https://orcid.org/0000-0003-4892-6235
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ABSTRACT
Systemic low-grade inflammation is a feature of chronic disease. C-reactive protein (CRP) is a common biomarker of inflammation and used as an indicator of disease risk; however, the role of inflammation in disease is not completely understood. Methylation is an epigenetic modification in the DNA which plays a pivotal role in gene expression. In this study we evaluated differential DNA methylation patterns associated with blood CRP level to elucidate biological pathways and genetic regulatory mechanisms to improve the understanding of chronic inflammation. The racially and ethnically diverse participants in this study were included as 50% White, 41% Black or African American, 7% Hispanic or Latino/a, and 2% Native Hawaiian, Asian American, American Indian, or Alaska Native (total n = 13,433) individuals. We replicated 113 CpG sites from 87 unique loci, of which five were novel (CADM3, NALCN, NLRC5, ZNF792, and cg03282312), across a discovery set of 1,150 CpG sites associated with CRP level (p < 1.2E–7). The downstream pathways affected by DNA methylation included the identification of IFI16 and IRF7 CpG-gene transcript pairs which contributed to the innate immune response gene enrichment pathway along with NLRC5, NOD2, and AIM2. Gene enrichment analysis also identified the nuclear factor-kappaB transcription pathway. Using two-sample Mendelian randomization (MR) we inferred methylation at three CpG sites as causal for CRP levels using both White and Black or African American MR instrument variables. Overall, we identified novel CpG sites and gene transcripts that could be valuable in understanding the specific cellular processes and pathogenic mechanisms involved in inflammation.
Acknowledgments
The authors acknowledge and gratefully thank the other investigators, the staff, and the participants of all studies for their important and valuable contributions, without whom this research would not be possible. The authors acknowledge PAGE 3A for supporting this work. The PAGE consortium thanks the staff and participants of the PAGE studies for their important contributions.
Disclosure statement
L.R. and S.S.R. are consultants for Westat®, the Administrative Coordinating Center for the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program. C.G. owns stock in 23andMe, Inc and has a patent submitted with Illumina. The other co-authors declare no known competing interests.
Authors’ contributions
J.L., C.K., L.R., C.A., C.C., and U.P. provided conceptual input to the manuscript. J.L. wrote the manuscript, with help from all other authors. Study design and interpretation of results: J.L., C.K., L.R., C.A., U.P., Y.H., C.C., and T.Y. Primary analyses: J.L. and J.H. Individual study design, analysis, and oversight: H.X. (AMISH); K.N. (ARIC); J.Bis, N.S., and J.Brody (CHS); E.B., R.J., C.L., and D.L. (FHS); J.S., S.Ratliff, W.Z., and F.A. (GENOA); A.L., L.R., C.A., A.R. (JHS); C.H. and S.P. (MEC); M.C., X.G., S.K., T.L., Y.L., S.Rich, J.R., R.T., and D.VdB (MESA); J.L., C.K., U.P., Y.H., C.C., and J.H. (WHI). Consortium management and coordination: C.G., R.L., E.K., T.M. All authors read and approved the final manuscript.
Availability of data and materials
Datasets used in this study are listed in . The data supporting the conclusions of this article are included within the article (and supplemental material). Data used for the analyses described in this manuscript are available on dbGaP under accession numbers phs000223 (ARIC), phs000220 (MEC), phs000974 (FHS), phs001416.v3.p1 (MESA), and phs000227 (WHI). Data for CHS can be requested at https://chs-nhlbi.org/node/6222. For studies not listed above, the data that support the findings of this study are available from the corresponding authors [L.R. (JHS), H.X. (AMISH), J.S. (GENOA)] upon reasonable request.
Disclaimer
The content is solely the responsibility of the authors and does not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.
Ethics approval and consent to participate
All methods were carried out in accordance with relevant guidelines and regulations. Individual studies were approved by the appropriate institutional review boards (IRB) and written informed consent was obtained from all participants. AMISH. Amish studies were approved by the IRB at the University of Maryland, Baltimore. Written informed consent (including permission to contact relatives) was obtained from each subject. ARIC. The ARIC study was approved by the Johns Hopkins Medicine IRB. CHS. The CHS study was approved by the IRB [or ethics review committee] of University Washington. FHS. The Boston University Medical Campus and Boston Medical Center IRB approved the core FHS contact and the FHS R01s. GENOA. The GENOA project was reviewed and approved by IRBs at the Mayo Clinic, the University of Mississippi Medical Center, and the University of Michigan. This analysis was approved by the Health Sciences and Health Behaviors IRB at University of Michigan (approval number: HUM00113791). JHS. The Jackson Heart Study has been approved the IRBs of the Jackson State University, University of Mississippi Medical Center, and Tougaloo College. MEC. The MEC study was approved by the University of Southern California IRB. MESA. All methods were carried out in accordance with relevant guidelines and regulations. Individual studies were approved by the appropriate IRBs. The MESA Study was reviewed and approved by the University of Washington IRB in accordance with the U.S. Department of Health and Human Services regulations at 45 CFR 46 (approval number: 98–6582-E05) and by the Cedars-Sinai Medical Center IRB (approval number: EX-1314) with Dr. Jerome I. Rotter, as Principal Investigator. When Dr. Rotter moved to LABioMed at Harbor-UCLA Medical Center which is now The Lundquist Institute at Harbor-UCLA Medical Center, the MESA Study was IRB approved with Project Number 21030–01. WHI. The WHI project was reviewed and approved by the Fred Hutchinson Cancer Center (Fred Hutch) IRB in accordance with the U.S. Department of Health and Human Services regulations at 45 CFR 46 (approval number: IR# 3467-EXT). Additional consent to review medical records was obtained through signed written consent. Fred Hutch has an approved Federalwide Assurance on file with the Office for Human Research Protections under assurance number 0001920.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/15592294.2024.2333668