p450 - publications

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1. Hum Mol Genet. 2012 Mar 26. [Epub ahead of print]

Use of a Predictive Model Derived from In Vivo Endophenotype Measurements to
Demonstrate Associations with a Complex Locus, CYP2A6.

Bloom AJ, Harari O, Martinez M, Madden PA, Martin NG, Montgomery GW, Rice JP,
Murphy SE, Bierut LJ, Goate A.

Department of Psychiatry, Washington University School of Medicine, St. Louis.

This study demonstrates a novel approach to test associations between highly
heterogeneous genetic loci and complex phenotypes. Previous investigations of the
relationship between Cytochrome P450 2A6 (CYP2A6) genotype and smoking phenotypes
made comparisons by dividing subjects into broad categories based on assumptions
that simplify the range of function of different CYP2A6 alleles, their numerous
possible diplotype combinations, and non-additive allele effects. A predictive
model that translates CYP2A6 diplotype into a single continuous variable was
previously derived from an in vivo metabolism experiment in 189 European
Americans. Here we apply this model to assess associations between genotype,
inferred nicotine metabolism, and smoking behaviors in larger samples without
direct nicotine metabolism measurements. CYP2A6 genotype is not associated with
nicotine dependence, as defined by the Fagerström Test of Nicotine Dependence
(FTND), demonstrating that cigarettes smoked per day (CPD) and nicotine
dependence have distinct genetic correlates. The predicted metric is
significantly associated with CPD among African Americans and European American
dependent smokers. Individual slow metabolizing genotypes are associated with
lower CPD, but the predicted metric is the best predictor of CPD. Furthermore,
optimizing the predictive model by including additional CYP2A6 alleles improves
the fit of the model in an independent data set and provides a novel method of
predicting the functional impact of alleles without direct metabolism
measurements. Lastly, comprehensive genotyping and in vivo metabolism data are
used to demonstrate that genome-wide significant associations between CPD and
single nucleotide polymorphisms (SNPs) are the result of synthetic associations.

PMID: 22451501 [PubMed - as supplied by publisher]