Novel genetic risk variants for pediatric celiac disease.

BACKGROUND: Celiac disease is a complex chronic immune-mediated disorder of the small intestine. Today, the pathobiology of the disease is unclear, perplexing differential diagnosis, patient stratification, and decision-making in the clinic. METHODS: Herein, we adopted a next-generation sequencing approach in a celiac disease trio of Greek descent to identify all genomic variants with the potential of celiac disease predisposition. RESULTS: Analysis revealed six genomic variants of prime interest: SLC9A4 c.1919G>A, KIAA1109 c.2933T>C and c.4268_4269delCCinsTA, HoxB6 c.668C>A, HoxD12 c.418G>A, and NCK2 c.745_746delAAinsG, from which NCK2 c.745_746delAAinsG is novel. Data validation in pediatric celiac disease patients of Greek (n = 109) and Serbian (n = 73) descent and their healthy counterparts (n = 111 and n = 32, respectively) indicated that HoxD12 c.418G>A is more prevalent in celiac disease patients in the Serbian population (P < 0.01), while NCK2 c.745_746delAAinsG is less prevalent in celiac disease patients rather than healthy individuals of Greek descent (P = 0.03). SLC9A4 c.1919G>A and KIAA1109 c.2933T>C and c.4268_4269delCCinsTA were more abundant in patients; nevertheless, they failed to show statistical significance. CONCLUSIONS: The next-generation sequencing-based family genomics approach described herein may serve as a paradigm towards the identification of novel functional variants with the aim of understanding complex disease pathobiology.

Genomic variants in members of the Krüppel-like factor gene family are associated with disease severity and hydroxyurea treatment efficacy in ß-hemoglobinopathies patients.

Aim: ß-Type hemoglobinopathies are characterized by vast phenotypic diversity as far as disease severity is concerned, while differences have also been observed in hydroxyurea (HU) treatment efficacy. These differences are partly attributed to the residual expression of fetal hemoglobin (HbF) in adulthood. The Krüppel-like family of transcription factors (KLFs) are a set of zinc finger DNA-binding proteins which play a major role in HbF regulation. Here, we explored the possible association of variants in KLF gene family members with response to HU treatment efficacy and disease severity in ß-hemoglobinopathies patients. Materials & methods: Six tag single nucleotide polymorphisms, located in four KLF genes, namely KLF3, KLF4, KLF9 and KLF10, were analyzed in 110 ß-thalassemia major patients (TDT), 18 nontransfusion dependent ß-thalassemia patients (NTDT), 82 sickle cell disease/ß-thalassemia compound heterozygous patients and 85 healthy individuals as controls. Results: Our findings show that a KLF4 genomic variant (rs2236599) is associated with HU treatment efficacy in sickle cell disease/ß-thalassemia compound heterozygous patients and two KLF10 genomic variants (rs980112, rs3191333) are associated with persistent HbF levels in NTDT patients. Conclusion: Our findings provide evidence that genomic variants located in KLF10 gene may be considered as potential prognostic biomarkers of ß-thalassemia clinical severity and an additional variant in KLF4 gene as a pharmacogenomic biomarker, predicting response to HU treatment.

Key Pharmacogenomic Considerations for Sickle Cell Disease Patients.

Sickle cell disease (SCD), although a monogenic disease, exhibits a complex clinical phenotype that hampers optimum patient stratification and disease management, especially on hydroxyurea treatment. Moreover, theranostics, the combination of diagnostics to individualize and optimize therapeutic interventions, has not been firmly on the forefront of SCD research and clinical management to date. We suggest that if tailor-made theranostics in SCD is envisaged, pharmacogenomics is anticipated to be the way forward. Herein, we present the current key pharmacogenomic opportunities and challenges in SCD, considering population variation, ethics, and socioeconomic aspects. We focus on pharmacogenomics and pain management, genethics, and cost-effectiveness in SCD. We searched for and synthesized data from PubMed and Google Scholar, and the references from relevant articles, using the keywords "pharmacogenomics," "sickle cell disease," "hydroxyurea," "ethics," "pain management," "morphine metabolism," "opioids," "pharmacogenomics and chronic pain," "cost-effectiveness," and "economic evaluation." Only articles published in English were included. So far, when pharmacogenomics in SCD has been considered, interindividual variability in hydroxyurea response/toxicity has been of primary interest. We underscore the need to extend pharmacogenomic considerations on other therapeutic interventions currently present using a holistic patient-centric approach, and taking disease complications into account as well. Furthermore, we raise awareness toward socioeconomic, ethical, and population differences in the way sickle cell pharmacogenomics might unfold in the future. If pharmacogenomics in SCD is to be used in the clinic in an evidence-based manner, cost-effectiveness and population-specific empirical ethics data are urgently needed.