María Talegón

The polymorphism rs763780 in the IL-17F gene is associated with response to biological drugs in patients with psoriasis

Psoriasis improves when IL-17 is blocked. Anti-TNF drugs reduce the IL-17 signaling pathway, and anti-IL-17 drugs are being developed to treat moderate-to-severe psoriasis. We analyzed three SNPs in IL-17A (rs2275913 and rs10484879) and IL-17F (rs763780) to look for an association with psoriasis and/or with response to anti-TNF drugs or ustekinumab. We included 197 healthy controls and 194 patients with moderate-to-severe psoriasis. The results of the univariate analysis showed an association between rs10484879 and psoriasis, although this relationship disappeared after adjustment for HLA-C (rs12191877). We also found an association between rs763780 (IL-17F) and response to ustekinumab (n = 70) and infliximab (n = 37) at 3 and 6 months and an association between rs763780 and the response to adalimumab at 6 months (n = 67).

Evaluation of the Relationship between Sex, Polymorphisms in CYP2C8 and CYP2C9, and Pharmacokinetics of Angiotensin Receptor Blockers

Angiotensin II receptor blockers (ARBs) are used to treat hypertension. Most ARBs are metabolized by CYP2C9. The aim of this study is to evaluate the possible association between sex, polymorphisms in the CYP2C8 and CYP2C9 genes, and the pharmacokinetics of losartan, valsartan, candesartan, and telmisartan. The study population comprised 246 healthy volunteers from seven single-dose clinical trials: 64 from two candesartan studies, 43 from a telmisartan study, 36 from a losartan study, and 103 from three valsartan studies. DNA was extracted from blood samples and single-nucleotide polymorphisms in the CYP2C8 (CYP2C8*2, CYP2C8*3, CYP2C8*4, CYP2C8*5) and CYP2C9 (CYP2C9*2, CYP2C9*3) genes were evaluated using real-time polymerase chain reaction. Sex only affected telmisartan pharmacokinetics, since women showed a higher telmisartan Cmax than men (590.5 ± 75.8 ng/ml versus 282.1 ± 30.8 ng/ml; P ≤ 0.01). CYP2C9 variants were associated only with losartan pharmacokinetics: the half-life of losartan was higher in CYP2C9*3 allele carriers (3.1 ± 0.4 hours) than in volunteers with the wild-type genotype (2.3 ± 0.1 hours) (P ≤ 0.05). CYP2C8 polymorphisms were associated only with valsartan pharmacokinetics, since *2 allele carriers showed faster clearance (1.07 ± 0.57 l/h·kg) than those with the wild-type genotype (0.48 ± 0.72 l/h·kg; P ≤ 0.01) and carriers of the *3 allele (0.35 ± 0.49 l/h·kg; P ≤ 0.001). These results suggest that genotypes for CYP2C9 and CYP2C8 are relevant to the pharmacokinetics of losartan and valsartan, respectively, but not the pharmacokinetics of candesartan or telmisartan.

Evaluation of the relationship between polymorphisms in CYP2C8 and CYP2C9 and the pharmacokinetics of celecoxib.

Celecoxib is metabolized by enzymes of the cytochrome P450 (CYP450) superfamily, mainly CYP2C9 and CYP3A4. Polymorphisms in the CYP2C9 gene have been associated with decreased enzyme activity and alteration of celecoxib pharmacokinetic parameters. However, literature reports are limited, and some results are contradictory. We enrolled 24 healthy volunteers in a single‐dose replicated crossover trial with celecoxib 200 mg. We evaluated the association between single‐nucleotide polymorphisms in the CYP2C8 and CYP2C9 genes (CYP2C8*2, CYP2C8*3, CYP2C8*4, CYP2C9*2, and CYP2C9*3) of these individuals and the pharmacokinetic parameters of celecoxib. Subjects carrying CYP2C9*1/*3 and CYP2C9*3/*3 had a higher AUC (2‐ and 7.7‐fold, respectively) and Cmax (1.5‐ and 1.8‐fold, respectively) and lower clearance (2.3‐ and 10‐fold, respectively) than those carrying CYP2C9*1/*1. Half‐life was 2.7‐fold higher in subjects with CYP2C9*3/*3 than in those with the wild type but not in those with CYP2C9*1/*3. We did not find any significant effect of gender or CYP2C8 polymorphisms on the pharmacokinetics of celecoxib. In conclusion, the recommended dose of celecoxib should be decreased in CYP2C9*3 carriers, especially in homozygous subjects.

Association between psoriasis and polymorphisms in the TNF , IL12B , and IL23R genes in Spanish patients

BACKGROUND & OBJECTIVES Susceptibility to psoriasis has been associated with the HLA-C*0602 allele, although it may be affected by other polymorphisms. MATERIALS & METHODS We genotyped 142 patients and 160 healthy volunteers to evaluate the possible relationship between susceptibility to psoriasis and the HLA-C*0602 allele and polymorphisms in the TNF, IL12B, and IL23R genes. RESULTS The frequency of the wild-type TNF-238, TNF-308, and TNF-1031 genotypes was greater in patients with psoriasis than in healthy volunteers, although that of the mutant TNF-857 genotype was higher. The only difference between psoriasis and psoriatic arthritis was TNF-857. The frequency of the HLAC*0602 allele was higher in psoriatic patients than in healthy volunteers. No differences were observed for IL12B and IL23R. Multivariate logistic regression analysis only confirmed these associations for TNF-238, TNF-857, and HLA-C*0602. CONCLUSION Our results support an association between susceptibility to psoriasis and TNF polymorphisms in the Spanish population.

Pharmacogenetics of ustekinumab in patients with moderate-to-severe plaque psoriasis

Aim/Materials & methods: Few studies have evaluated the influence of pharmacogenetics in psoriatic patients treated with ustekinumab. We evaluated 121 polymorphisms to study a possible association between these SNPs and the response to ustekinumab (PASI75 at 4 months; n = 69). RESULTS/CONCLUSION The adjusted results (false discovery rate) showed an association between five SNPs in TNFRSF1A, HTR2A, NFKBIA, ADAM33 and IL13 genes, and poor response to ustekinumab. Furthermore, six SNPs in CHUK, C17orf51, ZNF816A, STAT4, SLC22A4 and Corf72 genes were associated with better response to ustekinumab. However, there was no significant association between response to ustekinumab and SNPs in HLA-C as it has been recently described. Finally, a higher weight was obtained in nonresponders than responders (p = 0.018). Further studies would be necessary to be closer to personalized medicine.

Evaluation of the relationship between polymorphisms in CYP2C19 and the pharmacokinetics of omeprazole, pantoprazole and rabeprazole

AIM To evaluate the possible association between polymorphisms in CYP2C19 and the pharmacokinetics of omeprazole, rabeprazole and pantoprazole. MATERIALS & METHODS 151 healthy volunteers were evaluated for polymorphisms in the CYP2C19 gene using real-time polymerase chain reaction. Plasma concentrations were measured using high-performance liquid chromatography coupled to mass spectrometry. RESULTS Carriers of the *2 allele displayed poor metabolism for all the PPIs studied (around 50% decrease in clearance). Subjects with the *17 allele showed a light increase in clearance compared with *1/*1 (not significant). CONCLUSION CYP2C19*2 is associated with decreased clearance of all the PPIs, that could be associated with higher drug efficacy. CYP2C19*17 could increase clearance of these drugs, although the effect seems small.

New polymorphisms associated with response to anti-TNF drugs in patients with moderate-to-severe plaque psoriasis.

Anti-tumor necrosis factor (anti-TNF) drugs are effective against psoriasis, although 20–30% of patients are nonresponders. Few pharmacogenomic studies have been performed to predict the response to anti-TNF drugs in psoriasis. We studied 173 polymorphisms to establish an association with the response to anti-TNF drugs in patients with moderate-to-severe plaque psoriasis (N=144). We evaluated the response using PASI75 at 3, 6 and 12 months. The results of the multivariate analysis showed an association between polymorphisms in PGLYR4, ZNF816A, CTNNA2, IL12B, MAP3K1 and HLA-C genes and the response at 3 months. Besides, the results for polymorphisms in IL12B and MAP3K1 were replicated at 6 months. We also obtained significant results for IL12B polymorphism at 1 year. Moreover, polymorphisms in FCGR2A, HTR2A and CDKAL1 were significant at 6 months. This is the first study to show an association with these polymorphisms. However, these biomarkers should be validated in large-scale studies before implementation in clinical practice.

Polymorphisms associated with etanercept response in moderate-to-severe plaque psoriasis

AIM Few studies have evaluated the influence of pharmacogenetics in psoriatic patients treated with etanercept. MATERIALS & METHODS We evaluated the association between 124 polymorphisms with the response to etanercept in patients with moderate-to-severe plaque psoriasis at 3 months (n = 78) and 6 months of treatment (n = 68). RESULTS The results of the multivariate analysis showed an association between polymorphisms rs13437088 (HLA-B/MICA), rs96844 (MAP3K1), rs2431697 (PTTG1), rs9304742 (ZNF816A) and the response to etanercept at 3 months. Besides polymorphisms rs928655 (GBP6) and rs2546890 (IL12B) were associated to response at 6 months. CONCLUSIONS Nevertheless, these biomarkers should be validated in large-scale studies before its implementation in clinical practice.

New immune system genetic polymorphisms associated with moderate-to-severe plaque psoriasis: a case-control study.

