Tupakointi ja geenit Jaakko Kaprio HY ja KTL
Kansantautien geneettinen tausta Monitekijäisiä Mikä on geenien merkitys Miten tauti periytyy? (yksi geeni vai monitekijäinen tauti)? Tavoitteeni tunnistaa geenit ja Arvioida niiden merkitystä väestön sairastavuuden kannalta
Outline Family studies Adoption studies Twin studies Initiation Nicotine dependence/amount smoked Cessation and withdrawal Linkage studies to identify chromosomal areas Whole genome association studies Candidate gene studies Gene-environment interactions
Periytyvyysosuus Yksilöiden välisten geneettisten erojen osuus väestön sairausriskin kokonaisvaihtelusta Geenien osuus on abstraktio (kuten taudin ilmaantuvuus tai kuolevuus) Se on tutkitun väestön, ei yksilöiden ominaisuus Sillä ei ole yhtä tai oikeata arvoa, vaan se voi vaihdella ajan ja väestön muiden ominaisuuksien mukaan englanniksi heritability
Families are the basic unit
Perimän merkityksen arvioiminen kaksostutkimuksen avulla Kaksosten odotusarvoa suurempi samankaltaisuus tutkittavan taudin suhteen on osoitus taudin kasautumisesta perheissä MZ-parien suurempi samankaltaisuus taudin suhteen verrattuna DZ-pareihin on osoitus perimän vaikutuksesta MZ/DZ vertailun avulla voidaan arvioida: perimän osuutta yhteisten ulkoisten tekijöiden merkitystä
Different phenotypes, different effects of genes Genetic effects Non-genetic family effects Experimentation (age 12) 11% 73% Initiation/ever smoker 22-72% 0-56% Smoking amount 40-54% 0-30% Nicotine withdrawal (DSM-IV) 45% None Nicotine dependence (FTND or DSM-IV) 42-72% 0-51% Rose et al. Genetics of Smoking Behavior. In Handbook of Behavior Genetics (in press)
Mitä muuta kaksostutkimus voi kertoa geenien osuudesta A. Geenien osuus voi vaihdella iän tai sukupuolen mukaan B. Toistomittausten avulla voidaan arvioida geneettisten ja perhetekijöiden vaikutusten pysyvyyttä ja vaihtelua C. Voidaan arvioida kahden tai useamman taudin yhteistä geneettistä taustaa (esim. onko tupakoinnin aloittamisella ja lopettamisella eri vai samat geenit)
Outline General approach Family studies Adoption studies Twin studies Initiation Nicotine dependence/maintenance Cessation and withdrawal Linkage studies to identify chromosomal areas Whole genome association studies Candidate gene studies Gene-environment interactions
Co-transmission of disease and alleles Aa aa Aa Aa aa Aa Aa Aa aa Aa aa
SAMPLE COLLECTION Index cases are twins from pairs concordant for heavy smoking based on earlier questionnaires from the Finnish Twin Cohorts 1293 families (twin pairs) invited 762 families recruited with 2412 family members (1278 men, 1134 women) Interview, blood sample, informed consent
Chromosome 11- Candidate Genes for Nicotine withdrawal in Finnish and Australian families Chromosome 11- Nicotine Withdrawal 1. DRD4 2. TH 3. CHRNA10 Finnish 4. TPH1 Australian 5. ANKK1/DRD2, HTR3A, HTR3B LOD score 1 2 3 4 5 Pergadia et al, in press cm position
Genome-wide Case-Control Analyses involve anonymous markers, no candidate genes chips of 300,000 to 1,000,000 SNPS on a single array (Illumina, Affymetrix) Hundreds to thousands of cases and unrelated controls High-through-put genotyping of common SNPs such as those identified from HapMap project (tag SNPs) Over past two years many new genes (n 400) in common diseases have been identified
Genome-wide Case-Control Analyses Two recent GWAs on nicotine dependence (Uhl et al, 2007, Bierut et al, 2007) New GWA on smoking cessation (Uhl G, et al, Arch Gen Psychiatr, 2008 finds genes with very little overlap to earlier GWAs on nicotine dependence Lung cancer GWAs in 2008 identified chr 15 region with nicotinic receptors as linked to smoking Pooled GWAs in progress to increase sample size and power to detect contributing genes
Thorgeirsson et al (Nature 2008) 13945 Icelandic smokers genotyped found an association with amount smoked on chromosome 15q24 (alpha3/alpha5/ beta4 gene complex) SNP accounted for 1% of variance in amount smoked Mean cigarettes /day Genotype of RS1051730 GG GT TT 10.1 11.2 12.2 N 5956 6287 1702
