Causal Relationships Between Environmental Exposures, Iron Metabolism, Hematuria Markers, and Rheumatoid Arthritis: An Investigation Using Mendelian Randomization
<b>Background:</b> Rheumatoid arthritis (RA) is a globally prevalent chronic inflammatory disease. Environmental exposures, such as air pollution and smoking, are considered potential risk factors. However, the causal relationships and underlying mechanisms between these factors and RA a...
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2025-02-01
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| author | Chao Wang Wenqing Xie Chenggong Wang Yong Zhu Da Zhong |
| author_facet | Chao Wang Wenqing Xie Chenggong Wang Yong Zhu Da Zhong |
| author_sort | Chao Wang |
| collection | DOAJ |
| description | <b>Background:</b> Rheumatoid arthritis (RA) is a globally prevalent chronic inflammatory disease. Environmental exposures, such as air pollution and smoking, are considered potential risk factors. However, the causal relationships and underlying mechanisms between these factors and RA are not fully understood. <b>Methods:</b> This study utilized large-scale genome-wide association studies (GWASs) from European ethnic backgrounds and employed bidirectional two-sample Mendelian randomization (MR) to investigate the relationships between air pollution, smoking, and RA. Genetic correlations were assessed using linkage disequilibrium score regression (LDSC). Furthermore, mediation analysis was conducted to evaluate the potential mediating roles of iron metabolism and urinary biomarkers in these relationships. <b>Results:</b> The MR analysis revealed that genetically predicted lifetime smoking intensity was associated with an 85% increased risk of RA. Subgroup analysis differentiating between seropositive RA (SPRA) and seronegative RA (SNRA) showed a causal association with SPRA, but not with SNRA. C-reactive protein was identified as a mediator in the relationship between lifetime smoking and both RA and SPRA, mediating 18.23% and 32.45% of the effects, respectively. Genetic correlation analysis further confirmed a positive genetic association between smoking and both RA and SPRA. <b>Conclusions:</b> This study provides significant insights into the genetic and causal connections between air pollution, smoking, and the development of RA, highlighting the mediating role of C-reactive protein. These findings not only offer new perspectives on how smoking might enhance RA risk through inflammatory pathways but also underscore the importance of reducing smoking exposure in public health strategies. |
| format | Article |
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| spelling | doaj-art-873baeb9dee64b0d9296fb112eb48e1c2025-08-20T02:44:40ZengMDPI AGBiomedicines2227-90592025-02-0113251310.3390/biomedicines13020513Causal Relationships Between Environmental Exposures, Iron Metabolism, Hematuria Markers, and Rheumatoid Arthritis: An Investigation Using Mendelian RandomizationChao Wang0Wenqing Xie1Chenggong Wang2Yong Zhu3Da Zhong4Department of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, ChinaDepartment of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, ChinaDepartment of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, ChinaDepartment of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, ChinaDepartment of Orthopedics, Xiangya Hospital, Central South University, Changsha 410008, China<b>Background:</b> Rheumatoid arthritis (RA) is a globally prevalent chronic inflammatory disease. Environmental exposures, such as air pollution and smoking, are considered potential risk factors. However, the causal relationships and underlying mechanisms between these factors and RA are not fully understood. <b>Methods:</b> This study utilized large-scale genome-wide association studies (GWASs) from European ethnic backgrounds and employed bidirectional two-sample Mendelian randomization (MR) to investigate the relationships between air pollution, smoking, and RA. Genetic correlations were assessed using linkage disequilibrium score regression (LDSC). Furthermore, mediation analysis was conducted to evaluate the potential mediating roles of iron metabolism and urinary biomarkers in these relationships. <b>Results:</b> The MR analysis revealed that genetically predicted lifetime smoking intensity was associated with an 85% increased risk of RA. Subgroup analysis differentiating between seropositive RA (SPRA) and seronegative RA (SNRA) showed a causal association with SPRA, but not with SNRA. C-reactive protein was identified as a mediator in the relationship between lifetime smoking and both RA and SPRA, mediating 18.23% and 32.45% of the effects, respectively. Genetic correlation analysis further confirmed a positive genetic association between smoking and both RA and SPRA. <b>Conclusions:</b> This study provides significant insights into the genetic and causal connections between air pollution, smoking, and the development of RA, highlighting the mediating role of C-reactive protein. These findings not only offer new perspectives on how smoking might enhance RA risk through inflammatory pathways but also underscore the importance of reducing smoking exposure in public health strategies.https://www.mdpi.com/2227-9059/13/2/513rheumatoid arthritisiron homeostasishematuria markersMendelian randomizationgenome-wide association studies |
| spellingShingle | Chao Wang Wenqing Xie Chenggong Wang Yong Zhu Da Zhong Causal Relationships Between Environmental Exposures, Iron Metabolism, Hematuria Markers, and Rheumatoid Arthritis: An Investigation Using Mendelian Randomization Biomedicines rheumatoid arthritis iron homeostasis hematuria markers Mendelian randomization genome-wide association studies |
| title | Causal Relationships Between Environmental Exposures, Iron Metabolism, Hematuria Markers, and Rheumatoid Arthritis: An Investigation Using Mendelian Randomization |
| title_full | Causal Relationships Between Environmental Exposures, Iron Metabolism, Hematuria Markers, and Rheumatoid Arthritis: An Investigation Using Mendelian Randomization |
| title_fullStr | Causal Relationships Between Environmental Exposures, Iron Metabolism, Hematuria Markers, and Rheumatoid Arthritis: An Investigation Using Mendelian Randomization |
| title_full_unstemmed | Causal Relationships Between Environmental Exposures, Iron Metabolism, Hematuria Markers, and Rheumatoid Arthritis: An Investigation Using Mendelian Randomization |
| title_short | Causal Relationships Between Environmental Exposures, Iron Metabolism, Hematuria Markers, and Rheumatoid Arthritis: An Investigation Using Mendelian Randomization |
| title_sort | causal relationships between environmental exposures iron metabolism hematuria markers and rheumatoid arthritis an investigation using mendelian randomization |
| topic | rheumatoid arthritis iron homeostasis hematuria markers Mendelian randomization genome-wide association studies |
| url | https://www.mdpi.com/2227-9059/13/2/513 |
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