Chronic diseases such as cardiovascular disease, cancer, and diabetes are driven by systemic inflammation, a natural biological response to harmful stimuli, injuries, or infections. C-reactive protein (CRP) is a substance produced by the liver that increases in the blood in response to inflammation and is used as a common inflammatory biomarker to assess disease risk. Despite its clinical relevance, CRP is diagnostically ambiguous and does not pinpoint the underlying reasons and mechanisms leading to inflammation in the progression of chronic diseases. In an effort to understand the biological pathways underlying chronic inflammation, researchers study how genome-wide methylation patterns change in relation to CRP levels. DNA methylation is an epigenetic modification where a methyl group (a carbon and three hydrogen atoms) is added directly to DNA bases, leading to transcriptional repression where genes are ‘turned off’. In the same direction, a recent study from the Kooperberg group published in the journal Epigenetics, examined how differential DNA methylation patterns correlate with blood CRP levels across different race and ethnic populations, aiming to shed light on the genetic and epigenetic landscapes that define inflammation-related diseases.
Drs. Charles Kooperberg, Jessica Lundin and their collaborators used a technique called epigenome-wide association analysis (EWAS) to identify specific DNA methylation sites that are associated with CRP levels. Initially, they analyzed over 400,000 methylation sites and identified over 1,150 as associated with CRP levels across various racial and ethnic groups. This study, replicated 113 methylation sites at 87 unique loci that were consistently associated with CRP levels and were located near specific genes involved in inflammatory processes. Interestingly, they also identified five novel methylation sites, offering new avenues for research. The study also integrated an advanced genetic analysis, known as Mendelian randomization, to assess whether these methylation changes could causally influence CRP levels. Here, they identified three methylation sites that may mediate the genetic risk for CRP levels. This study highlights how certain genetic pathways, like those involving the immune response genes, are affected by methylation which, in turn, affects CRP levels.
![CpG sites significantly associated with CRP; (a) Manhattan and (b) volcano plots of 1,150 significant CpG sites in the discovery set (CRP discovery), and 113 replicated CpG sites (CRP replicated) with a red circle around the five novel CpG sites; (c) volcano plots of replicated CpG sites with post hoc meta-analysis performed separately by race and ethnic groups to demonstrate the consistent direction of effect [NS = not significant].](/content/dam/www/backgrounds/1x1-gray.gif)
These discoveries suggest potential new biomarkers for more accurate assessment of inflammation, which could lead to better targeted therapeutic interventions. Moreover, understanding these methylation patterns offers insight into why individuals may exhibit varied levels of inflammation and disease risk. "There are gaps in diversity in epigenome-wide studies of inflammation biomarkers, with a predominance of studies performed in European ancestry populations. This study replicated 113 methylation sites across the genome, and demonstrated these findings are robust with a consistent direction of effect across race and ethnic groups. We hope this will contribute to improving disease detection and progression across a heterogeneous population,” Dr. Lundin explained.
This significant advancement in the field of epigenetics, especially in its application to chronic diseases, not only deepens our understanding of human biology but also sets the stage for genetically tailored interventions. Looking forward, Dr. Lundin stated, “Forthcoming analysis will incorporate social determinants of health, sex/gender, lifestyle and behavioral factors, as well as genetic predictors such as polygenetic score that may further the understanding of the relationship of inflammation biomarkers and methylation profiles to improve detection, prevention, and treatment approaches for chronic illness.”
This study received support through grants from the PAGE and TOPMed programs.
Fred Hutch/UW/Seattle Children’s Cancer Consortium members Drs. Charles Kooperburg and Ulrike Peters contributed to this work.
Lundin JI, Peters U, Hu Y, Ammous F, Avery CL, Benjamin EJ, Bis JC, Brody JA, Carlson C, Cushman M, Gignoux C, Guo X, Haessler J, Haiman C, Joehanes R, Kasela S, Kenny E, Lapalainien T, Levy D, Liu C, Liu Y, Loos RJF, Lu A, Matise T, North KE, Park SL, Ra PAGE Study. Methylation patterns associated with C-reactive protein in racially and ethnically diverse populations. Epigenetics. 2024 Dec;19(1):2333668. doi: 10.1080/15592294.2024.2333668. Epub 2024 Apr 3. PMID: 38571307; PMCID: PMC10996836.