Predicting therapy response to mycophenolic acid using UGT1A9 genotyping: towards personalized medicine in atopic dermatitis

Atopic dermatitis (AD) is a very common chronic inflammatory skin disease requiring long-term treatment. Mycophenolic acid (MPA) is used off-label in treatment of patients with severe AD failing Cyclosporin A (CsA) treatment, however clinical efficacy is observed in only half of the AD patients. In blood, MPA levels are known to have a large interindividual variability. Low MPA exposure and increased enzyme activity correlates with the presence of UGT1A9 polymorphisms. In this retrospective study, 65 adult AD patients treated with MPA were classified as responder or non-responder to MPA treatment. UGT1A9 polymorphisms were determined using PCR. A significantly higher number of UGT1A9 polymorphisms was found in the group that did not respond to MPA treatment. Of the patients that carried a UGT1A9 polymorphism, 85.7% were non-responsive to MPA treatment. This implies that non-responsiveness in AD patients is more likely to occur in carriers of a UGT1A9 polymorphism. In a binary logistic regression analysis the odds ratio (OR) was 8.65 (95% confidence interval: 0.93–80.17). Our results show that UGT1A9 polymorphisms can be used to identify patients with non-responsiveness to MPA. Patients with UGT1A9 polymorphisms might benefit from higher MPA dosage

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and Tamoxifen Therapy

Personalised Therapeutic

Exposure to thioguanine during 117 pregnancies in women with inflammatory bowel disease

Background: Safety of thioguanine in pregnant patients with inflammatory bowel disease [IBD] is sparsely recorded. This study was aimed to document the safety of thioguanine during pregnancy and birth. Methods: In this multicentre case series, IBD patients treated with thioguanine during pregnancy were included. Data regarding disease and medication history, pregnancy course, obstetric complications, and neonatal outcomes were collected. Results: Data on 117 thioguanine-exposed pregnancies in 99 women were collected. Most [78%] had Crohn's disease and the mean age at delivery was 31 years. In 18 pregnancies [15%], IBD flared. Obstetric and infectious complications were seen in 15% [n = 17] and 7% [n = 8] of pregnancies, respectively. Ten pregnancies [8.5%] resulted in a first trimester miscarriage, one in a stillbirth at 22 weeks of gestational age and one in an induced abortion due to trisomy 21. In total, 109 neonates were born from 101 singleton pregnancies and four twin pregnancies. One child was born with a congenital abnormality [cleft palate]. In the singleton pregnancies, 10 children were born prematurely and 10 were born small for gestational age. Screening for myelosuppresion was performed in 16 neonates [14.7%]; two had anaemia in umbilical cord blood. All outcomes were comparable to either the general Dutch population or to data from three Dutch cohort studies on the use of conventional thiopurines in pregnant IBD patients. Conclusion: In this large case series, the use of thioguanine during pregnancy is not associated in excess with adverse maternal or neonatal outcomes.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Correction: A european spectrum of pharmacogenomic biomarkers: Implications for clinical pharmacogenomics (PLoS ONE (2016) 11:9 (e0162866) DOI: 10.1371/journal.pone.0162866)

The thirty-Third author's name is spelled incorrectly. The correct name is: Jadranka Sertić

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Peer reviewe