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OBJECTIVE:Genome-wide association studies in adults have identified 42 loci associated with thyroid stimulating hormone (TSH) and 21 loci associated with free thyroxine (FT4) concentrations. While biologically plausible, age-dependent effects have not been assessed. We aimed to study the association of previously identified genetic determinants of TSH and FT4 with TSH and FT4 concentrations in newborns and (pre)school children. METHODS: We selected participants from three population-based prospective cohorts with data on genetic variants and thyroid function: Generation R (N = 2169 children, mean age 6 years; N = 2388 neonates, the Netherlands), the Avon Longitudinal Study of Parents and Children (ALSPAC; N = 3382, age 7.5 years, United Kingdom), and the Brisbane Longitudinal Twin Study (BLTS; N = 1680, age 12.1 years, Australia). The association of single nucleotide polymorphisms (SNPs) with TSH and FT4 concentrations was studied with multivariable linear regression models. Weighted polygenic risk scores (PRSs) were defined to combine SNP effects.RESULTS:In childhood, 30/60 SNPs were associated with TSH and 11/31 SNPs with FT4 after multiple testing correction. The effect sizes for AADAT, GLIS3, TM4SF4, and VEGFA were notably larger than in adults. The TSH PRS explained 5.3%-8.4% of the variability in TSH concentrations; the FT4 PRS explained 1.5%-4.2% of the variability in FT4 concentrations. Five TSH SNPs and no FT4 SNPs were associated with thyroid function in neonates. CONCLUSIONS: The effects of many known thyroid function SNPs are already apparent in childhood and some might be notably larger in children as compared to adults. These findings provide new knowledge about genetic regulation of thyroid function in early life.

Aim of the study: Occurrence of hand-foot syndrome (HFS) during capecitabine treatment often results in treatment interruptions (26 %) or treatment discontinuation (17 %), and can severely decrease quality of life. In this study, we investigated whether single nucleotide polymorphisms (SNPs) in genes involved in capecitabine metabolism – other than DPYD – are associated with an increased risk for capecitabine-induced HFS. Methods: Patients treated with capecitabine according to standard of care were enrolled after providing written informed consent for genotyping purposes. Prospectively collected blood samples were used to extract genomic DNA, which was subsequently genotyped for SNPs in CES1, CES2 and CDA. SNPs and clinical baseline factors that were univariably associated with HFS with P ≤ 0.10, were tested in a multivariable model using logistic regression. Results: Of the 446 patients eligible for analysis, 146 (32.7 %) developed HFS, of whom 77 patients (17.3 %) experienced HFS ≥ grade 2. In the multivariable model, CES1 1165–33 C>A (rs2244613, minor allele frequency 19 %) and CDA 266 + 242 A>G (rs10916825, minor allele frequency 35 %) variant allele carriers were at higher risk of HFS ≥ grade 2 (OR 1.888; 95 %CI 1.075–3.315; P = 0.027 and OR 1.865; 95 %CI 1.087–3.200; P = 0.024, respectively). Conclusions: We showed that CES1 1165–33 C>A and CDA 266 + 242 A>G are significantly associated with HFS grade 2 and grade 3 in patients treated with capecitabine. Prospective studies should assess whether this increased risk can be mitigated in carriers of these SNPs, when pre-emptive genotyping is being followed by dose adjustment or by alternative treatment by a fluoropyrimidine that is not substrate to CES1, such as S1.

