Evidence on the associations between long-term exposure to multiple air pollutants and cardiopulmonary mortality is limited, especially for developing regions with higher pollutant levels. We aimed to characterise the individual and joint (multi-pollutant) associations of long-term exposure to air pollutants with cardiopulmonary mortality, and to identify air pollutant that primarily contributes to the mortality risk. We followed 37,442 participants with a mean age of 43.5 years in four cities in northern China (Tianjin, Shenyang, Taiyuan, and Rizhao) from January 1998 to December 2019. Annual particulate matter (PM) with diameters ≤2.5 μm (PM_2.5), ≤10 μm (PM₁₀), sulfur dioxide (SO₂) and nitrogen dioxide (NO₂) were estimated using daily average values from satellite-derived machine learning models and monitoring stations. Time-varying Cox proportional hazards model was used to evaluate the individual association between air pollutants and mortality from non-accidental causes, cardiovascular diseases (CVDs), non-malignant respiratory diseases (RDs) and lung cancer, accounting for demographic and socioeconomic factors. Effect modifications by age, sex, income and education level were also examined. Quantile-based g-Computation integrated with time-to-event data was additionally applied to evaluate the co-effects and the relative weight of contributions for air pollutants. During 785,807 person-years of follow-up, 5812 (15.5%) died from non-accidental causes, among which 2932 (7.8%) were from all CVDs, 479 (1.3%) from non-malignant RDs, and 552 (1.4%) from lung cancer. Long-term exposure to PM₁₀ (mean [baseline]: 136.5 μg/m³), PM_2.5 (mean [baseline]: 70.2 μg/m³), SO₂ (mean [baseline]: 113.0 μg/m³) and NO₂ (mean [baseline]: 39.2 μg/m³) were adversely and consistently associated with all mortality outcomes. A 10 μg/m³ increase in PM_2.5 was associated with higher mortality from non-accidental causes (hazard ratio 1.20; 95% confidence interval 1.17–1.23), CVDs (1.23; 1.19–1.28), non-malignant RDs (1.37; 1.25–1.49) and lung cancer (1.14; 1.05–1.23). A monotonically increasing curve with linear or supra-linear shape with no evidence of a threshold was observed for the exposure-response relationship of mortality with individual or joint exposure to air pollutants. PM_2.5 consistently contributed most to the elevated mortality risks related to air pollutant mixture, followed by SO₂ or PM₁₀. There was a strong and positive association of long-term individual and joint exposure to PM₁₀, PM_2.5, SO₂, and NO₂ with mortalities from non-accidental causes, CVDs, non-malignant RDs and lung cancer in high-exposure settings, with PM_2.5 potentially being the main contributor. The shapes of associations were consistent with a linear or supra-linear exposure-response relationship, with no lower threshold observed within the range of concentrations in this study. 10.13039/501100012166 National Key Research and Development Program of China , the 10.13039/501100004543 China Scholarship Council , the 10.13039/501100001809 National Natural Science Foundation of China , 10.13039/501100003453 Natural Science Foundation of Guangdong Province .

Particulate matter with diameters ≤2.5 μm (PM_2.5) has been identified as a significant air pollutant contributing to premature mortality. Nevertheless, the specific compositions within PM_2.5 that play the most crucial role remain unclear, especially in areas with high pollution concentrations. This study aims to investigate the individual and joint mortality risks associated with PM_2.5 inorganic chemical compositions and identify primary contributors. In 1998, we conducted a prospective cohort study in four northern Chinese cities (Tianjin, Shenyang, Taiyuan, and Rizhao). Satellite-based machine learning models calculated PM_2.5 inorganic chemical compositions, including sulfate (SO₄ ^2-), nitrate (NO₃ ^-), ammonium (NH₄ ⁺), and chloride (Cl^-). A time-varying Cox proportional hazards model was applied to analyze associations between these compositions and cardiorespiratory mortality, encompassing nonaccidental causes, cardiovascular diseases (CVDs), nonmalignant respiratory diseases (RDs), and lung cancer. The quantile-based g-computation model evaluated joint exposure effects and relative contributions of the compositions. Stratified analysis was used to identify vulnerable subpopulations. During 785,807 person-years of follow-up, 5812 (15.5%) deaths occurred from nonaccidental causes, including 2932 (7.8%) from all CVDs, 479 (1.3%) from nonmalignant RDs, and 552 (1.4%) from lung cancer. Every interquartile range (IQR) increase in SO₄ ^2- was associated with mortality from nonaccidental causes (hazard ratio: 1.860; 95% confidence interval: 1.809, 1.911), CVDs (1.909; 1.836, 1.985), nonmalignant RDs (2.178; 1.975, 2.403), and lung cancer (1.773; 1.624, 1.937). In the joint exposure model, a simultaneous rise of one IQR in all four compositions increased the risk of cardiorespiratory mortality by at least 36.3%, with long-term exposure to SO₄ ^2- contributing the most to nonaccidental and cardiopulmonary deaths. Individuals with higher incomes and lower education levels were found to be more vulnerable. Long-term exposure to higher levels of PM_2.5 inorganic compositions was associated with significantly increased cardiopulmonary mortality, with SO₄ ^2- potentially being the primary contributor. These findings offer insights into how PM_2.5 sources impact health, aiding the development of more effective governance measures.

Circumstantial evidence links one-carbon metabolism (OCM) related nutrients, such as folate and vitamin B₁₂, with gestational diabetes mellitus (GDM). However, few studies have evaluated the combined effects of these nutrients with OCM related gene polymorphisms on GDM. This study investigated whether OCM related genetic variants modified the associations of folate and B₁₂ with GDM. Logistic regression was used to estimate odds ratios (ORs) for OCM related nutrients and single nucleotide polymorphisms (SNPs) in genes encoding main OCM related enzymes (MTHFR, MTR, and MTRR) on GDM. Higher folate concentrations were associated with increased GDM risk (OR: 1.59; 95% CI: 1.22, 2.13). However, higher B₁₂ concentrations were associated with reduced GDM risk (OR: 0.76; 95% CI: 0.65, 0.92). Pregnancies with MTHFR rs1801131 G alleles had a significantly lower risk of GDM than pregnancies with T alleles (OR: 0.65; 95% CI: 0.47, 0.91) under the dominant model. The genotype-stratified analysis revealed the association between folate and GDM (OR: 1.66, 95% CI: 1.20, 2.30) or B₁₂ and GDM (OR: 0.80, 95% CI: 0.65, 0.98) was more evident in pregnancies with TT genotype. Higher folate and lower B₁₂ are associated with GDM. Pregnancies with MTHFR rs1801131 TT genotype are more susceptible to OCM nutrient-related GDM.