Genotyping, characterization, and imputation of known and novel CYP2A6 structural variants using SNP array data

CYP2A6 metabolically inactivates nicotine. Faster CYP2A6 activity is associated with heavier smoking and higher lung cancer risk. The CYP2A6 gene is polymorphic, including functional structural variants (SV) such as gene deletions (CYP2A6*4), duplications (CYP2A6*1 × 2), and hybrids with the CYP2A7...

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Published in:Journal of human genetics 2023-08, Vol.68 (8), p.533-541
Main Authors: Langlois, Alec W R, El-Boraie, Ahmed, Pouget, Jennie G, Cox, Lisa Sanderson, Ahluwalia, Jasjit S, Fukunaga, Koya, Mushiroda, Taisei, Knight, Jo, Chenoweth, Meghan J, Tyndale, Rachel F
Format: Article
Language:English
Subjects:
Alleles
Biobanks
Biomarkers
Cigarette smoking
Copy number
CYP2A6 gene
Drug addiction
Genetics
Genotype & phenotype
Genotypes
Genotyping
Hybrids
Lung cancer
Mental health
Nicotine
Phenotypes
Single-nucleotide polymorphism
Smoking cessation
Structure-function relationships
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Summary:CYP2A6 metabolically inactivates nicotine. Faster CYP2A6 activity is associated with heavier smoking and higher lung cancer risk. The CYP2A6 gene is polymorphic, including functional structural variants (SV) such as gene deletions (CYP2A6*4), duplications (CYP2A6*1 × 2), and hybrids with the CYP2A7 pseudogene (CYP2A6*12, CYP2A6*34). SVs are challenging to genotype due to their complex genetic architecture. Our aims were to develop a reliable protocol for SV genotyping, functionally phenotype known and novel SVs, and investigate the feasibility of CYP2A6 SV imputation from SNP array data in two ancestry populations. European- (EUR; n = 935) and African- (AFR; n = 964) ancestry individuals from smoking cessation trials were genotyped for SNPs using an Illumina array and for CYP2A6 SVs using Taqman copy number (CN) assays. SV-specific PCR amplification and Sanger sequencing was used to characterize a novel SV. Individuals with SVs were phenotyped using the nicotine metabolite ratio, a biomarker of CYP2A6 activity. SV diplotype and SNP array data were integrated and phased to generate ancestry-specific SV reference panels. Leave-one-out cross-validation was used to investigate the feasibility of CYP2A6 SV imputation. A minimal protocol requiring three Taqman CN assays for CYP2A6 SV genotyping was developed and known SV associations with activity were replicated. The first domain swap CYP2A6-CYP2A7 hybrid SV, CYP2A6*53, was identified, sequenced, and associated with lower CYP2A6 activity. In both EURs and AFRs, most SV alleles were identified using imputation (>70% and >60%, respectively); importantly, false positive rates were
ISSN:1434-5161
1435-232X
DOI:10.1038/s10038-023-01148-y