| Application: | 51470, Physical measurement, blood biochemistry, lifestyle, environmental exposure: causality, gene-environment interaction in relation to metabolic diseases and cancer risk. |
| Title: | Genetically Determined Chronic Low-Grade Inflammation and Hundreds of Health Outcomes in the UK Biobank and the FinnGen Population: A Phenome-Wide Mendelian Randomization Study |
| Size: | 3.3 MB |
| Archived: | 6 Sep 2021 |
| Stability: | Complete |
| Personal: | No individual-level data |
Return 3795
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Notes
BackgroundC-reactive protein (CRP) has been used as a biomarker of chronic low-grade inflammation in observational studies. We aimed to determine whether genetically determined CRP was associated with hundreds of human phenotypes to guide anti-inflammatory interventions.
Methods
We used individual data from the UK Biobank to perform a phenome-wide two-stage least squares (2SLS) Mendelian randomization (MR) analysis for CRP with 879 diseases. Summary-level data from the FinnGen consortium were utilized to perform phenome-wide two-sample MR analysis on 821 phenotypes. Systematic two-sample MR methods included MR-IVW, MR-WME, MR-Mod, and MR-PRESSO as sensitivity analyses combined with multivariable MR to identify robust associations. Genetic correlation analysis was applied to identify shared genetic risks.
Results
We found genetically determined CRP was robustly associated with 15 diseases in the UK Biobank and 11 diseases in the FinnGen population (P < 0.05 for all MR analyses). CRP was positively associated with tongue cancer, bronchitis, hydronephrosis, and acute pancreatitis and negatively associated with colorectal cancer, colon cancer, cerebral ischemia, electrolyte imbalance, Parkinson's disease, epilepsy, anemia of chronic disease, encephalitis, psychophysical visual disturbances, and aseptic necrosis of bone in the UK Biobank. There were positive associations with impetigo, vascular dementia, bipolar disorders, hypercholesterolemia, vertigo, and neurological diseases, and negative correlations with degenerative macular diseases, metatarsalgia, interstitial lung disease, and idiopathic pulmonary fibrosis, and others. in the FinnGen population. The electrolyte imbalance and anemia of chronic disease in UK Biobank and hypercholesterolemia and neurological diseases in FinnGen pass the FDR corrections. Neurological diseases and bipolar disorders also presented positive genetic correlations with CRP. We found no overlapping causal associations between the populations. Previous causal evidence also failed to support these associations (except for bipolar disorders).
Conclusions
Genetically determined CRP was robustly associated with several diseases in the UK Biobank and the FinnGen population, but could not be replicated, suggesting heterogeneous and non-repeatable effects of CRP across populations. This implies that interventions at CRP are unlikely to result in decreased risk for most human diseases in the general population but may benefit specific high-risk populations. The limited causal evidence and potential double-sided effects remind us to be cautious about CRP interventions.
Application 51470
Physical measurement, blood biochemistry, lifestyle, environmental exposure: causality, gene-environment interaction in relation to metabolic diseases and cancer risk.
Cancer and metabolic diseases account for a large proportion of the global burden of disease. Epidemiological association studies reported a variety of environmental risk factors and risk genes for these diseases. However, limited studies have definite causal effects on metabolic disease or cancer, except for few widely recognized risk factors such as smoking for lung cancer and high-calorie diet for obesity. In fact, the effects of these exposures and genes on the diseases are very complicated including direct effects, indirect effects, mediating effects, gene-environment interactions, gene pleiotropy, effect modification and so on. Meanwhile, routine observational studies inevitably suffer from confounding or reverse causality. Besides, metabolic diseases and cancer may also share common risk factors with each other, however, the causal effect and pathogenic mechanism of these factors may be highly heterogeneous. Therefore, for each potential risk factor, if the causal association with a specific disease was determined, we could intervene the exposure levels of risk factors promptly to reduce the morbidity or mortality of metabolic diseases and cancer. So we aimed to explore the potential causal effect of specific exposure or pathway (physical measurement, blood biochemistry, lifestyle, environment, genes, interactions) on chronic metabolic diseases or cancer and to provide evidence for intervention and prevention. Then we also expect to develop some novel causal inference methods and effective disease prediction methods. We intend to perform our research for the duration of three years. The study may have certain practicality values for public health and further research if our results are supported. Study on both genes and environmental exposures would provide strong evidence to clarify the relationship between various exposures and diseases. Causal findings may contribute to identify novel biological pathways for disease prevention, diagnosis and treatment or provide suitable prediction indicators. This is of great significance to public health for cancer and metabolic diseases controlling. Additionally, we may also provide new analytical strategies and methods, which may have some application values for further research.
| Lead investigator: | Professor Fuzhong Xue |
| Lead institution: | Shandong University |
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1 Publication
| Pub ID | Title | Author(s) | Year | Journal |
|---|---|---|---|---|
| 3796 | Genetically Determined Chronic Low-Grade Inflammation and Hundreds of Health Outcomes in the UK Biobank and the FinnGen Population: A Phenome-Wide Mendelian Randomization Study | Si S et al. | 2021 | Front Immunol |
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