Abstract
Background Antidepressant use has been associated with increased fall risk. Antidepressant-related adverse drug reactions (e.g. orthostatic hypotension) depend partly on genetic variation. We hypothesized that candidate genetic polymorphisms are associated with fall risk in older antidepressant users. Methods The association between antidepressant use and falls was cross-sectionally investigated in a cohort of Dutch older adults by logistic regression analyses. In case of significant interaction product term of antidepressant use and candidate polymorphism, the association between the variant genotype and fall risk was assessed within antidepressant users and the association between antidepressant use and fall risk was investigated stratified per genotype. Secondly, a look-up of the candidate genes was performed in an existing genome-wide association study on drug-related falls in antidepressant users within the UK Biobank. In antidepressant users, genetic associations for our candidate polymorphisms for fall history were investigated. Results In antidepressant users(n = 566), for rs28371725 (CYP2D6*41) fall risk was decreased in TC/variant allele carriers compared to CC/non-variant allele carriers (OR = 0.45, 95% CI 0.26–0.80). Concerning rs1057910 (CYP2C9*3), fall risk was increased in CA/variant allele carriers compared to AA/non-variant allele carriers (OR = 1.95, 95% CI 1.17–3.27). Regarding, rs1045642 (ABCB1), fall risk was increased in AG/variant allele carriers compared to GG/non-variant allele carriers (OR = 1.69, 95% CI 1.07–2.69). Concerning the ABCB1-haplotype (rs1045642/rs1128503), fall risk was increased in AA-AA/variant allele carriers compared to GG-GG/non-variant allele carriers (OR = 1.86, 95% CI 1.05–3.29). In the UK Biobank, in antidepressant users(n = 34,000) T/variant-allele of rs28371725 (CYP2D*41) was associated with increased fall risk (OR = 1.06, 95% CI 1.01–1.12). G/non-variant-allele of rs4244285 (CY2C19*2) was associated with decreased risk (OR = 0.96, 95% CI 0.92–1.00). Conclusion This is the first study showing that certain genetic variants modify antidepressant-related fall risk. The results were not always consistent across the studies and should be validated in a study with a prospective design. However, pharmacogenetics might have value in antidepressant (de)prescribing in falls prevention.
| Original language | English |
|---|---|
| Article number | e0266590 |
| Journal | PLoS ONE |
| Volume | 17 |
| Issue number | 4 April |
| DOIs | |
| Publication status | Published - 14 Apr 2022 |
Bibliographical note
Funding: This work was supported by the Clementine Brigitta Maria Dalderup fund (project numbers 20713 and 7303, receiver N. van der Velde), which is an Amsterdam University fund (https://www.auf.nl/en/about-the-fund/about.html). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The initial B-PROOF study has received funding so far by the Netherlands Organization for Health Research and Development (ZonMw, Grant 6130.0031), The Hague; unrestricted grant from NZO (Dutch Dairy Association), Zoetermeer; Orthica, Almere; Netherlands Consortium Healthy Ageing (NCHA) Leiden/Rotterdam; Ministry of Economic Affairs, Agriculture and Innovation (project KB-15-004-003), The Hague; Wageningen University, Wageningen; VUmc, Amsterdam; Erasmus Medical Center, Rotterdam. The Longitudinal Aging Study Amsterdam (LASA) is largely supported by a grant from the Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care. The data collection in 2012–2013 was financially supported by the Netherlands Organization for Scientific Research (NWO) in the framework of the project “New Cohorts of young old in the 21st century” (File Number 480-10-014). The Rotterdam Study is supported by the Erasmus MC University Medical Center and Erasmus University Rotterdam; The Netherlands Organisation for Scientific Research (NWO); The Netherlands Organisation for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); The Netherlands Genomics Initiative (NGI); the Ministry of Education, Culture and Science; the Ministry of Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. The UK Biobank was established by the Wellcome Trust medical charity, Medical Research Council, Department of Health, Scottish Government and the Northwest Regional Development Agency. It has also received funding from the Welsh Government, British Heart Foundation, Cancer Research UK and Diabetes UK. UK Biobank is supported by the National Health Service (NHS). UK Biobank is open to bona fide researchers anywhere in the world, including those funded by academia and industry. The medical research project is a non-profit charity which has received core funding of around £133 Million. Core funding continues to be received from the Wellcome Trust, the MRC, and more recently, from Cancer Research UK and NIHR. UK Biobank has received additional funding for: genotyping of all 500,000 participants (from the Department of Health, Medical Research Council, British Heart Foundation) The sponsors have no role in the design or implementation of the study, data collection, data management, data analysis, data interpretation, or in the preparation, review, or approval of the manuscript.Publisher Copyright: