Genome-wide association analysis of psoriasis patients treated with anti-TNF drugs.

While anti-TNF therapies are effective against psoriasis, 30%-50% of patients do not show an adequate response to these drugs. Different candidate-gene pharmacogenetics studies have identified single nucleotide polymorphisms that may predict anti-TNF drugs response in psoriasis. Nevertheless, only one paper has undertaken a pharmacogenomic approach failing to find significant biomarkers of biological drug response along the whole genome. Furthermore, most of the pharmacogenetic candidate biomarkers identified previously have not been confirmed in a different cohort of patients. The objective of this study was to find biomarkers that could predict anti-TNF drugs response along the whole genome and validate biomarkers identified previously. A genome-wide association study (GWAS) was performed using the Human Omni Express-8 v1.2 Beadchips in 243 psoriasis patients treated with anti-TNF drugs. This study was multicentric and did not interfere with clinical practice. Associations between single nucleotide polymorphisms (SNP) and PASI75 (a 75% reduction with respect to baseline PASI) at 3 months were evaluated. Imputation was performed using SNPs with R2  > 0.7. There were two SNPs located in NPFFR2 that were close to the significant threshold of 5 × 10-8 . These data suggest that NPFFR2 might be associated with anti-TNF drug response. However, further studies involving a larger cohort of patients are needed in order to confirm these results.

Association between Genetic Polymorphisms and Response to Anti-TNFs in Patients with Inflammatory Bowel Disease.

Tumor necrosis factor (TNF) alpha is a major proinflammatory cytokine involved in the immune response in inflammatory bowel disease (IBD). Anti-TNF drugs such as infliximab and adalimumab are used to treat IBD; however, approximately 30% of patients do not respond to treatment. Individual genetic differences could contribute to lack of efficacy. Genetic studies have tried to uncover the factors underlying differences in response, however, knowledge remains limited, and the results obtained should be validated, so that pharmacogenetic information can be applied in clinical practice. In this review, we gather current knowledge in the pharmacogenetics of anti-TNF drugs in patients with IBD. We observed a connection between the major genes described as possible predictors of response to anti-TNF drugs in IBD and the cytokines and molecules involved in the T helper (Th) 17 pathway.

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 C(max) 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.

Polymorphisms associated with adalimumab and infliximab response in moderate-to-severe plaque psoriasis.

AIM: This study evaluated the influence of pharmacogenetics in psoriatic patients treated with adalimumab and/or infliximab. MATERIALS & METHODS: Prospective observational study evaluating the association of 124 polymorphisms with the response to adalimumab or infliximab (PASI75) in patients with moderate-to-severe plaque psoriasis at 3 months (n = 95) and 6 months of treatment (n = 90). Significant SNPs for univariate analysis were subjected to multivariate analysis. RESULTS: Five SNPs were associated with PASI75 at 3 months: rs6661932 (IVL), rs2546890 (IL-12B), rs2145623 (NFKBIA), rs9304742 (ZNF816A) and rs645544 (SLC9A8). Furthermore, rs1061624 (TNFR1B) was associated with PASI75 at 6 months. CONCLUSION: Nevertheless, 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.

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.

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.

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).

Polymorphisms Associated with Age at Onset in Patients with Moderate-to-Severe Plaque Psoriasis.

Psoriasis is a chronic skin disease in which genetics play a major role. Although many genome-wide association studies have been performed in psoriasis, knowledge of the age at onset remains limited. Therefore, we analyzed 173 single-nucleotide polymorphisms in genes associated with psoriasis and other autoimmune diseases in patients with moderate-to-severe plaque psoriasis type I (early-onset, <40 years) or type II (late-onset, ≥40 years) and healthy controls. Moreover, we performed a comparison between patients with type I psoriasis and patients with type II psoriasis. Our comparison of a stratified population with type I psoriasis (n = 155) and healthy controls (N = 197) is the first to reveal a relationship between the CLMN, FBXL19, CCL4L, C17orf51, TYK2, IL13, SLC22A4, CDKAL1, and HLA-B/MICA genes. When we compared type I psoriasis with type II psoriasis (N = 36), we found a significant association between age at onset and the genes PSORS6, TNF-α, FCGR2A, TNFR1, CD226, HLA-C, TNFAIP3, and CCHCR1. Moreover, we replicated the association between rs12191877 (HLA-C) and type I psoriasis and between type I and type II psoriasis. Our findings highlight the role of genetics in age of onset of psoriasis.

Epigenetic effect of testosterone in the behavior of C. elegans. A clue to explain androgen-dependent autistic traits?

Current research indicates that the causes of autism spectrum disorders (ASDs) are multifactorial and include both genetic and environmental factors. To date, several works have associated ASDs with mutations in genes that encode proteins involved in neuronal synapses; however other factors and the way they can interact with the development of the nervous system remain largely unknown. Some studies have established a direct relationship between risk for ASDs and the exposure of the fetus to high testosterone levels during the prenatal stage. In this work, in order to explain possible mechanisms by which this androgenic hormone may interact with the nervous system, C. elegans was used as an experimental model. We observed that testosterone was able to alter the behavioral pattern of the worm, including the gentle touch response and the pharyngeal pumping rate. This impairment of the behavior was abolished using specific RNAi against genes orthologous to the human androgen receptor gene. The effect of testosterone was eliminated in the nhr-69 (ok1926) deficient mutant, a putative ortholog of human AR gene, suggesting that this gene encodes a receptor able to interact with the hormone. On the other hand the testosterone effect remained in the gentle touch response during four generations in the absence of the hormone, indicating that some epigenetic mechanisms could be involved. Sodium butyrate, a histone deacetylase inhibitor, was able to abolish the effect of testosterone. In addition, the lasting effect of testosterone was eliminated after the dauer stage. These results suggest that testosterone may impair the nervous system function generating transgenerational epigenetic marks in the genome. This work may provide new paradigms for understanding biological mechanisms involved in ASDs traits.

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.

Pharmacogenetics of topical and systemic treatment of psoriasis.

Psoriasis is a chronic inflammatory skin disease. The cause of psoriasis is unknown, although genetics may play a key role in its development. Treatment of the disease varies with severity. Topical drugs, such as corticosteroids, coal tar, retinoids and vitamin D analogs, are commonly used to treat mild psoriasis. Phototherapy and systemic drugs, such as calcineurin inhibitors, methotrexate, acitretin and biological drugs, are usually used to treat moderate-to-severe psoriasis. Not all patients respond well to treatment, and some can develop severe adverse effects. Interindividual differences in several genes may explain this variation in response to treatment. Pharmacogenetics and pharmacogenomics can facilitate more personalized medicine and prevent the adverse effects associated with treatment.

Genetics of psoriasis and pharmacogenetics of biological drugs.

Psoriasis is a chronic inflammatory disease of the skin. The causes of psoriasis are unknown, although family and twin studies have shown genetic factors to play a key role in its development. The many genes associated with psoriasis and the immune response include TNF α , IL23, and IL12. Advances in knowledge of the pathogenesis of psoriasis have enabled the development of new drugs that target cytokines (e.g., etanercept, adalimumab, and infliximab, which target TNF α , and ustekinumab, which targets the p40 subunit of IL23 and IL12). These drugs have improved the safety and efficacy of treatment in comparison with previous therapies. However, not all patients respond equally to treatment, possibly owing to interindividual genetic variability. In this review, we describe the genes associated with psoriasis and the immune response, the biological drugs used to treat chronic severe plaque psoriasis, new drugs in phase II and III trials, and current knowledge on the implications of pharmacogenomics in predicting response to these treatments.

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.

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.