The association of a single nucleotide polymorphism in the nuclear factor erythroid derived-2 like 2 (Nrf-2) gene with adverse drug reactions, multimorbidity and frailty in older people

Greg Scutt, Andrew Overall, Prijay Bakrania, Eliseveta Krasteva, Nikesh Parekh, Khalid Ali, Graham Davies, Chakravarthi Rajkumar

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Susceptibility to adverse drug reactions (ADRs), multimorbidity, and frailty are associated with human ageing, yet there is wide variation in the severity and age at which individuals are afflicted. Identifying genetic markers of increased risk of this phenotype would help stratify individuals to specialist interventions. Nuclear factor erythroid derived-2 like 2 (Nrf2) regulates a cell’s response to stressors, including the expression of enzymes involved in drug-metabolism. Its expression has been shown to decline in animal ageing models. In this study we tested the hypothesis that Nrf2 gene transcription/translation decline in human ageing, and that single nucleotide polymorphisms (SNPs) in the Nrf2 gene are associated with increased ADR risk, multi-morbidity, and frailty in older people. Gene expression and protein levels were measured in peripheral blood mononuclear cells (PBMCs) donated from healthy patients aged 18-80 years old. Nrf2 genotypes were determined at three loci in a sub-population of patients recruited to the PRIME study (a multicentre prospective cohort study that followed older adults for 8-weeks post-discharge to determine ADR). Both Nrf2 gene and protein expression declined significantly with age in human PBMCs. In the PRIME sub-study population, the rs35652124 Nrf2 SNP was associated with increased ADR risk, and decreased frailty and multi-morbidity scores.
Original languageEnglish
JournalJournals of Gerontology, Series A
DOIs
Publication statusPublished - 18 May 2019

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Drug-Related Side Effects and Adverse Reactions
Single Nucleotide Polymorphism
Comorbidity
Genes
Blood Cells
Morbidity
Gene Expression
Genetic Markers
Population
Multicenter Studies
Proteins
Cohort Studies
Animal Models
Genotype
Prospective Studies
Phenotype
Enzymes
Pharmaceutical Preparations

Bibliographical note

This is a pre-copyedited, author-produced version of an article accepted for publication in Journals of Gerontology, Series A following peer review. The version of record Greg Scutt, Andrew Overall, Prijay Bakrania, Eliseveta Krasteva, Nikesh Parekh, Khalid Ali, J Graham Davies, Chakravarthi Rajkumar, The association of a single nucleotide polymorphism in the nuclear factor erythroid derived-2 like 2 (Nrf-2) gene with adverse drug reactions, multimorbidity and frailty in older people, The Journals of Gerontology: Series A, , glz131 is available online at: https://academic.oup.com/biomedgerontology/advance-article-abstract/doi/10.1093/gerona/glz131/5491698 and https://doi.org/10.1093/gerona/glz131

Keywords

  • Nuclear-factor erythroid 2 like
  • precision medicine
  • pharmacogenomics
  • geriatrics
  • ageing

