Folefac Aminkeng

A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer.

Anthracyclines are used in over 50% of childhood cancer treatment protocols, but their clinical usefulness is limited by anthracycline-induced cardiotoxicity (ACT) manifesting as asymptomatic cardiac dysfunction and congestive heart failure in up to 57% and 16% of patients, respectively. Candidate gene studies have reported genetic associations with ACT, but these studies have in general lacked robust patient numbers, independent replication or functional validation. Thus, the individual variability in ACT susceptibility remains largely unexplained. We performed a genome-wide association study in 280 patients of European ancestry treated for childhood cancer, with independent replication in similarly treated cohorts of 96 European and 80 non-European patients. We identified a nonsynonymous variant (rs2229774, p.Ser427Leu) in RARG highly associated with ACT (P = 5.9 × 10−8, odds ratio (95% confidence interval) = 4.7 (2.7–8.3)). This variant alters RARG function, leading to derepression of the key ACT genetic determinant Top2b, and provides new insight into the pathophysiology of this severe adverse drug reaction.

Recommendations for genetic testing to reduce the incidence of anthracycline‐induced cardiotoxicity

Anthracycline‐induced cardiotoxicity (ACT) occurs in 57% of treated patients and remains an important limitation of anthracycline‐based chemotherapy. In various genetic association studies, potential genetic risk markers for ACT have been identified. Therefore, we developed evidence‐based clinical practice recommendations for pharmacogenomic testing to further individualize therapy based on ACT risk.

The emerging era of pharmacogenomics: current successes, future potential, and challenges

The vast range of genetic diversity contributes to a wonderful array of human traits and characteristics. Unfortunately, a consequence of this genetic diversity is large variability in drug response between people, meaning that no single medication is safe and effective in everyone. The debilitating and sometimes deadly consequences of adverse drug reactions (ADRs) are a major and unmet problem of modern medicine. Pharmacogenomics can uncover associations between genetic variation and drug safety and has the potential to predict ADRs in individual patients. Here we review pharmacogenomic successes leading to changes in clinical practice, as well as clinical areas probably to be impacted by pharmacogenomics in the near future. We also discuss some of the challenges, and potential solutions, that remain for the implementation of pharmacogenomic testing into clinical practice for the significant improvement of drug safety.

Higher frequency of genetic variants conferring increased risk for ADRs for commonly used drugs treating cancer, AIDS and tuberculosis in persons of African descent

There is established clinical evidence for differences in drug response, cure rates and survival outcomes between different ethnic populations, but the causes are poorly understood. Differences in frequencies of functional genetic variants in key drug response and metabolism genes may significantly influence drug response differences in different populations. To assess this, we genotyped 1330 individuals of African (n=372) and European (n=958) descent for 4535 single-nucleotide polymorphisms in 350 key drug absorption, distribution, metabolism, elimination and toxicity genes. Important and remarkable differences in the distribution of genetic variants were observed between Africans and Europeans and among the African populations. These could translate into significant differences in drug efficacy and safety profiles, and also in the required dose to achieve the desired therapeutic effect in different populations. Our data points to the need for population-specific genetic variation in personalizing medicine and care.

Pharmacogenomic diversity in Singaporean populations and Europeans

Differences in the frequency of pharmacogenomic variants may influence inter-population variability in drug efficacy and risk of adverse drug reactions (ADRs). We investigated the diversity of ∼4500 genetic variants in key drug-biotransformation and -response genes among three South East Asian populations compared with individuals of European ancestry. We compared rates of reported ADRs in these Asian populations to determine if the allelic differentiation corresponded to an excess of the associated ADR. We identified an excess of ADRs related to clopidogrel in Singaporean Chinese, consistent with a higher frequency of a known risk variant in CYP2C19 in that population. We also observed an excess of ADRs related to platinum compounds in Singaporean CHS, despite a very low frequency of known ADR risk variants, suggesting the presence of additional genetic and non-genetic risk factors. Our results point to substantial diversity at specific pharmacogenomic loci that may contribute to inter-population variability in drug response phenotypes.

HINT1 mutations define a novel disease entity - autosomal recessive axonal neuropathy with neuromyotonia.

Loss‐of‐function mutations in HINT1 cause axonal neuropathy with neuromyotonia

Association Between SLC16A5 Genetic Variation and Cisplatin-Induced Ototoxic Effects in Adult Patients With Testicular Cancer.

