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Scrutiny of the CHRNA5-CHRNA3-CHRNB4 Washington University School of Medicine Digital Commons@Becker Open Access Publications 2013 Scrutiny of the CHRNA5-CHRNA3-CHRNB4 smoking behavior locus reveals a novel association with alcohol use in a Finnish population based study Jenni Hällfors University of Helsinki Anu Loukola University of Helsinki Janne Pitkäniemi University of Helsinki Ulla Broms University of Helsinki Satu Männistö National Institute for Health and Welfare, Helsinki, Finland See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Recommended Citation Hällfors, Jenni; Loukola, Anu; Pitkäniemi, Janne; Broms, Ulla; Männistö, Satu; Salomaa, Veikko; Heliövaara, Markku; Lehtimäki, Terho; Raitakari, Olli; Madden, Pamela AF; Heath, Andrew C.; Montgomery, Grant W.; Martin, Nicholas G.; Korhonen, Tellervo; and Kaprio, Jaakko, ,"Scrutiny of the CHRNA5-CHRNA3-CHRNB4 smoking behavior locus reveals a novel association with alcohol use in a Finnish population based study." International Journal of Molecular Epidemiology and Genetics.4,2. 109-119. (2013). https://digitalcommons.wustl.edu/open_access_pubs/3075 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Authors Jenni Hällfors, Anu Loukola, Janne Pitkäniemi, Ulla Broms, Satu Männistö, Veikko Salomaa, Markku Heliövaara, Terho Lehtimäki, Olli Raitakari, Pamela AF Madden, Andrew C. Heath, Grant W. Montgomery, Nicholas G. Martin, Tellervo Korhonen, and Jaakko Kaprio This open access publication is available at Digital Commons@Becker: https://digitalcommons.wustl.edu/open_access_pubs/3075 Int J Mol Epidemiol Genet 2013;4(2):109-119 www.ijmeg.org /ISSN:1948-1756/IJMEG1306003 Original Article Scrutiny of the CHRNA5-CHRNA3-CHRNB4 smoking behavior locus reveals a novel association with alcohol use in a Finnish population based study Jenni Hällfors1,2, Anu Loukola2, Janne Pitkäniemi2, Ulla Broms2,3, Satu Männistö3, Veikko Salomaa3, Markku Heliövaara3, Terho Lehtimäki4,5, Olli Raitakari6,7, Pamela AF Madden8, Andrew C Heath8, Grant W Montgomery9, Nicholas G Martin9, Tellervo Korhonen2,3, Jaakko Kaprio1,2,3 1Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland; 2Department of Public Health, Hjelt Institute, University of Helsinki, Helsinki, Finland; 3National Institute for Health and Welfare, Hel- sinki, Finland; 4Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland; 5Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, Finland; 6Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland; 7Research Centre of Applied and Preventive Cardio- vascular Medicine, University of Turku, Turku, Finland; 8Department of Psychiatry, Washington University School of Medicine, Saint Louis, USA; 9Queensland Institute of Medical Research, Brisbane, Australia Received June 20, 2013; Accepted June 20, 2013; Epub June 25, 2013; Published June 30, 2013 Abstract: The CHRNA5-CHRNA3-CHRNB4 gene cluster on chromosome 15q25.1 encoding the cholinergic nicotinic receptor subunits is robustly associated with smoking behavior and nicotine dependence. Only a few studies to date have examined the locus with alcohol related traits and found evidence of association with alcohol abuse and dependence. Our main goal was to examine the role of three intensively studied single nucleotide polymorphisms, rs16969968, rs578776 and rs588765, tagging three distinct loci, in alcohol use. Our sample was drawn from two independent Finnish population-based surveys, the National FINRISK Study and the Health 2000 (Health Examina- tion) Survey. The combined sample included a total of 32,592 adult Finns (54% women) of whom 8,356 were as- sessed for cigarettes per day (CPD). Data on alcohol use were available for 31,812 individuals. We detected a novel association between rs588765 and alcohol use defined as abstainers and low-frequency drinkers versus drinkers (OR=1.15, p=0.00007). Additionally, we provide precise estimates of strength of the association between the three loci and smoking quantity in a very large population based sample. As a conclusion, our results provide further evi- dence for the nicotine-specific role of rs16969968 (locus 1). Further, our data suggest that the effect of rs588765 (locus 3) may be specific to alcohol use as the effect is seen also in never smokers. Keywords: Nicotinic acetylcholine receptors, 15q25.1, alcohol use, smoking behavior, public health, population- based sample, genetic association Introduction genetic basis for that shared predisposition is still largely unknown. Smoking, alcohol use and abuse are serious public health issues [1, 2]. Both genetic and Within the past few years, genetic