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A Genetic Framework for Addiction
Published in Hanna Pickard, Serge H. Ahmed, The Routledge Handbook of Philosophy and Science of Addiction, 2019
Philip Gorwood, Yann Le Strat, Nicolas Ramoz
Since these publications, these genes and other coding for the α and β subunits of nicotinic acetylcholine receptors, like CHRNA4 and CHRNB3 genes, have been sequenced in tobacco dependence, and some mutations and rare variants have been identified (Thorgeirsson 2010; Olfson 2016; Thorgeirsson 2016). Furthermore, genes have also been investigated in addiction to other substances, including alcohol, opioid and cocaine (Haller 2014). Several GWAS found an association between the initiation of smoking and the functional variant rs6265 of the BDNF gene that encodes the brain-derived neurotrophic factor. These studies also reported an association of the rs3733829 SNP of the CYP2A6 gene (implicated in the metabolism of nicotine into cotinine) and tobacco consumption, but also the development of lung cancer (Thorgeirsson 2010, Tobacco and Genetics Consortium 2010).
In vitro exposure of human lens epithelial cells to X-rays at varied dose-rates leads to protein-level changes relevant to cataractogenesis
Published in International Journal of Radiation Biology, 2021
Vinita Chauhan, Ngoc Q. Vuong, Simran Bahia, Nazila Nazemof, Premkumari Kumarathasan
A total of 20 proteins were shown to be differentially expressed in radiation-exposed groups relative to the control. Representative relationships between X-ray exposure doses and HLE cellular protein responses are illustrated for LDR and HDR delivery of ionizing radiation (Figure 1, expressed as mean ± SEM, Supplementary Table 1). The dose-response curves highlighted positive/negative excursions seen at very-low doses for the LDR and HDR exposures (Figure 1). Also, distinct protein-specific and dose-specific profiles are observed with LDR and HDR treatment, with a few exceptions. For example, at LDR exposure, PMSA1 and APOE increased at low doses but decreased at HDRs. Meanwhile, CHRNA4, WASF1 is increased at low dose exposures for both LDR and HDR. Two-way ANOVA identified dose main effects (p < .05) for all 20 proteins with RAB39B shown to be statistically significant across all doses for the HDR and LDR exposures. Dose-rate main effects (p < .05) were observed with fourteen proteins (ATP5F1D, CAMSAP1, CCDC97, CHRNA4, ELOA2, ENGASE, KIDINS220, PCBD1, POC5, PRG4, PSMA1, RAB39B, RB1 and WASF1). Statistically significant (p < .05) interactions noticed between the factors tested are shown in Supplementary Table 2.
Pharmacogenomics of drugs used to treat brain disorders
Published in Expert Review of Precision Medicine and Drug Development, 2020
The effects of galantamine are potentially influenced by APOE, APP, ACHE, BCHE, CHRNA4, CHRNA7 and CHRNB2 variants. This drug is a major substrate of CYP2D6, CYP3A4, ABCB1 and UGT1A1, and an inhibitor of ACHE and BCHE [92, 101–104]. Major metabolic pathways are glucuronidation, O-demethylation, N-demethylation, N-oxidation, and epimerization [105]. Galantamine is extensively metabolized by the enzymes CYP2D6 and CYP3A and is a substrate of ABCB1. CYP2D6 are major determinants of galantamine pharmacokinetics, with CYP2D6-PMs presenting 45% and 61% higher dose-adjusted galantamine plasma concentrations than heterozygous and homozygous CYP2D6-EMs [92, 106]; however, these pharmacokinetic changes might not substantially affect pharmacodynamics [107]. The co-administration of galantamine with CYP2D6 and CYP3A4 strong inhibitors increases its bioavailability [108, 109]. Interaction with foods and nutritional components may alter galantamine bioavailability and therapeutic effects [110].
From next-generation sequencing to targeted treatment of non-acquired epilepsies
Published in Expert Review of Molecular Diagnostics, 2019
Rikke S. Møller, Trine B. Hammer, Guido Rubboli, Johannes R. Lemke, Katrine M. Johannesen
Although NGS is increasingly entering into the diagnostic work-up, only around 15 genes have, so far, been linked to focal epilepsies (Figure 1). This raises the issue of its utility in real-life clinical practice. Indeed, at present only a few studies have investigated the diagnostic contribution of targeted gene panels or WES in elucidating the cause of focal epilepsies. A gene panel study of 251 patients with unexplained sporadic or familial focal epilepsies has found 11 novel or very rare variants in 5 genes (SCN1A, PCDH19, KCNT1, GRIN2B, and CHRNA4) [90]. Only two variants were predicted to be pathogenic or likely pathogenic, therefore explaining only 0.8% of the study group. The remaining variants were considered to be VUS, based on the available clinical and molecular genetic data. Similar findings have been obtained in another study, that has employed a customized focal epilepsy gene panel including 21 genes to investigate a large cohort (n = 593) of patients with common, non-lesional, focal epilepsies [91]. Pathogenic or likely pathogenic mutations in SCN1A, PRRT2, CHRNA4, DEPDC5, PCHD19, and SLC2A1 (GLUT1-deficiency) were detected in 11 (1.85%) subjects. Variants, classified as VUS due to inconsistent phenotype or lack of segregation data, were found in 16 additional patients. The conclusion of both studies was that mutations in known genes could explain the etiology in only a small fraction of patients with focal epilepsies. This low yield might depend also on the possibility that a proportion of mutations are somatic, limited to and detectable only in the brain [90].