The Genetic Determinants of Smoking

Batra, Vikas; Patkar, Ashwin A.; Berrettini, Wade H.; Weinstein, Stephen P.; Leone, Frank T.

doi:10.1378/chest.123.5.1730

Cited by 144 publications

(104 citation statements)

References 76 publications

(63 reference statements)

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“…The strongest evidence linking particular alleles to nicotine addiction comes from studies on genetic variation in the dopaminergic system, in cytochrome P450 enzymes, the serotonin transporter gene and monoamine oxidase. 9,10 None of these genes is located on chromosomes 3, 6, 10 or 14. However, most genes that play a major role in tobacco addiction are not yet known.…”

Section: Discussionmentioning

confidence: 99%

“…Association studies point to dopamine receptor genes, dopamine transporter genes, cytochrome P450 and serotonergic genes. 9,10 Association studies have relatively high statistical power, and can detect quantitative trait loci (QTLs) with only small effects. A possible disadvantage of the candidate gene approach is that the focus is on known pathways, which may lead us to overlook genes that are etiologically important, because of our ignorance of other biological systems involved.…”

Section: Introductionmentioning

confidence: 99%

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Linkage analysis of smoking initiation and quantity in Dutch sibling pairs

et al. 2004

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The heritability of smoking initiation (SI) and number of cigarettes smoked (NC) was determined in 3657 Dutch twin pairs. For SI a heritability of 36% was found and for NC of 51%. Both SI and NC were also significantly influenced by environmental factors shared by family members. The etiological factors that influence these traits partly overlap. Linkage analyses were performed on data of 536 DZ twins and siblings from 192 families, forming 592 sibling pairs. Results suggested QTLs on chromosome 6 (LOD ¼ 3.05) and chromosome 14 (LOD ¼ 1.66) for SI and on chromosome 3 (LOD ¼ 1.98) for NC. Strikingly, on chromosome 10 a peak was found in the same region for both SI (LOD ¼ INTRODUCTIONLarge-scale population-based twin and family studies have shown that genetic factors contribute to individual differences in smoking behavior. 1-4 Several different, possibly correlated, dimensions of smoking behavior can be distinguished: smoking initiation (SI), number of cigarettes smoked per day and nicotine dependence (ND). 5 Koopmans et al 6 investigated the heritability of SI and the number of cigarettes smoked per day (NC) in adolescent Dutch twins by considering a single liability model, an independent liability model and a combined model. The combined model best described the data and showed that 39% of the variance in SI and 86% of the variance in NC was explained by genetic influences. Kendler et al 7 found that liabilities to SI and ND were substantially correlated but not identical, and that heritable factors played an important role in both SI and in ND.The next step after obtaining evidence for significant heritability is to identify chromosomal regions involved in smoking behavior, either by linkage or association approaches. 8 Both human and animal studies have explored candidate genes for smoking behavior. Association studies point to dopamine receptor genes, dopamine transporter genes, cytochrome P450 and serotonergic genes. 9,10 Association studies have relatively high statistical power, and can detect quantitative trait loci (QTLs) with only small effects. A possible disadvantage of the candidate gene approach is that the focus is on known pathways, which may lead us to overlook genes that are etiologically important, because of our ignorance of other biological systems involved. In contrast, linkage analysis will identify chromosomal regions that harbor known and

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Linkage analysis of smoking initiation and quantity in Dutch sibling pairs

et al. 2004

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“…26 The possible candidate genes still include genes involved in the dopamine, norepinephrine or serotonin pathways as well as in nicotinic acetylcholine receptors expression. [27][28][29][30] Further progress will thus need larger genomic studies, taking into account new polymorphisms in various candidate genes together with phenotyping and behavioural studies.…”

Section: Gene Polymorphisms and Tobacco Consumptionmentioning

confidence: 99%

Association of CYP2A6*1B genetic variant with the amount of smoking in French adults from the Stanislas cohort