Cite this

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title = "The association of a single nucleotide polymorphism in the nuclear factor erythroid derived-2 like 2 (Nrf-2) gene with adverse drug reactions, multimorbidity and frailty in older people",
abstract = "Susceptibility to adverse drug reactions (ADRs), multimorbidity, and frailty are associated with human ageing, yet there is wide variation in the severity and age at which individuals are afflicted. Identifying genetic markers of increased risk of this phenotype would help stratify individuals to specialist interventions. Nuclear factor erythroid derived-2 like 2 (Nrf2) regulates a cell’s response to stressors, including the expression of enzymes involved in drug-metabolism. Its expression has been shown to decline in animal ageing models. In this study we tested the hypothesis that Nrf2 gene transcription/translation decline in human ageing, and that single nucleotide polymorphisms (SNPs) in the Nrf2 gene are associated with increased ADR risk, multi-morbidity, and frailty in older people. Gene expression and protein levels were measured in peripheral blood mononuclear cells (PBMCs) donated from healthy patients aged 18-80 years old. Nrf2 genotypes were determined at three loci in a sub-population of patients recruited to the PRIME study (a multicentre prospective cohort study that followed older adults for 8-weeks post-discharge to determine ADR). Both Nrf2 gene and protein expression declined significantly with age in human PBMCs. In the PRIME sub-study population, the rs35652124 Nrf2 SNP was associated with increased ADR risk, and decreased frailty and multi-morbidity scores.",
keywords = "Nuclear-factor erythroid 2 like, precision medicine, pharmacogenomics, geriatrics, ageing",
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The association of a single nucleotide polymorphism in the nuclear factor erythroid derived-2 like 2 (Nrf-2) gene with adverse drug reactions, multimorbidity and frailty in older people. / Scutt, Greg; Overall, Andrew; Bakrania, Prijay; Krasteva, Eliseveta; Parekh, Nikesh; Ali, Khalid; Davies, Graham; Rajkumar, Chakravarthi.

In: Journals of Gerontology, Series A, 18.05.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The association of a single nucleotide polymorphism in the nuclear factor erythroid derived-2 like 2 (Nrf-2) gene with adverse drug reactions, multimorbidity and frailty in older people

AU - Scutt, Greg

AU - Overall, Andrew

AU - Bakrania, Prijay

AU - Krasteva, Eliseveta

AU - Parekh, Nikesh

AU - Ali, Khalid

AU - Davies, Graham

AU - Rajkumar, Chakravarthi

N1 - This is a pre-copyedited, author-produced version of an article accepted for publication in Journals of Gerontology, Series A following peer review. The version of record Greg Scutt, Andrew Overall, Prijay Bakrania, Eliseveta Krasteva, Nikesh Parekh, Khalid Ali, J Graham Davies, Chakravarthi Rajkumar, The association of a single nucleotide polymorphism in the nuclear factor erythroid derived-2 like 2 (Nrf-2) gene with adverse drug reactions, multimorbidity and frailty in older people, The Journals of Gerontology: Series A, , glz131 is available online at: https://academic.oup.com/biomedgerontology/advance-article-abstract/doi/10.1093/gerona/glz131/5491698 and https://doi.org/10.1093/gerona/glz131

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N2 - Susceptibility to adverse drug reactions (ADRs), multimorbidity, and frailty are associated with human ageing, yet there is wide variation in the severity and age at which individuals are afflicted. Identifying genetic markers of increased risk of this phenotype would help stratify individuals to specialist interventions. Nuclear factor erythroid derived-2 like 2 (Nrf2) regulates a cell’s response to stressors, including the expression of enzymes involved in drug-metabolism. Its expression has been shown to decline in animal ageing models. In this study we tested the hypothesis that Nrf2 gene transcription/translation decline in human ageing, and that single nucleotide polymorphisms (SNPs) in the Nrf2 gene are associated with increased ADR risk, multi-morbidity, and frailty in older people. Gene expression and protein levels were measured in peripheral blood mononuclear cells (PBMCs) donated from healthy patients aged 18-80 years old. Nrf2 genotypes were determined at three loci in a sub-population of patients recruited to the PRIME study (a multicentre prospective cohort study that followed older adults for 8-weeks post-discharge to determine ADR). Both Nrf2 gene and protein expression declined significantly with age in human PBMCs. In the PRIME sub-study population, the rs35652124 Nrf2 SNP was associated with increased ADR risk, and decreased frailty and multi-morbidity scores.

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KW - Nuclear-factor erythroid 2 like

KW - precision medicine

KW - pharmacogenomics

KW - geriatrics

KW - ageing

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DO - 10.1093/gerona/glz131

M3 - Article

JO - Journals of Gerontology, Series A

JF - Journals of Gerontology, Series A

SN - 1079-5006

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