| Title: | Accelerometer-Derived Rest-Activity Rhythm Amplitude, Genetic Predisposition, and the Risk of Ischemic Heart Disease: Observational and Mendelian Randomization Study |
| Journal: | Journal of Medical Internet Research |
| Published: | 15 Dec 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41397692/ |
| DOI: | https://doi.org/10.2196/79301 |
Publication 17170
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Abstract
BACKGROUND: The rest-activity rhythm amplitude (RARA), as a fundamental human behavior, has been linked to various health conditions. However, its causal relationship with ischemic heart disease (IHD), along with the potential modification by genetic predisposition, remains unclear.</p>
OBJECTIVE: This study aimed to investigate the causal association between RARA and IHD using a triangulation approach that incorporated both observational and Mendelian randomization (MR) analyses, and to determine whether genetic predisposition modifies this relationship.</p>
METHODS: First, a prospective cohort analysis was conducted among individuals who had no history of IHD before wearing wrist actigraphy between 2013 and 2015 in the UK Biobank. RARA was derived nonparametrically from accelerometer data worn for at least 7 days. Disrupted RARA was established as the lowest quintile of accelerometer-derived amplitude. Incident IHD was identified through medical records using ICD-10 (International Statistical Classification of Diseases, Tenth Revision) codes I20-25. Genetic predisposition was assessed with polygenic risk scores for IHD (IHD-PRS), which were categorized into "low IHD-PRS" (lowest quartile), "intermediate IHD-PRS" (second and third quartiles), and "high IHD-PRS" (highest quartile). Cox proportional hazards models were used to assess the association between RARA and incident IHD, as well as the modification effects of IHD-PRS. Second, we obtained RARA genome-wide association study data from the UK Biobank and IHD genome-wide association study data from FinnGen. A 2-sample MR using inverse-variance weighted methods was performed to examine the causality between them. Several other well-established methods, including random-effects and radial inverse-variance weighted method, Mendelian randomization pleiotropy residual sum and outlier, and maximum likelihood, were also performed for sensitivity analyses.</p>
RESULTS: A total of 84,095 participants were followed up for a median of 7.90 (IQR 7.33-8.41) years. Overall, 3870 (4.60%) individuals developed IHD. Disrupted RARA was significantly associated with a higher risk of IHD (hazard ratio [HR] 1.20, 95% CI 1.12-1.30; P=.002). No significant modification effects by genetic predisposition on the multiplicative scale were found for this association (HR 0.92, 95% CI 0.76-1.11; P=.39 and HR 0.91, 95% CI 0.74-1.12; P=.37, respectively). The results remained consistent when we used the additive interaction scale to assess effect modification. Compared with participants with high RARA and low IHD-PRS (reference), those with disrupted RARA and high IHD-PRS had the highest risk of IHD (HR 2.63, 95% CI 2.29-3.02; P<.001), while those with disrupted RARA and low IHD-PRS had the smallest increased risk (HR 1.29, 95% CI 1.10-1.52; P<.001). The remaining groups showed intermediate risks in ascending order. MR results supported the observational findings (odds ratio [OR] 1.13, 95% CI 1.00-1.28; P=.047). This association was robust in our sensitivity MR analyses.</p>
CONCLUSIONS: The study suggests a potential causal relationship between RARA and IHD, independent of genetic predisposition, highlighting the significance of RARA for IHD prevention.</p>
14 Keywords
- Accelerometry
- Aged
- Exercise
- Female
- Genetic Predisposition to Disease
- Humans
- Male
- Mendelian Randomization Analysis
- Middle Aged
- Myocardial Ischemia
- Prospective Studies
- Rest
- Risk Factors
- United Kingdom
8 Authors
- Lele Wang
- Juying Zhang
- Xiong Xiao
- Xuewei Tang
- Jianxiang Tang
- Hao Xu
- Bing Guo
- Xing Zhao
1 Application
| Application ID | Title |
|---|---|
| 117185 | Research on risk factors and pathogenesis of aging-related chronic diseases |
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