findings for environmental factors clearly are of importance nicotine dependence and other smoking relat- in accounting for inter-individual differences in ed traits and diseases have pinpointed a region these common behaviors. Family and twin on chromosome 15q25.1. This region harbors studies show that alcohol use, abuse, and the CHRNA5-CHRNA3-CHRNB4 gene cluster dependence as well as smoking and nicotine coding for a5, a3, and b4 nicotinic acetylcholine dependence are transmitted within families [3, receptor (nAChR) subunits. Evidence of associa- 4]. Smoking and alcohol use often co-occur, tion with smoking behavior and nicotine depen- suggesting that they may have a shared genetic dence has been reported in a genome-wide predisposition [5]. However, the molecular association study (GWAS) [6] and confirmed in CHRNA5-CHRNA3-CHRNB4 locus associated with alcohol use large meta-analyses conducted by indepen- association between alcohol initiation and two dent consortia [7-10]. The most well-estab- CHRNB4 SNPs (rs1948 and rs11634351) in lished locus within this region is tagged by the young Americans of European descent [21]. single nucleotide polymorphism (SNP) The incongruity may in part be due to heteroge- rs16969968 (locus 1) [11]. Rs16969968 is a neity and varying linkage disequilibrium (LD) non-synonymous (D398N) SNP in exon 5 of structures between the study samples. To date CHRNA5, located in the cytoplasmic domain there have been no published studies of alco- preceding the M4 transmembrane domain [12]. hol use with respect to this gene cluster; thus, Asparagine (N) in the 398 position with its polar further studies are needed to clarify whether uncharged side chain lowers Ca2+ permeability genetic variation in the nAChR genes contrib- and increases short-term desensitization in utes to inter-individual differences in alcohol (α4β2)α5 nAChRs [12]. When the function of use. the subunit is decreased, α5-containing nAChRs fail to trigger a normal inhibitory moti- Our first aim was to replicate in a large popula- vational signal that is supposed to limit nicotine tion-based sample the results of the meta- intake [13]. analysis of Saccone and colleagues [7] report- ing an association between three distinct loci Three distinct loci tagged by rs16969968 at 15q25.1 and smoking quantity, thus provid- (locus 1), rs578776 (locus 2), and rs588765 ing precise estimates of the strength of the (locus 3) provided evidence of association with association in the population at large. The sec- smoking amount defined by cigarettes per day ond aim, our main goal, was to study the role of (CPD) in a meta-analysis of 38,617 smokers genetic variants on 15q25.1 in alcohol use and from 34 data-sets [7]. Three other meta-analy- to explore whether this role is independent of ses detected association with locus 1 and smoking. locus 2 but no independent effect was detect- ed for locus 3 [8-10], which emphasizes the Materials and methods need for further studies. Both locus 1 and locus 2 have been associated also with nicotine Study sample dependence defined by the Fagerström Test for Nicotine Dependence (FTND [14]) [15], and by Our sample was drawn from two independent the Diagnostic and Statistical Manual of Mental Finnish population-based surveys, the National Disorders 4th edition (DSM-IV [16]) [17, 18], FINRISK Study [25] and the Health 2000 with the minor allele of rs16969968 (locus 1) (Health Examination) Survey [26]. increasing the risk, and the minor allele of rs578776 (locus 2) exhibiting a protective The National FINRISK Study has been initiated effect. in 1972 and carried out since then every five years using independent, random, and repre- A few studies have reported association of this sentative samples from four to six different region with alcohol related traits, with some- parts of Finland depending on the year of the what discordant results. Chen and colleagues survey [25]. We used data from cohorts 1992, [19] found evidence of association between 1997, 2002, and 2007 (participation rates locus 1 (rs16969968) and symptoms of alco- 76%, 72%, 69% and 65%, respectively), com- hol abuse or dependence. Wang and colleagues prising of 26,800 genotyped subjects (53% [20] observed association between DSM-IV women) with self-reported information about alcohol dependence and a narrow region that their health-related habits, including tobacco included locus 3 (rs588765); however, no asso- and alcohol use. The mean age was 48 years. ciation was detected with locus 1 (rs16969968) or locus 2 (rs578776). Sherva and colleagues The Health 2000 population
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