Nature Communications has recently published a paper discussing the genetic sources of C-reactive protein, a well-known biomarker of chronic inflammation.
An extremely broad study with a wide variety of genes
Pulling genomic data from 427,367 participants in the UK Biobank and 148,164 people from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortia, which has been previously used in similar but less thorough research [1], these researchers have identified 266 genetic loci associated with C-reactive protein production, expanding upon the previous research with 211 previously unknown findings.
Many of these loci had hundreds of genetic variants, which is why such an enormous group of people was required and why such a study could not have possibly been completed without modern genomics and data analysis. Such an analysis uses Bayesian, probability-based techniques, and when so many potential associations are examined, sheer chance can easily result in false positives, so the standard p-value of 0.05 is insufficient.
Therefore, the researchers used Bonferroni thresholds instead, which take the number of tests into account and replace the p-value of 0.05 with far smaller numbers. Throughout this analysis, the amount of data led to some p-values that were much, much smaller than the Bonferroni threshold – a sign that the finding is, assuming that the study was properly conducted, nearly certain to be correct.
Basic functions and C-reactive protein production are interconnected
The researchers identified five genes that are practically certain (p-values between 8.40 x 10-162 and 5.32 x 10-147) to be associated with C-reactive protein and systemic inflammation: NECTIN2, PDE4B, OASL, IL6R, and APOE. IL6R is the interleukin-6 receptor, which is associated with inflammation [2], and APOE is well-known for its link to Alzheimer’s disease.
Links between many other genes and C-reactive protein were also plotted out, offering some useful and perhaps actionable information with which to develop therapies. Genes related to lipid (fat) transport, signaling pathways, and immune response were significant, and genes related to the regulation of gene expression were even more significant. The liver, as expected, and the blood were the most significantly affected by the expression of these genes.
Diseases linked to C-reactive protein
Many age-related diseases, including heart disease, atherosclerosis, and osteoarthritis, were found to be strongly related to the overexpression of C-reactive protein. By far, the most significant results involved the lungs: chronic obstructive pulmonary disease (COPD), bronchitis, and chronic airway obstruction were all found to be related to this systemic inflammation, according to a weighted risk score derived from the UK Biobank results.
Increased expression did seem to have some positive effects, however. Most notably, it seemed to be protective against schizophrenia, which prior research suggests is due to a reduced risk of childhood infections, which are linked with the disease [3].
Conclusion
While this study did not directly tackle aging or age-related diseases, systemic inflammation is well known to be related to aging (inflammaging), and gene expression changes with age. Studies such as this one offer useful information in determining which genes are associated with systemic inflammation, potentially paving the way for genetic or epigenetic therapies that directly target the overexpression of C-reactive protein and other inflammatory compounds.
There were, of course, a few limitations and caveats. This study focused on people of European descent, did not take BMI (which is linked to inflammation) into account as most of these genes are independent of BMI, and did not investigate rare variants of any gene. Further analysis would need to be done to see if there are any rare variants of specific genes that are linked to positive outcomes, and, if so, the biochemical pathways of such links.
Literature
[1] Ligthart, S., Vaez, A., Võsa, U., Stathopoulou, M. G., De Vries, P. S., Prins, B. P., … & Saba, Y. (2018). Genome analyses of> 200,000 individuals identify 58 loci for chronic inflammation and highlight pathways that link inflammation and complex disorders. The American Journal of Human Genetics, 103(5), 691-706.
[2] Tanaka, T., Narazaki, M., & Kishimoto, T. (2014). IL-6 in inflammation, immunity, and disease. Cold Spring Harbor perspectives in biology, 6(10), a016295.
[3] Hartwig, F. P., Borges, M. C., Horta, B. L., Bowden, J., & Smith, G. D. (2017). Inflammatory biomarkers and risk of schizophrenia: a 2-sample mendelian randomization study. JAMA psychiatry, 74(12), 1226-1233.
