Circadian imbalance and incident hypertension in the UK Biobank with exploratory molecular analyses

Q: What are the key findings of this study?

Each 1-point increase in the Circadian Imbalance Index was associated with an 8% higher risk of incident hypertension (HR 1.08).

Q: What is the clinical evidence from this study?

Study design: Cohort. Population: Incident hypertension (n=107270). Intervention: Circadian imbalance index (CII) vs. Low circadian imbalance index (CII) score. Primary outcome: Incident hypertension (HR 1.08, 95% CI 1.06-1.10, p=<0.001).

Q: What does this research mean for the field?

Higher circadian imbalance is associated with an increased risk of incident hypertension, with each 1-point increase in the Circadian Imbalance Index conferring an 8% higher risk. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To examine the prospective association between circadian imbalance and incident hypertension, assess interaction with genetic susceptibility, and identify mediating molecular pathways.

Jiaxing Ke; Zhaofu Tan; Yang Zhang; Xinyi Shao; Genlong Bai; Jianjie Ju; Haifeng Chen; Ziming Wang; Jingbo Zhang

doi:10.1038/s44325-026-00156-z

October 15, 2026npj Cardiovascular HealthOpen Access

Circadian imbalance and incident hypertension in the UK Biobank with exploratory molecular analyses

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Key result

Higher Circadian Imbalance Index linked to ~8% higher incident hypertension risk per point.

HR 1.08
95% CI 1.06-1.10
P<0.001
n=107,270

Why the study?

Circadian imbalance may contribute to hypertension, but its association with incident hypertension, genetic susceptibility, and molecular pathways remains unclear.

Does a higher circadian imbalance index increase the risk of incident hypertension in adults without baseline hypertension?

Key Points

To examine the prospective association between circadian imbalance and incident hypertension, assess interaction with genetic susceptibility, and identify mediating molecular pathways.
Analyzed prospective cohort data from 107,270 UK Biobank participants free of hypertension at baseline across 1,690,083 person-years (median follow-up of 16.53 years).
Constructed a circadian imbalance index (CII) evaluating chronotype, sleep duration, neuroticism, caffeinated coffee intake, and serum vitamin D levels.
Assessed additive and multiplicative interactions with polygenic risk scores and performed exploratory proteomic (n=9,540) and metabolomic mediation analyses.
During follow-up, 10,311 incident cases occurred; each 1-point increase in CII was associated with an 8% higher risk of hypertension (HR 1.08, 95% CI 1.06–1.10, P < 0.001).
Compared with the low CII group, incident hypertension hazard ratios were 1.10 (95% CI 1.05–1.14) for the middle CII group and 1.34 (95% CI 1.25–1.44) for the high CII group (P for trend < 0.001).
Participants with both high CII and high genetic risk had the highest risk (HR 2.43, 95% CI 2.11–2.81, P < 0.001), while 15 proteins and 58 metabolites were identified as potential statistical mediators.

Study Design

Type

Cohort (n=107,270)

Multicenter

Yes

Structured PICO

Does a higher circadian imbalance index increase the risk of incident hypertension in adults without baseline hypertension?

P

Population

107,270 adults aged 37 to 73 years from the UK Biobank, free of hypertension at baseline, followed for a median of 16.53 years to evaluate the association between circadian imbalance and incident hypertension.

E

Exposure

Higher Circadian Imbalance Index (CII) score (a composite derived from evening chronotype, short or long sleep duration, high neuroticism, atypical caffeinated coffee intake, and low serum vitamin D levels).

C

Comparator

Lower Circadian Imbalance Index (CII) score (CII 0-1).

O

Outcome

Incident hypertension

Main Result

Hazard Ratio: 1.08 (95% CI 1.06–1.1)

p-value: p=<0.001

A higher circadian imbalance index is independently associated with an increased risk of incident hypertension, with evidence of additive interaction with high genetic risk and potential mediation through proteomic and metabolomic pathways.

Limitations

Observational design limits causal inference with possible residual confounding and selection bias.
Excluding participants with baseline hypertension may introduce collider bias.
Hypertension ascertained from hospital records without repeated blood pressure measurements may lead to underascertainment.
Circadian imbalance index was assessed only at baseline and may not capture long-term dynamic changes.
Reverse causation cannot be fully excluded despite sensitivity analyses.
Limited transferability of polygenic risk scores across populations of different ancestries.

Implication

Circadian imbalance may inform future risk models; extends gene-environment observations but leaves causal effects and interventions open.

Abstract

Circadian imbalance may contribute to hypertension, but its association with incident hypertension, genetic susceptibility, and molecular pathways remains unclear. This prospective study included 107,270 UK Biobank participants free of hypertension at baseline. The circadian imbalance index (CII) was constructed from 5 factors: chronotype, sleep duration, neuroticism, caffeinated coffee intake, and serum vitamin D levels. During 1,690,083 person-years of follow-up, 10,311 cases occurred. Each 1-point increase in CII was associated with higher hypertension risk (hazard ratio [HR] 1.08 [95% CI 1.06–1.10]). Compared with the low CII group, the HRs were 1.10 (95% CI 1.05–1.14) for the middle CII group and 1.34 (95% CI 1.25–1.44) for the high CII group. Participants with both high CII and high genetic risk had the highest risk (HR 2.43, 95% CI 2.11–2.81), with evidence of additive interaction at high CII levels. Exploratory proteomic and metabolomic analyses identified 15 proteins and 58 metabolites as potential statistical mediators related to lipid, inflammatory, and vascular pathways.

Discussion

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Cite This Study

Ke et al. (2026) conducted a cohort in Incident hypertension (n=107,270). Circadian imbalance index (CII) vs. Low circadian imbalance index (CII) score was evaluated on Incident hypertension (HR 1.08, 95% CI 1.06-1.10, p=<0.001). Each 1-point increase in the Circadian Imbalance Index was associated with an 8% higher risk of incident hypertension (HR 1.08).

synapsesocial.com/papers/6ad21a2bfc66cec880534f10 https://doi.org/10.1038/s44325-026-00156-z

View Full Paper

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Circadian imbalance and incident hypertension in the UK Biobank with exploratory molecular analyses

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Circadian imbalance and incident hypertension in the UK Biobank with exploratory molecular analyses

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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