CYP2A6, MAOA, DBH, DRD4, and 5HT2A genotypes, smoking behaviour and cotinine levels in 1518 UK adolescents.
OBJECTIVE
Smoking is a major cause of death and often initiates in adolescence. Mutations in CYP2A6 slow metabolism of nicotine to cotinine. Haploinsufficiency in adults is associated with lower cigarette consumption, lower cotinine level and higher quit rates. Other genes are also implicated in smoking behaviour. We explored smoking behaviour and cotinine levels in relation to genotypes in adolescents.


METHODS
1518 subjects from the Ten Towns Heart Health Study were genotyped for CYP2A6 alleles *1A, *1B, *2, *4, *5, *9 and *12 to classify predicted nicotine metabolism rate. DBH(rs77905), MAOA(rs1801291+VNTR), DRD4(VNTR) and 5HT2A(rs6313) were also studied. Smoking status was established by questionnaire and salivary cotinine measurement at 13-15 and 18 years.


RESULTS
No significant associations were identified for DBH, MAOA, DRD4 and 5HT2A markers, with smoking status or cotinine level at either age. At age 18, haploinsufficiency (HI) for CYP2A6 was associated with a higher odds of being a current smoker compared with the *1B carriers (WT1B) (OR = 2.23 (1.16, 4.27) for current versus ex); *1A homozygotes (WT1A) were also at slightly higher risk (OR = 1.44 (1.01, 2.06)). Partial haploinsufficiency (PHI) was not associated with being a current smoker. There were no significant associations at age 13-15. PHI and HI were associated with higher cotinine levels amongst smokers at both 13-15 and at 18 years compared with WT1B and WT1A groups.


CONCLUSIONS
CYP2A6 haploinsufficiency increases likelihood of continuing smoking in teenagers. We hypothesize an explanatory 'occupancy' model to explain why haploinsufficiency results in faster progression to nicotine dependence, but lower subsequent consumption.
Huang
Shuwen
S
Human Genetics Division, Duthie Building, Southampton General Hospital, UK.
Cook
Derek G
DG
Hinks
Lesley J
LJ
Chen
Xiao-He
XH
Ye
Shu
S
Gilg
Julie A
JA
Jarvis
Martin J
MJ
Whincup
Peter H
PH
Day
Ian N M
IN
D000293:Adolescent; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D003367:Cotinine / Q000378:metabolism*; D065637:Cytochrome P-450 CYP2A6; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D006899:Mixed Function Oxygenases / Q000235:genetics*; D008995:Monoamine Oxidase / Q000235:genetics*; D009538:Nicotine / Q000378:metabolism; D011110:Polymorphism, Genetic; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics*; D050638:Receptors, Dopamine D4; D012907:Smoking / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism
C493599:DRD4 protein, human; D044402:Receptor, Serotonin, 5-HT2A; D050638:Receptors, Dopamine D4; D009538:Nicotine; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D008995:Monoamine Oxidase; D003367:Cotinine