Micro-ribonucleic acids (miRNAs) are non-coding RNA molecules crucial in the post-transcriptional regulation of gene expression, via complementary binding to specific messenger RNAs (mRNAs). MiRNAs play a role in many biological processes, such as cell proliferation and differentiation. Consequently, tightly regulated miRNA expression is important in organogenesis, whereas dysregulation is related to various diseases, including cancer. In Wilms tumor, the most common form of pediatric kidney cancer, differences in miRNA profiles between the blastemal and recessive subtypes are found. In addition, mutations in miRNA biogenesis genes, DROSHA, DGCR8 and DICER1, are found in Wilms tumors. Patients with Perlman syndrome, who show increased susceptibility to Wilms tumor formation, harbor biallelic mutations in DIS3L2. DIS3L2 is an exoribonuclease involved in miRNA degradation, specifically important in the DIS3L2-LIN28-let-7 pathway. Besides, recently germline as well as somatic second hit mutations in DIS3L2 were found in a higher-than-expected number of sporadic Wilms tumors. These findings suggest an important role of miRNA processing enzymes in Wilms carcinogenesis. Therefore, we investigated the correlation between various subtypes of Wilms tumors, focusing on exploring the similarities in Wilms tumor development in patients carrying mutations in general miRNA processing genes, DROSHA, DGCR8 and DICER1, compared to mutations DIS3L2. Current identified germline and somatic mutations in Wilms tumor patients are described, and their effect on miRNA levels and tumorigenesis is investigated. Overall, mutations in all investigated genes resulted in increased cell proliferation in vitro, which is an important cancer characteristic. Wilms tumor harboring mutations in general miRNA processing genes showed decreased mature miRNA expression, whereas the effect of mutations in DIS3L2 on miRNA levels is less well understood. Multiple studies have identified Wilms tumor patients c

Introduction: Endoxifen—the principal metabolite of tamoxifen—is subject to a high inter-individual variability in serum concentration. Numerous attempts have been made to explain this, but thus far only with limited success. By applying predictive modeling, we aimed to identify factors that determine the inter-individual variability. Our purpose was to develop a prediction model for endoxifen concentrations, as a strategy to individualize tamoxifen treatment by model-informed dosing in order to prevent subtherapeutic exposure (endoxifen < 16 nmol/L) and thus potential failure of therapy. Methods: Tamoxifen pharmacokinetics with demographic and pharmacogenetic data of 303 participants of the prospective TOTAM study were used. The inter-individual variability in endoxifen was analyzed according to multiple regression techniques in combination with multiple imputations to adjust for missing data and bootstrapping to adjust for the over-optimism of parameter estimates used for internal model validation. Results: Key predictors of endoxifen concentration were CYP2D6 genotype, age and weight, explaining altogether an average-based optimism corrected 57% (95% CI 0.49–0.64) of the inter-individual variability. CYP2D6 genotype explained 54% of the variability. The remaining 3% could be explained by age and weight. Predictors of risk for subtherapeutic endoxifen (< 16 nmol/L) were CYP2D6 genotype and age. The model showed an optimism-corrected discrimination of 90% (95% CI 0.86–0.95) and sensitivity and specificity of 66% and 98%, respectively. Consecutively, there is a high probability of misclassifying patients with subtherapeutic endoxifen concentrations based on the prediction rule. Conclusion: The inter-individual variability of endoxifen concentration could largely be explained by CYP2D6 genotype and for a small proportion by age and weight. The model showed a sensitivity and specificity of 66 and 98%, respectively, indicating a high probability of (misclassif

Cytochrome P450 3A4 (CYP3A4) is the most important drug metabolizing enzyme in the liver, responsible for the oxidative metabolism of ∼50% of clinically prescribed drugs. Therefore, genetic variation in CYP3A4 could potentially affect the pharmacokinetics, toxicity and clinical outcome of drug treatment. Thus far, pharmacogenetics for CYP3A4 has not received much attention. However, the recent discovery of the intron 6 single-nucleotide polymorphism (SNP) rs35599367C > T, encoding the CYP3A4∗22 allele, led to several studies into the pharmacogenetic effect of CYP3A4∗22 on different drugs. This allele has a relatively minor allele frequency of 3-5% and an effect on CYP3A4 enzymatic activity. Thus far, no review summarizing the data published on several drugs is available yet. This article therefore addresses the current knowledge on CYP3A4∗22. This information may help in deciding if, and for which drugs, CYP3A4∗22 genotype-based dosing could be helpful in improving drug therapy. CYP3A4∗22 was shown to significantly influence the pharmacokinetics of several drugs, with currently being most thoroughly investigated tacrolimus, cyclosporine, and statins. Additional studies, focusing on toxicity and clinical outcome, are warranted to demonstrate clinical utility of CYP3A4∗22 genotype-based dosing.