Gambier

Marie

et al. 2005

Pharmacogenomics J

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This study was designed in order to investigate the influence of the genetic polymorphism of CYP2A6 on the amount of smoking. In all, 463 French adults included in the Stanislas cohort were studied and underwent two examinations at 5 years distance (t 0 and t þ 5 years). Information on their smoking habits was collected. They were genotyped by RFLP for the CYP2A6*1A, CYP2A6*1B and CYP2A6*4 alleles. CYP2A6*1B and CYP2A6*4 allele frequencies were 32 and 4%, respectively. The subjects carrying the CYP2A6*1B allele oxidize nicotine to cotinine faster than subjects with the CYP2A6*1A allele. The number of cigarettes smoked per day was significantly higher in the CYP2A6*1B/*1B group as compared to the CYP2A6*1A/*1A group (P ¼ 0.01 at t 0 ; P ¼ 0.001 t þ 5 years), with a larger increase in their daily cigarettes consumption over the 5-year period (P ¼ 0.006). No significant difference in the smoking status was observed according to the CYP2A6 genotype. These data suggest that the CYP2A6*1B is associated with the number of cigarettes smoked per day.

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“…Our sample is significantly larger than those used in most previous studies of ND (for reviews see Batra et al 41 and Noble 42 ), and thus provides greater power to detect potential associations of genetic variants with ND. Furthermore, our sample represents two major ethnic groups in the US, permitting an examination of genetic differences in ND across these populations.…”

Section: Discussionmentioning

confidence: 99%

Linkage and association studies in African- and Caucasian-American populations demonstrate that SHC3 is a novel susceptibility locus for nicotine dependence

Sun

Lou

et al. 2006

Mol Psychiatry

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Our previous linkage study demonstrated that the 9q22-q23 chromosome region showed a 'suggestive' linkage to nicotine dependence (ND) in the Framingham Heart Study population. In this study, we provide further evidence for the linkage of this region to ND in an independent sample. Within this region, the gene encoding Src homology 2 domain-containing transforming protein C3 (SHC3) represents a plausible candidate for association with ND, assessed by smoking quantity (SQ), the Heaviness of Smoking Index (HSI) and the Fagerströ m Test for ND (FTND). We utilized 11 single-nucleotide polymorphisms within SHC3 to examine the association with ND in 602 nuclear families of either African-American (AA) or EuropeanAmerican (EA) origin. Individual SNP-based analysis indicated three SNPs for AAs and one for EAs were significantly associated with at least one ND measure. Haplotype analysis revealed that the haplotypes A-C-T-A-T-A of rs12519-rs3750399-rs4877042-rs2297313-rs1547696-rs1331188, with a frequency of 27.8 and 17.6%, and C-T-A-G-T of rs3750399-rs4877042-rs2297313-rs3818668-rs1547696, at a frequency of 44.7 and 30.6% in the AA and Combined samples, respectively, were significantly inversely associated with the ND measures. In the EA sample, another haplotype with a frequency of 10.6%, A-G-T-G of rs1331188-rs1556384-rs4534195-rs1411836, showed a significant inverse association with ND measures. These associations remained significant after Bonferroni correction. We further demonstrated the SHC3 contributed 40.1-59.2% (depending on the ND measures) of the linkage signals detected on chromosome 9. As further support, we found that nicotine administered through infusion increased the Shc3 mRNA level by 60% in the rat striatum, and decreased it by 22% in the nucleus accumbens (NA). At the protein level, Shc3 was decreased by 38.0% in the NA and showed no change in the striatum. Together, these findings strongly implicate SHC3 in the etiology of ND, which represents an important biological candidate for further investigation.

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The Genetic Determinants of Smoking

Cited by 144 publications

References 76 publications

Linkage analysis of smoking initiation and quantity in Dutch sibling pairs

Linkage analysis of smoking initiation and quantity in Dutch sibling pairs

Association of CYP2A6*1B genetic variant with the amount of smoking in French adults from the Stanislas cohort

Linkage and association studies in African- and Caucasian-American populations demonstrate that SHC3 is a novel susceptibility locus for nicotine dependence

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