Background Air pollution exposure is increasingly recognized as a risk factor for chronic kidney disease (CKD), but the underlying mechanisms, especially the complex gene-environment interactions as reflected in genetic susceptibility, transcriptomic, and proteomic signatures, remain to be elucidated. Methods We conducted a large-scale prospective cohort study including 330,002 UK Biobank participants with an average follow-up of 13.0 years. Annual average concentrations of PM2.5, PM2.5−10, PM10, NO2, and NOX were assessed. Cox proportional hazards models were applied to estimate CKD risk associated with long-term air pollution exposure. We further evaluated non-linear relationships using restricted cubic splines (RCS), potential mediators via mediation analyses, and CKD susceptibility through additive interaction analyses with baseline comorbidities and polygenic risk scores (PRS). Additionally, transcriptome-wide association study (TWAS) and proteome-wide two-step Mendelian randomization (MR) were integrated to explore potential molecular pathways. Results Higher exposures to PM2.5 (HR: 1.36, 95% CI: 1.22–1.51, per 5 µg/m³), PM2.5−10 (HR: 1.25, 95% CI: 1.07–1.46, per 5 µg/m³), PM10 (HR: 1.20, 95% CI: 1.06–1.36, per 10 µg/m³), and NOX (HR: 1.04, 95% CI: 1.02–1.07, per 20 µg/m³) were significantly associated with increased CKD risk, whereas NO2 showed no significant association (HR: 0.98, 95% CI: 0.95–1.00, per 10 µg/m³). RCS revealed non-linear relationships for PM2.5−10 and PM10. Mediation analyses indicated that incident hypertension and type 2 diabetes mellitus (T2DM) acted as potential mediators in these associations. Crucially, additive interaction analyses revealed that participants with pre-existing hypertension or type 1 diabetes mellitus (T1DM) were significantly more vulnerable to specific pollution-driven CKD. Compared to individuals with low genetic risk and low air pollution exposure, those with both high genetic risk and high exposure exhibited the highest CKD risk, demonstrating a clear gradient effect across categories. TWAS identified shared genes potentially linking air pollutants with CKD, including upregulated transcripts (STX2, PHOSPHO2, NECAB3) and downregulated transcripts (CDK3, MEIOB, NDUFAF1, CRIPAK). Furthermore, proteome-wide MR analyses identified ALDH3A1, F12, and SNCG as potential risk proteins, and GNLY and MEGF10 as protective proteins. Conclusions This study provides comprehensive evidence that long-term air pollution exposure is associated with increased CKD risk and offers exploratory insights into the potential molecular pathways underlying this association, advocating the incorporation of renal health considerations into air quality control policies. Graphical Abstract

Association between air pollution exposure and increased chronic kidney disease risk: the modifying effects of genetic susceptibility, transcriptomic, and proteomic signatures

期刊论文
出版模式：

开放获取
发表日期：

2026年5月9日

查看全文

Jian Lu,
Shuaigang Sun,
Xinru Shang,
Zekai Deng,
Shunwei Wang,
Shimin Jiang,
Wenge Li

摘要

Background

Air pollution exposure is increasingly recognized as a risk factor for chronic kidney disease (CKD), but the underlying mechanisms, especially the complex gene-environment interactions as reflected in genetic susceptibility, transcriptomic, and proteomic signatures, remain to be elucidated.

Methods

We conducted a large-scale prospective cohort study including 330,002 UK Biobank participants with an average follow-up of 13.0 years. Annual average concentrations of PM_2.5, PM_2.5−10, PM₁₀, NO₂, and NO_X were assessed. Cox proportional hazards models were applied to estimate CKD risk associated with long-term air pollution exposure. We further evaluated non-linear relationships using restricted cubic splines (RCS), potential mediators via mediation analyses, and CKD susceptibility through additive interaction analyses with baseline comorbidities and polygenic risk scores (PRS). Additionally, transcriptome-wide association study (TWAS) and proteome-wide two-step Mendelian randomization (MR) were integrated to explore potential molecular pathways.

Results

Higher exposures to PM_2.5 (HR: 1.36, 95% CI: 1.22–1.51, per 5 µg/m³), PM_2.5−10 (HR: 1.25, 95% CI: 1.07–1.46, per 5 µg/m³), PM₁₀ (HR: 1.20, 95% CI: 1.06–1.36, per 10 µg/m³), and NO_X (HR: 1.04, 95% CI: 1.02–1.07, per 20 µg/m³) were significantly associated with increased CKD risk, whereas NO₂ showed no significant association (HR: 0.98, 95% CI: 0.95–1.00, per 10 µg/m³). RCS revealed non-linear relationships for PM_2.5−10 and PM₁₀. Mediation analyses indicated that incident hypertension and type 2 diabetes mellitus (T2DM) acted as potential mediators in these associations. Crucially, additive interaction analyses revealed that participants with pre-existing hypertension or type 1 diabetes mellitus (T1DM) were significantly more vulnerable to specific pollution-driven CKD. Compared to individuals with low genetic risk and low air pollution exposure, those with both high genetic risk and high exposure exhibited the highest CKD risk, demonstrating a clear gradient effect across categories. TWAS identified shared genes potentially linking air pollutants with CKD, including upregulated transcripts (STX2, PHOSPHO2, NECAB3) and downregulated transcripts (CDK3, MEIOB, NDUFAF1, CRIPAK). Furthermore, proteome-wide MR analyses identified ALDH3A1, F12, and SNCG as potential risk proteins, and GNLY and MEGF10 as protective proteins.

Conclusions

This study provides comprehensive evidence that long-term air pollution exposure is associated with increased CKD risk and offers exploratory insights into the potential molecular pathways underlying this association, advocating the incorporation of renal health considerations into air quality control policies.

Graphical Abstract