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

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.