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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).
Recent advancements in understanding the genetic involvement of alpha-1 antitrypsin deficiency associated lung disease: a look at future precision medicine approaches
Published in Expert Review of Respiratory Medicine, 2022
Auyon J. Ghosh, Brian D. Hobbs
The findings from several candidate gene studies in the late 1990s to the early 2000s, which evaluated the lung function association of genes suspected to be involved in pulmonary pathobiology, have not been replicated in independent cohorts (Table 3) [48–50]. Subsequently, based on the results of a genome-wide association study (GWAS) of COPD, Kim and colleagues examined the association of the chromosome 15q25 region with lung function in PiZZ individuals from the Alpha-1 Genetic Modifiers Study [51]. While the authors identified two variants (intronic SNP in IREB2 and exonic SNP in CHRNA3) with nominal significance (i.e. p < 0.05, but did not meet the significance threshold after adjusting for multiple testing) in association with post-bronchodilator FEV1 and FEV1/FVC ratio, they were unable to replicate their findings in an independent validation cohort.
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].
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].