Outline General approach Family studies Adoption studies Twin studies Initiation Nicotine dependence/maintenance Cessation and withdrawal Linkage studies to identify chromosomal areas Candidate gene studies Whole genome association studies Gene-environment interactions
Candidate Gene Studies A strong candidate is CYP2A6 which metabolizes nicotine to cotinine, and cotinine to 3- hydroxycotiine) Slow metabolizers of nicotine less likely to smoke, they smoke less and can quit more readily Genetic variants in CYP2A6 account for about 4 percent of the variance in metabolic rate The heritability of metabolic rate is about 50% Other genes are also involved
A Pharmacogenetics model for smoking cessation Lerman et al, Am J Prev Med 2007
Other candidates 2008 Of interest among these neurotransmitter genes are the nicotinic receptor genes, such as those coding for the alpha 4 (CHRNA4), alpha 5 (CHRNA5), alpha 7 (CHRNA7) and beta 2 (CHRNB2) subunits of the fiveunit receptor. The alpha4-beta2 receptor is a well-known binding site for nicotine and the site of action of varenicline. Genetic variation in the dopamine genes, in particular DRD2, glutamate receptor genes and in the gammaaminobutyric acid neurotransmitter genes, such as GABAB2, has been inconsistently related to the studied phenotypes These are more likely to be general addiction genes (Li et al, PLoS Comput Biol 2008)
Li C-Y et al, PLoS Comput Biol 2008
Outline General approach Family studies Adoption studies Twin studies Linkage studies to identify chromosomal areas Whole genome association studies Candidate gene studies Gene-environment interactions
Gene x Environment Interactions Kendler & Eaves, 1986 Genes and environment have additive, independent effects Genes control degree of sensitivity to environmental influence Genes control susceptibility to environmental pathogenesis Liability to Illness AA Aa aa Liability to Illness AA Aa aa Liability to Illness AA Aa aa Protective Environment Predisposing Protective Environment Predisposing Protective Environment Predisposing
Gene-environment correlations (rge) refer to genetic effects on individual differences in liability to exposure to particular environmental circumstances. (Background is the extensive evidence that environmental risk exposure is far from randomly distributed) Gene-environment interactions (GxE) concern genetically influenced individual differences in the sensitivity to specific environmental factors. (Background is the extensive evidence of huge individual differences in vulnerability to all manner of environmental hazards)
Cessation rates after therapy depend on combination of genetic make-up and bupropion (Lee et al. Biol Psychiatr 2007). The CYP2B6*6 group (n = 147) had a significantly higher abstinence rate on bupropion compared with placebo at the end of treatment and at the 6-month follow-up. The CYP2B6*1 group (n = 179) did not benefit from bupropion.
IMPLICATIONS OF rge & GxE for Research i) Analyses of genetic effects must take account of environmental risk exposure and evaluate rge and GxE. ii) Analyses of environmental effects must take account of genetic risks and evaluate rge and GxE. iii) Molecular epidemiology is crucial to study naturenurture interplay. iv) Known genes account for only a small fraction of variability in disease risk Adapted from M. Rutter, 2002
IMPLICATIONS OF rge & GxE for clinical work and public health i) Conceptualization of disorders into those that are due to stress/adversity and those that are genetically determined is seriously misleading ii) People shape and select their environments as a result of how they behave, such behavior being genetically influenced iii) The huge individual differences in environmental risk exposure is due, in part, to rge iv) The huge individual differences in response to stress/adversity is due, in part, to GxE Adapted from M. Rutter, 2002
Mineur YS, Picciotto MR. Genetics of nicotinic acetylcholine receptors: Relevance to nicotine addiction. Biochem Pharmacol. 2008;75:323-33.