Background: Severe maternal iodine deficiency during pregnancy leads to marked intellectual disability in the offspring. Although recent studies showed that even mild-to-moderate maternal iodine deficiency is associated with lower intelligence quotient and attention deficit hyperactivity disorder in offspring, the underlying neurobiological mechanism of these associations remains unknown. The aim of this study was to investigate the association of maternal iodine excretion during pregnancy with offspring brain morphology during pre-adolescence. Methods: This study was embedded within Generation R, a prospective population-based birth cohort in Rotterdam, the Netherlands. We included 990 mother–child pairs with data on urinary iodine concentration (UIC) and creatinine during pregnancy. The UIC was assessed at <18 and/or 18–25 weeks of gestation and offspring brain imaging data were acquired with magnetic resonance imaging (MRI) at age 10 years. We used linear regression to study the association of the iodine-to-creatinine ratio (UI/Creat) with offspring brain MRI outcomes. Results: Maternal UI/Creat during pregnancy was not consistently associated with offspring brain morphology. A low UI/Creat (<150 lg/g) during pregnancy was nominally associated with smaller total gray matter volume, but this did not survive correction for multiple testing. Also, we could not identify a linear association between continuous iodine excretion and offspring brain morphology. Instead, our results suggest a curvilinear association between UI/Creat and brain morphology. In sensitivity analyses using the World Health Organization categorization for UIC values, both low and high UI/Creat were associated with smaller total gray matter volume. Conclusions: The current study provides some but no conclusive evidence for an association of maternal iodine excretion during pregnancy with offspring brain morphology. Our results suggest that the exact definition of the reference group is i

Cytochrome P450 3A4 (CYP3A4) is the most important drug metabolizing enzyme in the liver, responsible for the oxidative metabolism of ∼50% of clinically prescribed drugs. Therefore, genetic variation in CYP3A4 could potentially affect the pharmacokinetics, toxicity and clinical outcome of drug treatment. Thus far, pharmacogenetics for CYP3A4 has not received much attention. However, the recent discovery of the intron 6 single-nucleotide polymorphism (SNP) rs35599367C > T, encoding the CYP3A4∗22 allele, led to several studies into the pharmacogenetic effect of CYP3A4∗22 on different drugs. This allele has a relatively minor allele frequency of 3-5% and an effect on CYP3A4 enzymatic activity. Thus far, no review summarizing the data published on several drugs is available yet. This article therefore addresses the current knowledge on CYP3A4∗22. This information may help in deciding if, and for which drugs, CYP3A4∗22 genotype-based dosing could be helpful in improving drug therapy. CYP3A4∗22 was shown to significantly influence the pharmacokinetics of several drugs, with currently being most thoroughly investigated tacrolimus, cyclosporine, and statins. Additional studies, focusing on toxicity and clinical outcome, are warranted to demonstrate clinical utility of CYP3A4∗22 genotype-based dosing.

Tamoxifen is a major option for adjuvant endocrine treatment in estrogen receptor (ER) positive breast cancer patients. The conversion of the prodrug tamoxifen into the most active metabolite endoxifen is mainly catalyzed by the enzyme cytochrome P450 2D6 (CYP2D6). Genetic variation in the CYP2D6 gene leads to altered enzyme activity, which influences endoxifen formation and thereby potentially therapy outcome. The association between genetically compromised CYP2D6 activity and low endoxifen plasma concentrations is generally accepted, and it was shown that tamoxifen dose increments in compromised patients resulted in higher endoxifen concentrations. However, the correlation between CYP2D6 genotype and clinical outcome is still under debate. This has led to genotype-based tamoxifen dosing recommendations by the Clinical Pharmacogenetic Implementation Consortium (CPIC) in 2018, whereas in 2019, the European Society of Medical Oncology (ESMO) discouraged the use of CYP2D6 genotyping in clinical practice for tamoxifen therapy. This paper describes the latest developments on CYP2D6 genotyping in relation to endoxifen plasma concentrations and tamoxifen-related clinical outcome. Therefore, we focused on Pharmacogenetic publications from 2018 (CPIC publication) to 2021 in order to shed a light on the current status of this debate.