CYP2C9 genotypes modify benzodiazepine-related fall risk: Original results from three studies with meta-analysis

A.C. Ham, Gijsbertus Ziere, Linda Broer, J.P. van Wijngaarden, N.L. van der Zwaluw, E.M. Brouwer, R.A.M. Dhonukshe-Rutten, C.P.G.M. de Groot, R.F. Witkamp

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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
LanguageEnglish
Pages88.e1-88.e15
JournalJournal of the American Medical Directors Association
Volume18
Issue number1
DOIs
Publication statusPublished - 2017

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Benzodiazepines
Meta-Analysis
Genotype
Alleles
Confidence Intervals
Odds Ratio
Cytochrome P-450 CYP2C9
Independent Living
Homozygote
Proportional Hazards Models

Cite this

@article{772ffa5ca1e64fc68d0cd9f8efe6c3c4,
title = "CYP2C9 genotypes modify benzodiazepine-related fall risk: Original results from three studies with meta-analysis",
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",
author = "A.C. Ham and Gijsbertus Ziere and Linda Broer and {van Wijngaarden}, J.P. and {van der Zwaluw}, N.L. and E.M. Brouwer and R.A.M. Dhonukshe-Rutten and {de Groot}, C.P.G.M. and R.F. Witkamp",
year = "2017",
doi = "10.1016/j.jamda.2016.09.021",
language = "English",
volume = "18",
pages = "88.e1--88.e15",
journal = "Journal of the American Medical Directors Association",
issn = "1525-8610",
publisher = "Elsevier",
number = "1",

}

CYP2C9 genotypes modify benzodiazepine-related fall risk: Original results from three studies with meta-analysis. / Ham, A.C.; Ziere, Gijsbertus; Broer, Linda; van Wijngaarden, J.P.; van der Zwaluw, N.L.; Brouwer, E.M.; Dhonukshe-Rutten, R.A.M.; de Groot, C.P.G.M.; Witkamp, R.F.

In: Journal of the American Medical Directors Association, Vol. 18, No. 1, 2017, p. 88.e1-88.e15.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - CYP2C9 genotypes modify benzodiazepine-related fall risk: Original results from three studies with meta-analysis

AU - Ham, A.C.

AU - Ziere, Gijsbertus

AU - Broer, Linda

AU - van Wijngaarden, J.P.

AU - van der Zwaluw, N.L.

AU - Brouwer, E.M.

AU - Dhonukshe-Rutten, R.A.M.

AU - de Groot, C.P.G.M.

AU - Witkamp, R.F.

PY - 2017

Y1 - 2017

N2 - 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

AB - 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

U2 - 10.1016/j.jamda.2016.09.021

DO - 10.1016/j.jamda.2016.09.021

M3 - Article

VL - 18

SP - 88.e1-88.e15

JO - Journal of the American Medical Directors Association

T2 - Journal of the American Medical Directors Association

JF - Journal of the American Medical Directors Association

SN - 1525-8610

IS - 1

ER -