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CYP2C9 Genotypes Modify Benzodiazepine-Related Fall Risk: Original Results From Three Studies With Meta-Analysis
- Source :
- Journal of the American Medical Directors Association, 18(1), 88.e1-88.e15. Elsevier Inc., Journal of the American Medical Directors Association, 18(1), 88.e1-88.e15, Ham, A C, Ziere, G, Broer, L, Swart, K M A, Enneman, A W, van Dijk, S C, van Wijngaarden, J P, van der Zwaluw, N L, Brouwer-Brolsma, E M, Dhonukshe-Rutten, R A M, van Schoor, N M, Zillikens, M C, van Gelder, T, de Vries, O J, Lips, P, Deeg, D J H, de Groot, L C P G M, Hofman, A, Witkamp, R F, Uitterlinden, A G, Stricker, B H & van der Velde, N 2017, ' CYP2C9 Genotypes Modify Benzodiazepine-Related Fall Risk : Original Results From Three Studies With Meta-Analysis ', Journal of the American Medical Directors Association, vol. 18, no. 1, pp. 88.e1-88.e15 . https://doi.org/10.1016/j.jamda.2016.09.021, Journal of the American Medical Directors Association 18 (2017) 1
- Publication Year :
- 2017
- Publisher :
- Elsevier Inc., 2017.
-
Abstract
- Objective To investigate whether the CYP2C9*2 and *3 variants modify benzodiazepine-related fall risk. Design Three prospective studies; the Rotterdam Study, B-PROOF, and LASA. Setting Community-dwelling individuals living in or near five Dutch cities. Participants There were 11,485 participants aged ≥55 years. Measurements Fall incidents were recorded prospectively. Benzodiazepine use was determined using pharmacy dispensing records or interviews. Cox proportional hazard models adjusted for age and sex were applied to determine the association between benzodiazepine use and fall risk stratified for CYP2C9 genotype and comparing benzodiazepine users to nonusers. The results of the three studies were combined applying meta-analysis. Within benzodiazepine users, the association between genotypes and fall risk was also assessed. Results Three thousand seven hundred five participants (32%) encountered a fall during 91,996 follow-up years, and 4% to 15% (depending on the study population) used benzodiazepines. CYP2C9 variants had frequencies of 13% for the *2 allele and 6% for the *3 allele. Compared to nonusers, current benzodiazepine use was associated with an 18% to 36% increased fall risk across studies with a combined hazard ratio (HR) = 1.26 (95% confidence interval [CI], 1.13; 1.40). CYP2C9*2 or *3 allele variants modified benzodiazepine-related fall risk. Compared to nonusers, those carrying a CYP2C9*2 or *3 allele and using benzodiazepines had a 45% increased fall risk (HR, 1.45 95% CI, 1.21; 1.73), whereas CYP2C9*1 homozygotes using benzodiazepines had no increased fall risk (HR, 1.14; 95% CI, 0.90; 1.45). Within benzodiazepine users, having a CYP2C9*2 or *3 allele was associated with an increased fall risk (HR, 1.35; 95% CI, 1.06; 1.72). Additionally, we observed an allele dose effect; heterozygous allele carriers had a fall risk of (HR = 1.30; 95% CI, 1.05; 1.61), and homozygous allele carriers of (HR = 1.91 95% CI, 1.23; 2.96). Conclusions CYP2C9*2 and *3 allele variants modify benzodiazepine-related fall risk. Those using benzodiazepines and having reduced CYP2C9 enzyme activity based on their genotype are at increased fall risk. In clinical practice, genotyping might be considered for elderly patients with an indication for benzodiazepine use. However, because the exact role of CYP2C9 in benzodiazepine metabolism is still unclear, additional research is warranted.
- Subjects :
- Male
CYP2C9
medicine.medical_specialty
Genotype
Nutrition and Disease
030226 pharmacology & pharmacy
03 medical and health sciences
Rotterdam Study
Benzodiazepines
0302 clinical medicine
Internal medicine
Voeding en Ziekte
falls
medicine
Humans
030212 general & internal medicine
Prospective Studies
Allele
Prospective cohort study
General Nursing
Aged
Cytochrome P-450 CYP2C9
Netherlands
Proportional Hazards Models
VLAG
Human Nutrition & Health
pharmacogenetics
Aged, 80 and over
Global Nutrition
Wereldvoeding
business.industry
Health Policy
Hazard ratio
Humane Voeding & Gezondheid
General Medicine
Confidence interval
Nutritional Biology
Onderwijsinstituut
meta-analyses
Meta-analysis
Population study
Accidental Falls
Female
Geriatrics and Gerontology
business
Pharmacogenetics
Subjects
Details
- ISSN :
- 15389375 and 15258610
- Volume :
- 18
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal of the American Medical Directors Association
- Accession number :
- edsair.doi.dedup.....fbc9bb3d10b3eb31cb56f59f07aa60a3