PubMed · 5220404
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J Shindo. 1966. [On CRP].. https://pubmed.ncbi.nlm.nih.gov/5220404/
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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.
C-Reactive protein (CRP), the classic acute-phase reactant in humans, diminishes accumulation of neutrophils at inflammatory sites. To evaluate the underlying mechanisms, we have studied whether CRP and peptides derived from CRP could affect the first step of neutrophil extravasation, the L-selectin-mediated interaction of neutrophils with endothelial cells. CRP markedly attenuated attachment of human neutrophils to cultured LPS-activated human coronary artery and pulmonary microvascular endothelial cells with apparent IC50 values of 20 and 22 microg/ml, respectively. At similar concentrations, CRP rapidly downregulated the expression of L-selectin on the neutrophil surface, whereas it failed to affect expression of CD11b and CD45 or to induce granule enzyme release. The loss of L-selectin was due to cleavage and shedding of the molecule from the cell surface, as quantitated by the soluble form of L-selectin in cell-free supernatants. The effects of CRP could be prevented by an anti-CRP antiserum and by KD-IX-73-4, which inhibits shedding of L-selectin. Inhibition of adhesion with CRP was additive with function-blocking anti-E-selectin and anti-CD18 antibodies, but was not additive with anti-L-selectin antibody. Neutrophil attachment and L-selectin expression were also diminished by CRP peptides 174-185 and 201-206, but not peptide 77-82, albeit these peptides showed a weaker inhibitory effect than the parent protein. These studies indicate a specific activation-independent action of CRP and CRP peptides 174-185 and 201-206 on expression of L-selectin, and suggest that by attenuating neutrophil adhesion to the endothelium and consequently neutrophil traffic into tissues, native CRP and peptides 174-185 and 201-206 may be major mechanisms to attenuate or limit the inflammatory response.
We have reported previously that residues Lys57, Arg58, and Trp67 of human C-reactive protein (CRP) contribute to the structure of the phosphocholine (PCh)-binding site. In this study, based on the three-dimensional structures of human CRP and serum amyloid P, we constructed an additional mutant, T76Y, to probe the structural determinants of the PCh-binding site of CRP. Binding properties of four mutant CRPs, K57Q/R58G, W67K, K57Q/R58G/W67K, and T76Y were compared. Wild-type (wt) and all mutant CRPs were purified by affinity chromatography on PCh-, pneumococcal C-polysaccharide (PnC)-, or phosphoethanolamine-conjugated agarose columns. Purified mutant CRPs, K57Q/R58G/W67K and T76Y failed to bind to solid phase, PCh-substituted BSA. They did, however, bind to immobilized PnC, although with substantially decreased avidity compared with wt CRP. W67K, K57Q/R58G/W67K, and T76Y CRP required a 10-fold higher Ca2+ concentration than wt CRP to bind PnC and exhibited decreased avidity for mAb EA4.1, which recognizes a Ca2+-dependent epitope. We conclude that Thr76 is a determinant of the PCh-binding site, probably interacting with the choline group. This conclusion is supported by recent crystallographic data indicating that this residue participates in the formation of a hydrophobic pocket that constitutes the binding site for choline. Trp67, Lys57, and Arg58 do not directly contact PCh, but appear to be required for the proper conformation of the binding site.