PubMed · 15994486
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Maureane Hoffman. Excess factor VIII and hypercoagulability.. https://doi.org/10.3122/jabfm.18.4.328
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Inflammation and depression have been consistently associated, with elevated C-reactive protein (CRP) levels observed in a significant subset of affected individuals. However, the genetic mechanisms underlying this association remain poorly understood. We integrated results from large-scale genome-wide association studies (GWAS) of depression and CRP levels in a cross-trait analysis specifically focusing on identifying horizontally pleiotropic loci. Identified variants were stratified as concordant versus discordant based on their direction of effects on the two traits and followed up using functional annotation, gene set enrichment, and colocalization analyses. We also explored causal relationships using Mendelian Randomization (MR) analysis with extensive sensitivity analyses, including adjustment for body mass index (BMI). We identified 9 novel loci. Functional analyses revealed that concordant loci were enriched in genes linked to immune and inflammatory processes, while discordant loci mostly mapped to metabolic pathways, including lipid regulation. MR provided strong evidence for body mass index driving a causal relationship between the genetic liability of depression on CRP levels. Our findings suggest that the association between depression and CRP levels is partly driven by shared genetic influences, pointing to different biological pathways depending on whether genetic effects are concordant or discordant. These results underscore the importance of considering effect direction when assessing the genetic overlap between depression and inflammatory processes. In addition, they highlight BMI as a key factor in the causal relationship between depression and systemic inflammation.
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Serum levels of advanced glycation end products (AGEs) are associated with an acute phase reactant, C-reactive proteins (CRP) in diabetic patients. However, whether AGEs could directly stimulate hepatic CRP production remains to be elucidated. We found here that AGEs upregulated CRP mRNA levels in cultured Hep3B cells via Rac-1 activation, which was blocked by pigment epithelium-derived factor (PEDF). Our present study suggests that AGEs are one of the potent inducers of CRP and that PEDF may work as an anti-inflammatory agent against AGEs in the liver.