Association of Physical Frailty and Genetic Predisposition with Risk of Irreversible Eye Diseases

Abstract

Objective: The evidence linking frailty to overall and specific irreversible eye diseases is limited. Moreover, it is unclear whether frailty is associated with similar increased risk across individuals with different genetic risk profiles. The aim of this study was to examine the association between frailty and overall and specific irreversible eye diseases and explore the modification effect of genetic risk of glaucoma, diabetic retinopathy, and age-related macular degeneration (AMD) in such associations.

Design: Prospective cohort study.

Participants: The study included a total of 409 579 White participants in the UK Biobank study.

Methods: Physical frailty was defined by 5 components: weight loss, exhaustion, low physical activity, slow walking speed, and low grip strength. Participants were classified as nonfrail, prefrail, or frail. Polygenic risk score was categorized as low (tertile 1), intermediate (tertile 2), or high (tertile 3). Cox regression was used to assess the association of physical frailty with irreversible eye diseases.

Main outcomes and measures: Irreversible eye diseases were identified using hospital admission electronic health records and death registries.

Results: Among 409 579 individuals (mean age, 56.5 years; 46.5% male) with a median follow-up of 13.1 years, 10 927, 7 095, and 919 were diagnosed with irreversible eye disease in the nonfrail, prefrail, and frail groups, respectively. Prefrail and frail individuals showed increased risks of overall irreversible eye diseases, with a 12% higher risk for prefrail individuals (hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.09-1.16) and a 47% higher risk for frail individuals (HR, 1.47; 95% CI, 1.37-1.58). Increased risks were also observed for specific irreversible eye diseases, including glaucoma (HR, 1.11 [95% CI, 1.06-1.17] for prefrailty; HR, 1.43 [95% CI, 1.28-1.61] for frailty), diabetic retinopathy (HR, 1.12 [95% CI, 1.03-1.21] for prefrailty; HR, 1.53 [95% CI, 1.34-1.73] for frailty), and AMD (HR, 1.13 [95% CI, 1.08-1.19] for prefrailty; HR, 1.35 [95% CI, 1.20-1.52] for frailty). Furthermore, individuals with more severe frailty status and higher genetic risk exhibited higher risks of irreversible eye diseases than those with low genetic risk and nonfrailty.

Conclusions: Frailty was associated with an increased risk of irreversible eye diseases, particularly among individuals with higher genetic risk. These findings suggest that targeted strategies to prevent and manage frailty may contribute to reducing the risk of irreversible eye diseases.

Financial disclosures: The authors have no proprietary or commercial interest in any materials discussed in this article.

Keywords: Genetic predisposition; Irreversible eye diseases; Physical frailty.

Figure 2

Cumulative incidence of irreversible eye disease in participants with nonfrailty, prefrailty, and frailty. A, Overall irreversible eye disease; B, glaucoma; C, diabetic retinopathy; D, age-related macular degeneration (AMD).

Figure 3

Risk of specific irreversible eye disease according to genetic risk and frailty status. A, Glaucoma; B, diabetic retinopathy; C, age-related macular degeneration (AMD). Error bars indicate 95% confidence interval. Cox regression models were adjusted for age, sex, body mass index, educational level, smoking, alcohol consumption, sleep time, Townsend Deprivation Index, systolic and diastolic blood pressure, triglycerides, high-density lipoprotein, low-density lipoprotein, food intake status (including vegetables, fruit, meat, and fish), diabetes, and multimorbidity. PRS = polygenic risk score.