The <i>CHRNA5-CHRNA3-CHRNB4</i> Nicotinic Receptor Subunit Gene Cluster Affects Risk for Nicotine Dependence in African-Americans and in European-Americans

Saccone, Nancy L.; Wang, Jen C.; Breslau, Naomi; Johnson, Eric O.; Hatsukami, Dorothy K.; Saccone, Scott F.; Grucza, Richard A.; Sun, Lingwei; Duan, Wansuo; Budde, John; Culverhouse, Robert; Fox, Louis; Hinrichs, Anthony L.; Steinbach, Joseph H.; Wu, Meng; Rice, John P.; Goate, Alison M.; Bierut, Laura J.

doi:10.1158/0008-5472.can-09-0786

Cited by 251 publications

(260 citation statements)

References 33 publications

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“…15 Previous GWAS and replication studies have found associations between IREB2 polymorphisms and COPD and COPD-related phenotypes. 5,11,14,15 However, because the region of chromosome 15q25 where IREB2 gene is located was found to be linked to nicotine addiction, [18][19][20][21] and there is high levels of LD between SNPs in IREB2 and SNPs in CHRNA3/5 in this region, 5 association findings in IREB2 may be the result of independent association with smoking behavior or the result of high LD with SNPs in the CHRNA3/5 gene cluster, and key functional variants may actually be in the CHRNA3/5 gene cluster. We identified two SNPs in IREB2 associated with COPD in non-smoking subjects, in the same direction as previously reported, while the association was not observed in current-smokers and Analyses of pulmonary function phenotypes were adjusted for age, gender, BMI, current smoking status and pack-years by linear regression; analyses of pack-years for ever-smoker were adjusted for age, gender and current smoking status by linear regression.…”

Section: Association Of Ireb2 and Chrna3/5 With Copd In A Chinese Hanmentioning

confidence: 99%

Association of IREB2 and CHRNA3/5 polymorphisms with COPD and COPD-related phenotypes in a Chinese Han population

Zhou

Yang

et al. 2012

J Hum Genet

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Genome-wide association studies and integrative genomics approaches have demonstrated significant associations between chronic obstructive pulmonary disease (COPD) and single-nucleotide polymorphisms (SNPs) in the chromosome 15q25 region that includes iron-responsive element binding protein 2 gene (IREB2) and CHRNA3/5 in non-Asian populations. We investigated whether IREB2 and CHRNA3/5 polymorphisms would be associated with COPD susceptibility and COPD-related phenotypes in a Chinese Han population. Eight SNPs (rs2568494, rs2656069, rs10851906, rs1964678, rs12593229, rs965604, rs13180, rs17483929) in IREB2 gene and four SNPs (rs16969968, rs1051730, rs938682, rs8034191) in or near CHRNA3/5 locus were genotyped in a case-control study (680 COPD patients and 687 controls). No significant associations were found between any of the SNPs and COPD in either former-smokers or current-smokers. Two SNPs (rs2656069 and rs10851906) in IREB2 were associated with COPD (P ¼ 0.045 and 0.032, respectively) in non-smoker. Four SNPs (rs1964678, rs12593229, rs965604 and rs13180) in IREB2 were associated with forced expiratory volume in 1 s (FEV 1 )% predicted and three SNPs (rs16969968, rs8034191 and rs1051730) in CHRNA3/5 were both associated with FEV 1 % predicted and FEV 1 /FVC in COPD cases (P range 0.007-0.050). The SNP rs8034191 near CHRNA3/5 locus was significantly associated with pack-years of smoking in COPD patients (P ¼ 0.033). We demonstrated IREB2 polymorphisms were associated with COPD in non-smoking subjects, and the effect of IREB2 gene on COPD may be independent from smoking and independent from CHRNA3/5 gene cluster. Besides, we confirmed that SNPs in these two gene loci were associated with pulmonary function and CHRNA3/5 polymorphism was associated with pack-year of smoking in COPD patients in the Chinese Han population.

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Section: Association Of Ireb2 and Chrna3/5 With Copd In A Chinese Hanmentioning

confidence: 99%

Association of IREB2 and CHRNA3/5 polymorphisms with COPD and COPD-related phenotypes in a Chinese Han population

Zhou

Yang

et al. 2012

J Hum Genet

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“…Human genetic studies have highlighted the polymorphic nature of the CHRNA5-CHRNA3-CHRNB4 genomic cluster, encoding subunits α5, α3, and β4, and its implication in smoking behaviors (Bierut et al, 2008). Furthermore, variants in the β4 regulatory domain reduce the age of tobacco initiation, while gain-offunction variants in CHRNB4 reduce the risk of nicotine dependence (Haller et al, 2012;Saccone et al, 2009;Schlaepfer et al, 2008). Although cholinergic responses are unaffected in CHRNB4 coding variants, nicotine-elicited currents are increased (Haller et al, 2012), which is reflected as aberrant nicotine aversion in mice expressing these variants (Slimak et al, 2014), and as fewer cigarettes smoked per day in humans (Haller et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Role of β4* Nicotinic Acetylcholine Receptors in the Habenulo–Interpeduncular Pathway in Nicotine Reinforcement in Mice

