Genome-wide association study of letrozole plasma concentrations identifies non-exonic variants that may affect
Daniel L Hertz1, Julie A Douglas2,3, Kelley M Kidwell4
1Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, Michigan.
Objectives:
Letrozole is a nonsteroidal aromatase inhibitor used to treat hormone-receptor-positive breast cancer. Variability in letrozole efficacy and toxicity may be partially attributable to variable systemic drug exposure, which may be influenced by germline variants in the enzymes responsible for letrozole metabolism, including cytochrome P450 2A6 (CYP2A6). The objective of this genome-wide association study (GWAS) was to identify polymorphisms associated with steady-state letrozole concentrations.
Methods:
The Exemestane and Letrozole Pharmacogenetics (ELPh) Study randomized postmenopausal patients with hormone-receptor-positive nonmetastatic breast cancer to letrozole or exemestane treatment. Germline DNA was collected pretreatment and blood samples were collected after 1 or 3 months of treatment to measure steady-state letrozole (and exemestane) plasma concentrations via HPLC/MS. Genome-wide genotyping was conducted on the Infinium Global Screening Array (>650 000 variants) followed by imputation. The association of each germline variant with age- and BMI-adjusted letrozole concentrations was tested in self-reported white patients via linear regression assuming an additive genetic model.
Results:
There were 228 patients who met the study-specific inclusion criteria and had both DNA and letrozole concentration data for this GWAS. The association for one genotyped polymorphism (rs7937) with letrozole concentration surpassed genome-wide significance (P = 5.26 × 10-10), explaining 13% of the variability in untransformed steady-state letrozole concentrations. Imputation around rs7937 and in silico analyses identified rs56113850, a variant in the CYP2A6 intron that may affect CYP2A6 expression and activity. rs7937 was associated with age- and BMI-adjusted letrozole levels even after adjusting for genotype-predicted CYP2A6 metabolic phenotype (P = 3.86 × 10-10).
Conclusion:
Our GWAS findings confirm that steady-state letrozole plasma concentrations are partially determined by germline polymorphisms that affect CYP2A6 activity, including variants near rs7937 such as the intronic rs56113850 variant. Further research is needed to confirm whether rs56113850 directly affects CYP2A6 activity and to integrate nonexonic variants into CYP2A6 phenotypic activity prediction systems.
Insights
Germline variants near CYP2A6 influence letrozole drug levels in breast cancer patients. This genome-wide association study identified a key polymorphism, rs7937, impacting drug concentration and potentially treatment efficacy.
Area of Science:
- Pharmacogenomics
- Oncology
- Genetics
Background:
- Letrozole is a key treatment for hormone-receptor-positive breast cancer.
- Individual responses to letrozole vary, potentially due to genetic differences in drug metabolism.
- Cytochrome P450 2A6 (CYP2A6) is involved in letrozole metabolism.
Purpose of the Study:
- To identify genetic polymorphisms associated with steady-state letrozole plasma concentrations using a genome-wide association study (GWAS).
- To understand how germline variants affect letrozole exposure and potentially its efficacy and toxicity.
Main Methods:
- The study analyzed germline DNA and steady-state letrozole concentrations from 228 postmenopausal breast cancer patients in the Exemestane and Letrozole Pharmacogenetics (ELPh) Study.
- Genome-wide genotyping was performed, followed by imputation of genetic variants.
- Associations between germline variants and letrozole concentrations were tested using linear regression, adjusting for age and BMI.
Main Results:
- A significant association was found between the polymorphism rs7937 and letrozole concentration (P = 5.26 × 10⁻¹⁰), explaining 13% of the variability.
- The variant rs56113850, located in a CYP2A6 intron, was identified and may influence CYP2A6 expression and activity.
- The association of rs7937 with letrozole levels remained significant even after accounting for genotype-predicted CYP2A6 metabolic phenotype.
Conclusions:
- Germline polymorphisms, including those near rs7937 and the intronic variant rs56113850, partially determine steady-state letrozole plasma concentrations by affecting CYP2A6 activity.
- Further research is required to confirm the direct impact of rs56113850 on CYP2A6 activity and to integrate nonexonic variants into predictive models.
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