title: CYP2C9 Genotypes Modify Benzodiazepine-Related Fall Risk: Original Results From Three Studies With Meta-Analysis.
abstract: To investigate whether the CYP2C9*2 and *3 variants modify benzodiazepine-related fall risk.
  
  
  
  Three prospective studies; the Rotterdam Study, B-PROOF, and LASA.
  
  
  
  Community-dwelling individuals living in or near five Dutch cities.
  
  
  
  There were 11,485 participants aged ≥55 years.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Department of Internal Medicine, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, the Netherlands.
authors.forename: Annelies C
authors.initials: AC
authors.lastname: Ham
authors.affiliation: Department of Internal Medicine, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, the Netherlands; Department of Epidemiology, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, the Netherlands.
authors.forename: Gijsbertus
authors.initials: G
authors.lastname: Ziere
authors.affiliation: Department of Internal Medicine, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, the Netherlands.
authors.forename: Linda
authors.initials: L
authors.lastname: Broer
authors.affiliation: Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Karin M A
authors.initials: KM
authors.lastname: Swart
authors.affiliation: Department of Internal Medicine, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, the Netherlands.
authors.forename: Anke W
authors.initials: AW
authors.lastname: Enneman
authors.affiliation: Department of Internal Medicine, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, the Netherlands.
authors.forename: Suzanne C
authors.initials: SC
authors.lastname: van Dijk
authors.affiliation: Division of Human Nutrition, Wageningen University, Wageningen, the Netherlands.
authors.forename: Janneke P
authors.initials: JP
authors.lastname: van Wijngaarden
authors.affiliation: Division of Human Nutrition, Wageningen University, Wageningen, the Netherlands.
authors.forename: Nikita L
authors.initials: NL
authors.lastname: van der Zwaluw
authors.affiliation: Division of Human Nutrition, Wageningen University, Wageningen, the Netherlands.
authors.forename: Elske M
authors.initials: EM
authors.lastname: Brouwer-Brolsma
authors.affiliation: Division of Human Nutrition, Wageningen University, Wageningen, the Netherlands.
authors.forename: Rosalie A M
authors.initials: RA
authors.lastname: Dhonukshe-Rutten
authors.affiliation: Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Natasja M
authors.initials: NM
authors.lastname: van Schoor
authors.affiliation: Department of Internal Medicine, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, the Netherlands.
authors.forename: M Carola
authors.initials: MC
authors.lastname: Zillikens
authors.affiliation: Department of Internal Medicine, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, the Netherlands.
authors.forename: Teun
authors.initials: T
authors.lastname: van Gelder
authors.affiliation: Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Oscar J
authors.initials: OJ
authors.lastname: de Vries
authors.affiliation: Department of Internal Medicine, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, the Netherlands; Department of Endocrinology, VU University Medical Centre, Amsterdam, the Netherlands.
authors.forename: Paul
authors.initials: P
authors.lastname: Lips
authors.affiliation: Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Dorly J H
authors.initials: DJ
authors.lastname: Deeg
authors.affiliation: Division of Human Nutrition, Wageningen University, Wageningen, the Netherlands.
authors.forename: Lisette C P G M
authors.initials: LC
authors.lastname: de Groot
authors.affiliation: Department of Epidemiology, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, the Netherlands; Department of Epidemiology, Harvard H.T. Chan School of Public Health, Boston, MA.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Division of Human Nutrition, Wageningen University, Wageningen, the Netherlands.
authors.forename: Renger F
authors.initials: RF
authors.lastname: Witkamp
authors.affiliation: Department of Internal Medicine, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, the Netherlands; Department of Epidemiology, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, the Netherlands.
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Department of Internal Medicine, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, the Netherlands; Department of Epidemiology, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, the Netherlands; Inspectorate of Health Care, Utrecht, the Netherlands.
authors.forename: Bruno H
authors.initials: BH
authors.lastname: Stricker
authors.affiliation: Department of Internal Medicine, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, the Netherlands; Department of Internal Medicine, Section of Geriatric Medicine, Academic Medical Centre, Amsterdam, the Netherlands. Electronic address: n.vandervelde@erasmusmc.nl.
authors.forename: Nathalie
authors.initials: N
authors.lastname: van der Velde
mesh_terms: D000058:Accidental Falls; D000368:Aged; D000369:Aged, 80 and over; D001569:Benzodiazepines / Q000009:adverse effects*; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D009426:Netherlands; D010597:Pharmacogenetics; D016016:Proportional Hazards Models; D011446:Prospective Studies
chemical_list: D001569:Benzodiazepines; D065729:Cytochrome P-450 CYP2C9
keywords: Benzodiazepines; CYP2C9; falls; meta-analyses; pharmacogenetics