Harrington

Viñals

Herrera-Solís

et al. 2015

Neuropsychopharmacol

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Nicotine exerts its psychopharmacological effects by activating the nicotinic acetylcholine receptor (nAChR), composed of alpha and/or beta subunits, giving rise to a diverse population of receptors with a distinct pharmacology. β4-containing (β4*) nAChRs are located almost exclusively in the habenulo-interpeduncular pathway. We examined the role of β4* nAChRs in the medial habenula (MHb) and the interpeduncular nucleus (IPN) in nicotine reinforcement using behavioral, electrophysiological, and molecular techniques in transgenic mice. Nicotine intravenous self-administration (IVSA) was lower in constitutive β4 knockout (KO) mice at all doses tested (7.5, 15, 30, and 60 μg/kg/infusion) compared with wild-type (WT) mice. In vivo microdialysis showed that β4KO mice have higher extracellular dopamine (DA) levels in the nucleus accumbens than in WT mice, and exhibit a differential sensitivity to nicotine-induced DA outflow. Furthermore, electrophysiological recordings in the ventral tegmental area (VTA) demonstrated that DA neurons of β4KO mice are more sensitive to lower doses of nicotine than that of WT mice. Re-expression of β4* nAChRs in IPN neurons fully restored nicotine IVSA, and attenuated the increased sensitivity of VTA DA neurons to nicotine. These findings suggest that β4* nAChRs in the IPN have a role in maintaining nicotine IVSA.

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“…Most prominent among these are the human genetic association studies showing that single nucleotide polymorphisms in the gene cluster CHRNA5/Α3/Β4, encoding for the α3, α5, and β4 nAChR subunits, are closely associated with the risk for heavy smoking, inability to quit, and increased sensitivity to nicotine. [7][8][9][10][11] Further, studies in knockout mice show that the β4 nAChR subunit is necessary for nicotine withdrawal because withdrawal is greatly diminished in β4 null mice, but not in β2 null mice. 12,13 Unlike the wide distribution of α4β2 nAChR in the brain, the α3 and β4 subunits are expressed in a restricted number of brain areas, mainly the medial habenula and interpeduncular nucleus, major cholinergic tracts in the brain that have recently garnered increasing attention for their involvement in various aspects of nicotine dependence.…”

Section: Introductionmentioning

confidence: 99%

Functional Characterization of AT-1001, an α3β4 Nicotinic Acetylcholine Receptor Ligand, at Human α3β4 and α4β2 nAChR

Zaveri

Bertrand

Yasuda

et al. 2014

Nicotine &Amp; Tobacco Research

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Introduction: Genome-wide association studies linking the α3, β4, and α5 nicotinic acetylcholine receptor (nAChR) subunits to nicotine dependence suggest that α3β4* nAChR may be targets for smoking cessation pharmacotherapies. We previously reported that AT-1001, a selective α3β4* nAChR ligand binds with high affinity to rat α3β4 and human α3β4α5 nAChR, antagonizes epibatidine-induced activation of rat α3β4 nAChR in HEK cells and potently inhibits nicotine selfadministration in rats. Methods: Two-electrode voltage clamp was used for functional characterization of AT-1001 at recombinant human α3β4 and α4β2 nAChR expressed in Xenopus oocytes. Results: Concentration-response curves show that AT-1001 is a partial agonist at human α3β4 nAChR, evoking up to 35% of the maximal acetylcholine (ACh) response (50% effective concentration [EC 50 ] = 0.37 μM). AT-1001 showed very little agonist activity at the α4β2 nAChR, evoking only 6% of the ACh response (EC 50 = 1.5 μM). Pre-and co-application of various concentrations of AT-1001 with 50 μM ACh revealed a complex pattern of activation-inhibition by AT-1001 at α3β4 nAChR, which was best fitted by a 2-site equation. At α4β2 nAChR, co-exposure of AT-1001 with ACh only showed inhibition of ACh current with a shallower curve. Conclusions: AT-1001 is a partial agonist at the human α3β4 nAChR and causes desensitization at concentrations at which it evokes an inward current, resulting in an overall functional antagonism of α3β4 nAChR. AT-1001 does not significantly activate or desensitize α4β2 nAChR at the same concentrations as at the α3β4 nAChR, but does inhibit ACh responses at α4β2 nAChR at higher concentrations. A combination of these mechanisms may underlie the inhibition of nicotine selfadministration by AT-1001, suggesting that AT-1001 and compounds from this class may have clinical potential for smoking cessation pharmacotherapy.

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The CHRNA5-CHRNA3-CHRNB4 Nicotinic Receptor Subunit Gene Cluster Affects Risk for Nicotine Dependence in African-Americans and in European-Americans

Cited by 251 publications

References 33 publications

Association of IREB2 and CHRNA3/5 polymorphisms with COPD and COPD-related phenotypes in a Chinese Han population

Association of IREB2 and CHRNA3/5 polymorphisms with COPD and COPD-related phenotypes in a Chinese Han population

Role of β4* Nicotinic Acetylcholine Receptors in the Habenulo–Interpeduncular Pathway in Nicotine Reinforcement in Mice

Functional Characterization of AT-1001, an α3β4 Nicotinic Acetylcholine Receptor Ligand, at Human α3β4 and α4β2 nAChR

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