title: Genetic basis of tobacco smoking: strong association of a specific major histocompatibility complex haplotype on chromosome 6 with smoking behavior.
abstract: The genetic basis for addiction to tobacco smoking--particularly that of the perception of olfactory stimuli that may be important in reinforcing smoking addiction--is largely unknown. A cluster of genes for olfactory receptors is in close proximity to the MHC region on chromosome 6. Polymorphisms of MHC class III genes (RCCX modules, TNFA promoter polymorphisms) were determined in 101 healthy subjects and 232 coronary artery disease (CAD) patients from Hungary with defined tobacco smoking habits. A highly significant association between ever smoking (past + current smokers) and a specific MHC haplotype was observed (odds ratios = 2.14-4.13; P-values = 0.012 to <0.001). This haplotype is characterized by the presence of C4A null alleles and a solitary short C4B gene linked to the TNF2 allele of the promoter for TNFA gene. This haplotype occurred more frequently in the ever smokers than in the never smokers [odds ratio: 4.97 (1.96-12.62); P = 0.001], and such associations were stronger in women (odds ratio = 13.6) than in men (odds ratio = 2.79). An independent study of complement C4 protein polymorphism and smoking habits in Icelandic subjects (n = 351) yielded similar and confirmative results. Considering the documented link between olfactory stimuli and smoking in females, and the presence of a cluster of odorant receptor genes close to the MHC class I region, our findings implicate a potential role of the MHC-linked olfactory receptor genes in the initiation of smoking.
authors.affiliation: Third Department of Internal Medicine, Semmelweis University and Hungarian Academy of Sciences, Budapest, Hungary. FustGe@kut.sote.hu
authors.forename: George
authors.initials: G
authors.lastname: Füst
authors.forename: Gudmundur J
authors.initials: GJ
authors.lastname: Arason
authors.forename: Judith
authors.initials: J
authors.lastname: Kramer
authors.forename: Csaba
authors.initials: C
authors.lastname: Szalai
authors.forename: Jeno
authors.initials: J
authors.lastname: Duba
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.forename: Erwin K
authors.initials: EK
authors.lastname: Chung
authors.forename: Bi
authors.initials: B
authors.lastname: Zhou
authors.forename: Carol A
authors.initials: CA
authors.lastname: Blanchong
authors.forename: Marja-Liisa
authors.initials: ML
authors.lastname: Lokki
authors.forename: Sigurdur
authors.initials: S
authors.lastname: Bödvarsson
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Prohászka
authors.forename: István
authors.initials: I
authors.lastname: Karádi
authors.forename: Agnes
authors.initials: A
authors.lastname: Vatay
authors.forename: Margit
authors.initials: M
authors.lastname: Kovács
authors.forename: László
authors.initials: L
authors.lastname: Romics
authors.forename: Gudmundur
authors.initials: G
authors.lastname: Thorgeirsson
authors.forename: C Yung
authors.initials: CY
authors.lastname: Yu
mesh_terms: D000328:Adult; D015139:Blotting, Southern; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D015934:Complement C4a / Q000235:genetics; D015935:Complement C4b / Q000235:genetics; D003324:Coronary Artery Disease / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006649:Histocompatibility Antigens / Q000235:genetics*; D006801:Humans; D006814:Hungary; D007055:Iceland; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D018035:Receptors, Odorant / Q000235:genetics; D012737:Sex Factors; D012907:Smoking / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D006649:Histocompatibility Antigens; D018035:Receptors, Odorant; D014409:Tumor Necrosis Factor-alpha; D015934:Complement C4a; D015935:Complement C4b