Asthma and the Missing Heritability Problem: Necessity for Multiomics Approaches in Determining Accurate Risk Profiles.

Asthma is ranked among the most common chronic conditions and has become a significant public health issue due to the recent and rapid increase in its prevalence. Investigations into the underlying genetic factors predict a heritable component for its incidence, estimated between 35% and 90% of causation. Despite the application of large-scale genome-wide association studies (GWAS) and admixture mapping approaches, the proportion of variants identified accounts for less than 15% of the observed heritability of the disease. The discrepancy between the predicted heritable component of disease and the proportion of heritability mapped to the currently identified susceptibility loci has been termed the 'missing heritability problem.' Here, we examine recent studies involving both the analysis of genetically encoded features that contribute to asthma and also the role of non-encoded heritable characteristics, including epigenetic, environmental, and developmental aspects of disease. The importance of vertical maternal microbiome transfer and the influence of maternal immune factors on fetal conditioning in the inheritance of disease are also discussed. In order to highlight the broad array of biological inputs that contribute to the sum of heritable risk factors associated with allergic disease incidence that, together, contribute to the induction of a pro-atopic state. Currently, there is a need to develop in-depth models of asthma risk factors to overcome the limitations encountered in the interpretation of GWAS results in isolation, which have resulted in the missing heritability problem. Hence, multiomics analyses need to be established considering genetic, epigenetic, and functional data to create a true systems biology-based approach for analyzing the regulatory pathways that underlie the inheritance of asthma and to develop accurate risk profiles for disease.

Targeting Wnt/EZH2/microRNA-708 signaling pathway inhibits neuroendocrine differentiation in prostate cancer.

Prostate cancer (PC) castration resistance has been linked to the differentiation of PC luminal cells into hormone-refractory neuroendocrine (NE) cells. However, the molecular mechanisms controlling the emergence of lethal NE prostate cancer (NEPC) remain unclear. The present study aimed to investigate the mechanisms underlying the transition from prostate adenocarcinoma to NEPC. The microRNA miR-708 was involved in NE differentiation and was downregulated in NEPC cells and tumor specimens. miR-708 targeted Sestrin-3 to inhibit Forkhead Box O1 (FOXO1) phosphorylation, resulting in apoptosis of prostate adenocarcinoma cells and AKT-inactivated NEPC cells, the latter of which was consistent with the progression of tumor xenografts in mice under miR-708 treatment. In silico analysis of PC and NEPC tumor specimens suggested that the polycomb repressive complex subunit Enhancer of zeste homolog 2 (EZH2) was particularly overexpressed in NEPC. Notably, EZH2 bound to the miR-708 promoter and induced its silencing in NEPC. Inhibition of EZH2 prevented NE differentiation of PC cells. EZH2 expression was regulated by both Cyclin Dependent Kinase 1 (CDK1) and Wnt signaling. Silencing transcription factor 4 (TCF4), as a key protein in Wnt signaling, prevented NEPC formation. These results provide a molecular basis for the roles of miR-708 and EZH2 in NE differentiation in PC and highlight a new paradigm in NEPC formation and survival.

Neuronal ceroid lipofuscinosis in Qatar: report of a novel mutation in ceroid-lipofuscinosis, neuronal 5 in the Arab population.

This study sought to genetically define the first family diagnosed with neuronal ceroid lipofuscinosis from Qatar. Onset was in late infancy (3 years), and sequencing in the affected children revealed a novel homozygous c.613C>T change in exon 3 of ceroid-lipofuscinosis, neuronal 5, corresponding to a missense mutation of a conserved amino acid, p.Pro205Ser. The clinical manifestations of the disease in this family largely resemble those of ceroid-lipofuscinosis, neuronal 5 disease, variant late infantile that was first described in Finland and include mental decline, visual deterioration, ataxia, and epileptic seizures. This description of ceroid-lipofuscinosis, neuronal 5 disease in an Arab family adds to the clinical and molecular diversity of the variant late-infantile neuronal ceroid lipofuscinoses, which were originally reported in Europe and are increasingly recognized in other populations.