Ham Annelies C, Ziere Gijsbertus, Broer Linda, Swart Karin M A, Enneman Anke W, van Dijk Suzanne C, van Wijngaarden Janneke P, van der Zwaluw Nikita L, Brouwer-Brolsma Elske M, Dhonukshe-Rutten Rosalie A M, van Schoor Natasja M, Zillikens M Carola, van Gelder Teun, de Vries Oscar J, Lips Paul, Deeg Dorly J H, de Groot Lisette C P G M, Hofman Albert, Witkamp Renger F, Uitterlinden André G, Stricker Bruno H, van der Velde Nathalie
Department of Internal Medicine, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, the Netherlands.
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.
J Am Med Dir Assoc. 2017 Jan;18(1):88.e1-88.e15. doi: 10.1016/j.jamda.2016.09.021. Epub 2016 Nov 23.
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). CYP2C92 or 3 allele variants modified benzodiazepine-related fall risk. Compared to nonusers, those carrying a CYP2C92 or 3 allele and using benzodiazepines had a 45% increased fall risk (HR, 1.45 95% CI, 1.21; 1.73), whereas CYP2C91 homozygotes using benzodiazepines had no increased fall risk (HR, 1.14; 95% CI, 0.90; 1.45). Within benzodiazepine users, having a CYP2C92 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.
研究细胞色素P450 2C9（CYP2C9）2和3变体是否会改变苯二氮䓬类药物相关的跌倒风险。
三项前瞻性研究；鹿特丹研究、B-PROOF研究和LASA研究。
居住在荷兰五个城市或其附近的社区居民。
11485名年龄≥55岁的参与者。
前瞻性记录跌倒事件。使用药房配药记录或访谈确定苯二氮䓬类药物的使用情况。应用经年龄和性别调整的Cox比例风险模型，以确定苯二氮䓬类药物使用与根据CYP2C9基因型分层的跌倒风险之间的关联，并比较苯二氮䓬类药物使用者与非使用者。应用荟萃分析合并三项研究的结果。在苯二氮䓬类药物使用者中，还评估了基因型与跌倒风险之间的关联。
在91996人年的随访期间，3705名参与者（32%）发生了跌倒，4%至15%（取决于研究人群）使用了苯二氮䓬类药物。CYP2C9变体中，2等位基因频率为13%，3等位基因频率为6%。与非使用者相比，在各项研究中，当前使用苯二氮䓬类药物与跌倒风险增加18%至36%相关，合并风险比（HR）=1.26（95%置信区间[CI]，1.13；1.40）。CYP2C92或3等位基因变体改变了苯二氮䓬类药物相关的跌倒风险。与非使用者相比，携带CYP2C92或3等位基因且使用苯二氮䓬类药物的人跌倒风险增加45%（HR，1.45；95%CI，1.21；1.73），而使用苯二氮䓬类药物的CYP2C91纯合子跌倒风险未增加（HR，1.14；95%CI，0.90；1.45）。在苯二氮䓬类药物使用者中，携带CYP2C92或*3等位基因与跌倒风险增加相关（HR，1.35；95%CI，1.06；1.72）。此外，我们观察到等位基因剂量效应；杂合等位基因携带者的跌倒风险为（HR = 1.30；95%CI，1.05；1.61），纯合等位基因携带者的跌倒风险为（HR = 1.91；95%CI，1.23；2.96）。
CYP2C92和3等位基因变体改变了苯二氮䓬类药物相关的跌倒风险。根据基因型，使用苯二氮䓬类药物且CYP2C9酶活性降低的人跌倒风险增加。在临床实践中，对于有使用苯二氮䓬类药物指征的老年患者，可能需要考虑进行基因分型。然而，由于CYP2C9在苯二氮䓬类药物代谢中的确切作用仍不清楚，因此有必要进行更多研究。