DEAR EDITOR, Genes for factors such as interleukin-23 receptor (IL-23R), IL-12B and tumour necrosis factor (TNF)-a have been widely associated with psoriasis and related diseases [rheumatoid arthritis (RA), psoriatic arthritis (PsA) and Crohn disease (CD)]. These genes are therapeutic targets to treat psoriasis. However, results with other candidate genes are controversial. Therefore, large-scale studies are needed to verify the genetic factors that trigger psoriasis. We evaluated the possible association between 192 single-nucleotide polymorphisms (SNPs) and moderate-to-severe chronic plaque psoriasis. This approach may help us to find new targets for safer and more effective drugs. We recruited 197 healthy volunteers without a personal or family history of psoriasis, and 198 patients with moderateto-severe plaque psoriasis between 16 October 2007 and 17 December 2012, in four hospitals in Madrid, Spain. All patients were white. The protocol fulfilled Spanish law on biomedical research. DNA was obtained from peripheral blood samples (MagNA Pure System; Roche, Pleasanton, CA, U.S.A.). All samples were sent to the Human Genotyping Unit (CEGEN, Madrid, Spain), except two samples that had insufficient volume, to genotype 192 SNPs (VeraCode genotyping platform; Illumina, San Diego, CA, U.S.A.). The SNPs were preselected based on reports of psoriasis and other autoimmune diseases (RA, PsA and CD; 449 articles). We finally selected SNPs based on minor allele frequency ≥ 0 05, and on the results of studies performed in white patients with psoriasis (Table S1; see Supporting Information). We calculated the Hardy–Weinberg equilibrium (HWE; P > 0 05), and allele and genotype frequencies (snpStats R). The SNPs that did not fulfil the HWE in controls were removed from the subsequent analysis. Univariate analysis was performed using R version 3.0.2 (SNPassoc; http://www. r-project.org/). We constructed logistic regression models (codominant, dominant, recessive and additive). We then repeated these analyses in stratified populations: patients with psoriasis without and with PsA. The results were adjusted for rs12191877, which was strongly associated with the human leucocyte antigen (HLA)-C*0602 allele with high prevalence in our population. The optimal model was selected by the Akaike information criterion. We also calculated the haplotype frequencies and the association with psoriasis (snpStats). SNPs with P < 0 1 in the univariate analysis (adjusted for rs12191877) were included in a multivariate logistic regression model (SPSS 15 0; IBM, Armonk, NY, U.S.A.). Our population included 197 controls (98 men and 99 women; aged 24 5 4 3 years) and 191 patients (111 men and 80 women; aged 50 1 15 4 years). We evaluated the effect of sex on our results and did not find any significant association. CEGEN quality criteria were not met in 19 SNPs and five patients, and nine SNPs in the controls were not in HWE (Table S1). Sixty-four SNPs with P < 0 1 were included in the multivariate analysis (Table S2; see Supporting Information), and only nine SNPs maintained their associations with psoriasis (Table 1). We provide the first description of the following SNPs in psoriasis (Tables 1 and 2). 1 rs2476601 (PTPN22; AA/AG decreased the risk of psoriasis 3 80-fold). The minor allele only has been associated with CD, RA and PsA. 2 rs3783543 (IL1A; TT/CT increased the risk 1 94-fold). The haplotype analysis showed an association between psoriasis and the TGC haplotype (rs3783543, rs17561 and rs1143634, respectively) in the IL1A and IL1B genes (P = 0 0072) (Table S3; see Supporting Information). Only one study has associated PsA with a region including rs3783543. 3 rs12188300 (IL12B; TT/AT increased the risk 5 54-fold). Only one genome-wide association study (GWAS) has associated this SNP (T allele) with susceptibility to PsA. The p40 subunit of IL-12 (encoded by IL12B) is used as a target in the treatment of psoriasis (ustekinumab). Thus this cytokine is clearly involved in the immunopathogenesis of psoriasis. 4 rs10499194 (TNFAIP3; CT increased the risk 2 50-fold). In a GWAS, this SNP has been associated only with RA. 5 rs11986055 (IKBKB; AC decreased the risk 4 85-fold). rs11986055 (C allele) has been associated only with a more pronounced response to anti-TNF drugs after 6 months of treatment in RA. 6 rs3792876 (SLC22A4; TT/CT increased the risk 4 01-fold). rs3792876 has been associated more with paediatric-onset CD than with adult-onset CD. One meta-analysis showed a significant association between RA and rs3792876 in a Japanese population, although not in white patients.

Effect of gender and CYP2C9 and CYP2C8 polymorphisms on the pharmacokinetics of ibuprofen enantiomers

AIM To evaluate the effect of polymorphisms in CYP2C9 and CYP2C8 and gender on the pharmacokinetics of the enantiomeric forms of ibuprofen. MATERIALS & METHODS 122 healthy volunteers were genotyped for polymorphisms in CY2C8 and CYP2C9 using real-time PCR. RESULTS CYP2C8 polymorphisms affected neither R- nor S-ibuprofen. CYP2C9*3 and CYP2C9*2 carriers had a lower S-ibuprofen clearance and a higher S-ibuprofen AUC and half-life. R-ibuprofen clearance was decreased in CYP2C9*3 carriers. Gender affected R-ibuprofen and S-ibuprofen pharmacokinetics. Multiple regression analysis showed that CYP2C9*2, CYP2C9*3 and gender were associated with S-ibuprofen clearance, but only CYP2C9*3 was associated with R-ibuprofen clearance. CONCLUSION The pharmacokinetics of S-ibuprofen and R-ibuprofen is affected by CYP2C9 polymorphisms and gender. CYP2C8 polymorphisms do not have a significant role. Original submitted 6 February 2015; Revision submitted 1 April 2015.