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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
According to the World Health Organization (WHO), the total of tobacco consumers is 1.3 billion people leading to approximately 5 million deaths per year. In 2007, the first large-scale genetic analysis on nicotine dependence was carried out on 348 candidate genes, by genotyping 3,713 SNPs in 1,050 patients addicted to tobacco and 879 non-dependent smoker subjects (Saccone 2007). This study showed variants associated with nicotine dependence in the cluster of the genes CHRNA3, CHRNA5 and CHRNB4 coding respectively the subunits α3, α3 and β4, involved in the formation of nicotinic heteromeric receptors in acetylcholine (Figure 22.3).
Molecular links between COPD and lung cancer: new targets for drug discovery?
Published in Expert Opinion on Therapeutic Targets, 2019
Gaetano Caramori, Paolo Ruggeri, Sharon Mumby, Antonio Ieni, Federica Lo Bello, Vrushali Chaminka, Chantal Donovan, Filippo Andò, Francesco Nucera, Irene Coppolino, Giovanni Tuccari, Philip M. Hansbro, Ian M. Adcock
Two single-nucleotide polymorphisms (SNPs) in chromosome 15 (15q25.1) are associated with lung cancer risk. This region contains a cluster of six genes: nicotinic acetylcholine receptor alpha subunits 3 (CHRNA3) and 5 (CHRNA5), the β4 nicotinic acetylcholine receptor (nAChR) subunit (CHRNB4), proteasome alpha 4 subunit isoform 1 (PMSA4), the IREB2 iron-sensing response element, and LOC123688, a gene of unknown function [33]. Fourteen percent of lung cancer risk is associated with this region with the strongest association with rs16969968 in exon 5 of CHRNA5 that induces an amino acid substitution (D398N). The functional effect of this substitution is unknown [33]. A synonymous variant in exon 5 (rs1051730) of CHRNA3 is also strongly associated with lung cancer. There is a fivefold greater risk of lung cancer in subjects who have both a family history of lung cancer and two copies of the high-risk alleles rs8034191 (odds ratio [OR] = 7.20) or rs1051730 (OR = 5.67), which are located in the 15q24-25.1 locus [34].
Direct and indirect evidences of BDNF and NGF as key modulators in depression: role of antidepressants treatment
Published in International Journal of Neuroscience, 2019
Amal Chandra Mondal, Mahino Fatima
Nerve growth factor level is increased with AD treatment [24] and also, NGF itself acts as AD in rats [28]. Administration of NGF improves depressive behavior in rats by modifying the gene expression of Drd5, Prokr1, Htr3a, Chrna5, Maoa, Chrnb4, Sstr3, and Cckar in amygdala and hippocampus. Simultaneously, NGF reduces the expression of cholinergic gene CHRNA5 following fluoxetine treatment and decreases in prokineticin receptor 1 (PROKR1) by amitriptyline treatment [123]. Nerve growth factor improves mood and cognition and its involvement in anxiety disorder is evident as children with one or more copies of allele NGF rs6330 have lesser susceptibility to develop anxiety [124]. Inconsistency in data related to stress-dependent alterations of serum NGF in humans has been evident as its level has found to be increased [125] or unchanged [126,127] during acute stress. Thus, alterations in NGF could be considered as key factor in the progression of depressive disorders and NGF polymorphism rs6330 and serum NGF levels may be predictor of efficient psychological therapies, provided with consistent control [128,129]. Figure 2 shows involvement of NGF mediated signaling patways in depression and effect of ADs treatment on neurogenesis.
Five New Cases of Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome (MMIHS), with One Case Showing a Novel Mutation
Published in Fetal and Pediatric Pathology, 2021
Alyssa Kalsbeek, Renee Dhar-Dass, Abdul Hanan, Eman Al-Haddad, Iman William, Adina Alazraki, Janet Poulik, Kasey McCollum, Aya Almashad, Bahig M. Shehata
Acetylcholine is the principal excitatory neurotransmitter in the enteric plexus and the bladder, and any abnormality that blocks the function of this neurotransmitter can contribute to gastrointestinal hypoperistalsis and reduced bladder contractility and thus is a good candidate gene to target for the etiopathogenesis of MMIHS. The ηAChR is composed of α3 and β4 subunits and have been identified in enteric plexuses [12,13]. The α3 subunit of the ηAChR mediates fast synaptic transmission in the enteric ganglia and plays a major role in gut motility and bladder contractility. In a previous study, mice with null alleles for α3 and β4 subunits of ηAChR develop a disorder very similar to the congenital disorder of MMIHS in humans [14,15]. The α3 subunit of the ηAChR was missing in the tissue of infants born with MMIHS, which is consistent with the hypothesis that absence of the α3 subunit of ηAChR can contribute to the development of MMIHS [16]. Three different CNRNA3 biallelic mutations have been detected in three families with congenital anomalies of the kidney and urinary tract, and these mutations were shown to decrease the ability of ηAChR to generate a current and contraction after stimulation with acetylcholine [17]. High-frequency polymorphisms in both CHRNA3 and CHRNB4 were identified in 13 families with MMIHS, however, no loss-of-function mutations were identified [18]. The ηAChR genes are known to be located on chromosome 15, and deletion of the proximal long arm of chromosome 15 (15q11.2) has been reported in a patient with MMIHS [19]. Mydriasis was reported in a female infant with MMIHS, which further lends support to the hypothesis that mutations in the ηAChR are pathogenically linked to MMIHS [20].