid arthritis, the most common disease activity score, the DAS28,29 is a composite score that measures the degree of inflammation in the synovial joints and at the systemic level. Therefore, our results suggest that while blocking TNF is an effective means of controlling the inflammatory activity in psoriasis and rheumatoid arthritis, the biological mechanisms that underlie both types of treatment response are markedly different. There is substantial evidence that the cell-type features that characterize the psoriasis lesion with the rheumatoid arthritis synovial inflammation are clearly different.30 Furthermore, in some rheumatoid arthritis patients, TNF blocking has shown to induce psoriasis,31, 32 clearly supporting the existence of very different pathogenic mechanisms. Recently, pharmacogenetic studies of FCGR2A and FCGR3A gene variants and anti-TNF therapy response have provided suggestive evidence for opposite genetic effects between rheumatoid arthritis and Crohn’s disease,33 rheumatoid arthritis and psoriatic arthritis34 and even between rheumatoid arthritis and psoriasis.20 Taken together, these results support the existence of different TNF-related pathways and, consequently, different biologic mechanisms by which TNF blocking is an effective treatment.

Stratifying by the type of anti-TNF agent, we found that the genetic association was only statistically significant in the group of psoriasis patients treated with etanercept. Recently, Tejasvi et al.16 reported a significant association of TNFAIP3 locus with anti-TNF response exclusively in etanercept-treated patients. The previous study, including the data from the adalimumab- and infliximab-treated patients, did not improve the statistical significance. However, our study, including all three anti-TNF agents, clearly increased the significance of the association. This result suggests that the observed PDE3A-SLCO1C1 locus association with anti-TNF therapy in psoriasis is not specific to one single agent. However, the reduction in sample size after stratifying by anti-TNF treatment precludes definite conclusions for each agent. Future studies with larger sample sizes per anti-TNF agent will allow to characterize this aspect of this new pharmacogenetic association.

In the present study, we have found an association between the PDE3A-SLCO1C1 locus and the response to anti-TNF therapy in psoriasis. The allele associated with a positive response in psoriasis is the same allele associated with a lack of clinical response in rheumatoid arthritis, suggesting the existence of large biological differences at the molecular level, despite the similar efficacy of TNF blockers. The results of this study are an important step in the translational research in psoriasis and will clearly lead to new research lines that will improve the prognosis of psoriasis patients with more severe disease.

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Acknowledgements

This work was supported by the Spanish Ministry of Economy and Competitiveness Strategic Project grants (PSE-010000-2006-6, IPT-010000-2010-36).

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Correspondence to S Marsal.

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Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website

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Julià, A., Ferrándiz, C., Dauden, E. et al. Association of the PDE3A-SLCO1C1 locus with the response to anti-TNF agents in psoriasis. Pharmacogenomics J 15, 322–325 (2015). https://doi.org/10.1038/tpj.2014.71

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