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CHOLINERGIC NICOTINIC RECEPTOR GENES IMPLICATED IN A NICOTINE DEPENDENCE
To discover genetic variants that influence risk for nicotine
dependence, we targeted over 300 candidate genes and analyzed
3713 single nucleotide polymorphisms (SNPs) in 1050 cases and
879 controls. The FagerstrGm test for nicotine dependence (FTND)
was used to assess dependence, in which cases were required to
have an FTND of 4 or more. The control criterion was strict:
control subjects must have smoked at least 100 cigarettes in
their lifetimes and had an FTND of 0 during the heaviest period
of smoking. After correcting for multiple testing by controlling
the false discovery rate, several cholinergic nicotinic receptor
genes dominated the top signals. The strongest association was
from an SNP representing CHRNB3, the 3 nicotinic receptor
subunit gene (P = 9.4 x 105). Biologically, the most compelling
evidence for a risk variant came from a non-synonymous SNP in the
{alpha}5 nicotinic receptor subunit gene CHRNA5 (P = 6.4 x 104).
This SNP exhibited evidence of a recessive mode of inheritance,
resulting in individuals having a 2-fold increase in risk of
developing nicotine dependence once exposed to cigarette
smoking. Other genes among the top signals were KCNJ6 and
GABRA4. This study represents one of the most powerful and
extensive studies of nicotine dependence to date and has found
novel risk loci that require confirmation by replication
studies.
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