Abstract
Previous studies have demonstrated that the γ-aminobutyric acid type B (GABAB) receptor plays an essential role in modulating neurotransmitter release and regulating the activity of ion channels and adenyl cyclase. However, whether the naturally occurring polymorphisms in the two GABAB receptor subunit genes interact with each other to alter susceptibility to nicotine dependence (ND) remains largely unknown. In this study, we genotyped 5 and 33 single nucleotide polymorphisms (SNPs) for GABAB receptor subunit 1 and 2 genes (GABBR1, GABBR2), respectively, in a sample of 2037 individuals from 602 nuclear families of African- American (AA) or European-American (EA) origin. We conducted association analyses to determine (1) the association of each subunit gene with ND at both the individual SNP and haplotype levels and (2) the collective effect(s) of SNPs in both GABAB subunits on the development of ND. Several individual SNPs and haplotypes in GABBR2 were significantly associated with ND in both ethnic samples. Two haplotypes in AAs and one haplotype in EAs showed a protective effect against ND, whilst two other haplotypes in AAs and three haplotypes in EAs showed a risk effect for developing ND. Interestingly, these significant haplotypes were confined to two regions of GABBR2 in the AA and EA samples. Additionally, we found two minor haplotypes in GABBR1 to be positively associated with Heaviness of Smoking Index (HSI) in the EA sample. Finally, we demonstrated the presence of epistasis between GABBR1 and GABBR2 for developing ND. The variants of GABBR1 and GABBR2 are significantly associated with ND, and the involvement of GABBR1 is most likely through its interaction with GABBR2, whereas GABBR2 polymorphisms directly alter susceptibility to ND. Future studies are needed with more dense SNP coverage of GABBR1 and GABBR2 to verify the epistatic effects of the two subunit genes.
Highlights
Tobacco smoking is a serious public health concern worldwide, as nearly a third of adults smoke tobacco or related products [1]
For GABBR1, analysis revealed no significant association with nicotine dependence (ND) for any individual single nucleotide polymorphisms (SNPs) in the three samples; rs29230 exhibited a trend with FTND in the pooled sample (p = 0.08)
The pharmacologically active GABAB receptors are formed by heterodimerization of GABAB1 and GABAB2 subunit proteins encoded by GABBR1 and GABBR2 genes, respectively
Summary
Tobacco smoking is a serious public health concern worldwide, as nearly a third of adults smoke tobacco or related products [1]. The first gene identified from this linkage region was GABBR2 (G-protein coupled receptor 51), for which several SNPs were found to be significantly associated with ND in the Mid-South Tobacco Family (MSTF) cohort [11]. The GABA system is diffusely expressed in the brain; areas other than the mesolimbic system may be partly responsible for these effects Evidence exists from both animal and human studies supporting the value of GABAB receptor agonists in the treatment of drug abuse. A recent animal study examined the effect of nicotine on GABBR2 expression in various brain regions in a rodent model [16]. GABBR2 mRNA was significantly regulated in several brain regions generally associated with addiction, providing further evidence that the GABA system is involved in addictive processes. We found no evidence for significant associations of GABBR1 with ND in either ethnic sample, we detected a significant gene-gene interactive (epistatic) effect between the two subunits by using a newly developed pedigree-based generalized multifactor dimensionality reduction (PGMDR) approach
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