Importance Cisplatin-induced ototoxic effects are an important complication that affects testicular cancer survivors as a consequence of treatment. The identification of genetic variants associated with this adverse drug reaction will further our mechanistic understanding of its development and potentially lead to strategies to prevent ototoxic effects. Objective To identify the genetic variants associated with cisplatin-induced ototoxic effects in adult testicular cancer patients. Design, Setting, and Participants This retrospective study was performed by the Canadian Pharmacogenomics Network for Drug Safety using patients recruited from 5 adult oncology treatment centers across Canada. Male patients who were 17 years or older, diagnosed with germ cell testicular cancer, and previously treated with cisplatin-based chemotherapy were recruited from July 2009 to April 2013 using active surveillance methodology. Cisplatin-induced ototoxic effects were independently diagnosed by 2 audiologists. Patients were genotyped for 7907 variants using a custom pharmacogenomic array. Logistic regression was used to identify genetic variants that were significantly associated with ototoxic effects. The validity of these findings was confirmed through independent replication and cell-based functional assays. Exposures Cisplatin-based chemotherapy. Main Outcomes and Measures Cisplatin-induced ototoxic effects. Results After exclusions, 188 patients (median [interquartile range] age, 31 [24-39] years) were enrolled in this study to form the discovery and replication cohorts. Association and fine-mapping analyses identified a protein-coding variant, rs4788863 in SLC16A5, that was associated with protection against cisplatin-induced ototoxic effects in 2 independent cohorts (combined cohort: odds ratio, 0.06; 95% CI, 0.02-0.22; P = 2.17 × 10−7). Functional validation of this transporter gene revealed that in vitro SLC16A5–silencing altered cellular responses to cisplatin treatment, supporting a role for SLC16A5 in the development of cisplatin-induced ototoxic effects. These results were further supported by the literature, which provided confirmatory evidence for the role that SLC16A5 plays in hearing. Conclusions and Relevance This study has identified a novel association between protein-coding variation in SLC16A5 and cisplatin-induced ototoxic effects. These findings have provided insight into the molecular mechanisms of this adverse drug reaction in adult patients with germ cell testicular cancer. Given that previous studies have shown that cimetidine, an SLC16A5-inhibitor, prevents murine cisplatin-induced ototoxic effects, the findings from this study have important implications for otoprotectant strategies in humans.

Clinical and biological characteristics of diabetic patients under age 40 in Cameroon: relation to autoantibody status and comparison with Belgian patients.

AIMS We investigated the prevalence of diabetes autoantibodies (Abs) in Cameroonian patients and controls, assessed their contribution in disease classification and compared results with data from Belgium. METHODS Abs against GAD (GADA), IA-2 (IA-2A) and zinc transporter 8 (ZnT8A) were assessed in 302 recently diagnosed Cameroonian patients with diabetes and 184 control subjects without diabetes aged below 40 years. RESULTS Only 27 (9%) Cameroonian patients were younger than 15 years. Overall, 29% of patients presented at least one diabetes-associated antibody vs 9% in healthy controls (24% vs 7% for GADA (p<0.001), 10% vs 3% for IA-2A (p<0.006), 4% vs 2% for ZnT8A). Ab(+) patients had lower C-peptide levels (p<0.001), were more often insulin-treated (p<0.002) and were as frequently diagnosed with type 1 diabetes as Ab(-) patients. Only 43% of Ab(+) patients aged 15-39 years were clinically classified as having type 1 diabetes in Cameroon vs 96% in Belgium (p<0.001). Not one Ab(+) Cameroonian patient carried HLA-DQ2/DQ8 genotype vs 23% of Belgian Ab(+) patients (p<0.001). Younger age at diagnosis and antibody positivity were independent predictors of insulin therapy. Ab(+) Cameroonian patients were older (p<0.001), had higher BMI (p<0.001) and lower Ab titers than Belgian Ab(+) patients. In ketonuric patients, prevalence of autoantibodies was similar as in non-ketonuric patients. CONCLUSIONS In Cameroonian patients with diabetes aged under 40 years, antibody-positivity is not clearly related to disease phenotype, but may help predict the need for insulin treatment.

GFI1B mutation causes autosomal dominant gray platelet syndrome

A dominant‐negative GFI1B mutation in the gray platelet syndrome.

WDR45 mutations define a novel disease entity—Static Encephalopathy of Childhood with Neurodegeneration in Adulthood

De novo mutations in the autophagy gene encoding WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood