Phenome-wide association study for CYP2A6 alleles: rs113288603 is associated with hearing loss symptoms in elderly smokers.
- Authors
- Polimanti, Renato; Jensen, Kevin P; Gelernter, Joel
- Year
- 2017
- Journal
- Scientific reports
- PMID
- 28432340
- DOI
- 10.1038/s41598-017-01098-4
- PMCID
- PMC5430682
To identify novel phenotypic associations related to Cytochrome P450 Family 2 Subfamily A Member 6 (CYP2A6), we investigated the human phenome in a total of 11,271 individuals. Initially, we conducted a phenome-wide association study in 3,401 nicotine-exposed elderly subjects considering 358 phenotypic traits. We identified a significant association between CYP2A6 rs113288603 and hearing loss symptoms (p = 5.75 × 10). No association was observed in a sample of 3,245 nicotine-unexposed individuals from the same discovery cohort, consistent with the conclusion that the finding is related to CYP2A6 involvement in nicotine metabolism. Consistent results were obtained (p < 0.1) in an independent sample of 2,077 nicotine-exposed elderly subjects, and similarly, no significance was observed in the nicotine-unexposed sample (n = 2,548) of the replication cohort. Additional supporting evidence for this association was provided by gene expression data: rs113288603 is associated with increased CYP2A6 expression in cerebellar hemispheres (p = 7.8 × 10). There is a well-known correlation between smoking and age-related hearing loss. Cigarette smoking is associated with structural changes in the brain and CYP2A6 mediates these changes. In this context, the regulatory role of rs113288603 in cerebellum appears to be consistent with the known involvement of this brain region in auditory function.
Differences in the association between CYP2A6 rs113288603*T and hearing loss symptoms in nicotine-exposed and nicotine-unexposed subjects from the WHI cohort.
CYP2A6 expression across rs113288603 genotypes in cerebellar hemisphere.
| # | Section | Preview |
|---|---|---|
| 20 | Discussion | Multiple studies have confirmed the role of cerebellum in auditory function20, 21, nicotinic… |
| 21 | Discussion | In conclusion, our PheWAS identified novel evidence supporting the role of CYP2A6 variation as an… |
| 22 | Discussion | of life of the growing elderly population. Additionally, knowledge of this genotype could identify… |
| 23 | Electronic supplementary material | Supplemental Tables |
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External
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|---|---|---|---|---|
| A phenome-wide association study of genetically determined nicotine metabolism reveals novel links with health-related outcomes. | Buchwald J et al. | — | 2025 | → |
| CYP2A6 associates with respiratory disease risk and younger age of diagnosis: a phenome-wide association Mendelian Randomization study. | Giratallah H et al. | — | 2024 | → |
| The genetic landscape of age-related hearing loss. | Ninoyu Y et al. | — | 2024 | → |
| Sex differences in the polygenic architecture of hearing problems in adults. | De Angelis F et al. | — | 2023 | → |
| Sex differences, cross-ancestry generalizability, and noise-smoking interactions in the polygenic architecture of hearing loss in adults | De Angelis F et al. | — | 2022 | — |
| Cytochrome P450 expression and regulation in the brain. | Kuban W et al. | — | 2021 | → |
| Genetics of substance use disorders in the era of big data. | Gelernter J et al. | — | 2021 | → |
| Genomic and Phenomic Research in the 21st Century. | Hebbring S | — | 2019 | → |
| Phenomic Impact of Genetically-Determined Euthyroid Function and Molecular Differences between Thyroid Disorders. | Ravera S et al. | — | 2018 | → |
| The genetic epidemiology of substance use disorder: A review. | Prom-Wormley EC et al. | — | 2017 | → |