Role of Clonal Hematopoiesis of Indeterminant Potential–Related Germline TET2 Variation in Inflammation and Cardiovascular Disease Risk: A Mendelian Randomization Study

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 43, No. 6Role of Clonal Hematopoiesis of Indeterminant Potential–Related Germline TET2 Variation in Inflammation and Cardiovascular Disease Risk: A Mendelian Randomization Study Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBRole of Clonal Hematopoiesis of Indeterminant Potential–Related Germline TET2 Variation in Inflammation and Cardiovascular Disease Risk: A Mendelian Randomization Study Héléne T. Cronjé and Dipender Gill Héléne T. CronjéHéléne T. Cronjé Correspondence to: Héléne Toinét Cronjé, PhD, Department of Public Health, Section of Epidemiology, University of Copenhagen, Oster Farimagsgade 5, Copenhagen, Denmark, 1353. Email E-mail Address: [email protected] https://orcid.org/0000-0001-6855-8324 Department of Public Health, Section of Epidemiology, University of Copenhagen, Denmark (H.T.C.). Search for more papers by this author and Dipender GillDipender Gill https://orcid.org/0000-0001-7312-7078 Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, United Kingdom (D.G.). Search for more papers by this author Originally published27 Apr 2023https://doi.org/10.1161/ATVBAHA.123.319259Arteriosclerosis, Thrombosis, and Vascular Biology. 2023;43:e227–e229Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: April 27, 2023: Ahead of Print Clonal hematopoiesis of indeterminant potential (CHIP) describes the nonmalignant proliferation of blood cell lineages that carry age-related somatic mutations in driver genes, most often DNMT3A (DNA methyltransferases) or TET2 (ten-eleven translocation-2).1 The adverse clinical effects of CHIP span hematologic, metabolic, and cardiovascular systems and can vary across CHIP subtypes (ie, the somatic loci driving clonality). Among CHIP carriers, those with somatic mutations (ie, occurring after conception) in the TET2 gene (TET2-CHIP subtype carriers) have a disproportionate increase in cardiovascular disease (CVD) risk, including coronary artery disease and stroke, potentially mediated through increased inflammation.1 Individuals with TET2-CHIP have also been shown to benefit from anti-inflammatory intervention more than those with non-TET2 CHIP subtypes.2 However, evidence related to the causal relevance of CHIP (and CHIP subtypes) on inflammation and CVD risk remains limited in humans. Furthermore, it is not known whether germline (ie, present at the time of conception) TET2 variants associated with CHIP also increase CVD risk.In a recent genome-wide association study of CHIP in 368,526 individuals of European ancestry,3 germline variation in TET2 was associated with risk of carrying (any) CHIP and DNMT3A-CHIP, but not with TET2-CHIP. In the current work, we perform Mendelian randomization to investigate the association of genetic liability to CHIP, and specifically germline TET2-related CHIP, with IL-6 (interleukin-6)–mediated inflammation and CVD risk.Genome-wide association summary statistics were downloaded on January 3, 2023, from deCODE genetics for IL-6 (https://download.decode.is/form/folder/proteomics) and the Genome-Wide Association Study Catalog4 for coronary artery disease (study accession GCST90132315), CHIP liability (GCST90165267), CRP (C-reactive protein, GCST90029070), and stroke (GCST90104534). CHIP liability was instrumented using 31 single-nucleotide polymorphisms across the genome conditionally associated with CHIP carrier status (P<5×10−8, pruned to pairwise r2<0.1 using the 1000G European reference panel). To investigate the role of TET2 germline variation, we separately instrumented the single independent TET2 variant (rs144317085) associated with CHIP liability.3 Conventional 2-sample Mendelian randomization analysis was performed. Specifically, the random-effects inverse-variance method was used in the main analysis for the 31 single-nucleotide polymorphism CHIP instrument, with the Egger and weighted median approaches used as sensitivity analyses that are more robust to the presence of pleiotropic variants. The Wald ratio method was used for the TET2 variant.5The study design and results are displayed in the Figure. Genome-wide predicted CHIP was associated with a lower risk of coronary artery disease (odds ratio [OR], 0.95 [95% CI, 0.91–0.98] per logOR increase in CHIP liability; P=0.004), but not with the risk of stroke (OR, 1.02 [95% CI, 0.97–1.07]) or with circulating IL-6 [SD difference per logOR increase in CHIP liability, 0.02 [95% CI, −0.02 to 0.06] or CRP (SD, 0.01; 95% CI, −0.03 to 0.01) levels. Similar results were obtained when performing Egger (all intercept test P>0.2) and weighted median sensitivity analyses. In contrast, germline TET2-related CHIP liability was associated with higher circulating IL-6 (SD, 0.27 [95% CI, 0.07–0.46]; P=0.008) and CRP (SD, 0.09 [95% CI, 0.03–0.15]; P=0.002) levels, as well as elevated coronary artery disease (OR, 1.17 [95% CI, 1.01–1.36]; P=0.04) and stroke (OR, 1.33 [95% CI, 1.12–1.58]; P=0.001) risk.Download figureDownload PowerPointFigure. Schematic overview of study design and results. Results as squares reflect inverse-variance weighted Mendelian randomization estimates considering the germline 31 single-nucleotide polymorphism (SNP) polygenic instrument for clonal hematopoiesis of indeterminant potential (CHIP) liability, whereas those as circles depict Wald ratio Mendelian randomization estimates considering the TET2 germline SNP predisposing to CHIP. Full descriptions of the populations analyzed in the genome-wide association studies from which summary data were obtained for analyses are available in the original publications. Created with BioRender.com. CAD indicates coronary artery disease; CRP, C-reactive protein; EAS, East Asian; EUR, European; IL-6, interleukin-6; OR, odds ratio; and TET2, ten-eleven translocation-2.This Mendelian randomization analysis provides evidence to support heterogeneity in the effect of distinct germline genetic drivers of CHIP on inflammation and CVD risk. Our results agree with prior findings that genetic predisposition to CHIP when considering variants from across the genome does not increase IL-6–mediated inflammation or CVD risk,3 but show that the germline TET2 variation related to CHIP risk does increase IL-6–mediated inflammation and CVD risk. Taken together with published work,1–3 these findings suggest that both germline and somatic mutations in TET2 that cause CHIP increase inflammation and CVD risk.The strength of this work is that it uses existing data to efficiently investigate the association of distinct genetic mechanisms underlying CHIP with inflammation and CVD risk. Furthermore, the Mendelian randomization paradigm is more robust to the environmental confounding and reverse causation bias that can affect traditional epidemiological study designs, thereby providing support for causal inferences. A limitation of our approach is that the available data largely represent European cohorts; the findings may therefore not directly translate to other ancestry groups. Additionally, germline genetic variants related to CHIP liability were not identified at the DNMT3A gene locus, and therefore, analyses such as those we performed for TET2 were not possible. As the germline TET2 variant studied also affects blood cell traits and risk of hematologic malignancy, it is not known whether its effect on inflammation and CVD is a direct consequence or related to some pleiotropic pathway. Finally, while this study contributes to understanding the inflammatory mechanisms relating CHIP to CVD, further work is required to clarify whether therapeutically intervening on these inflammatory pathways will ameliorate this increased risk.Article InformationSources of FundingNone.Disclosures Data sharing: Only publicly available genome-wide association study (GWAS) summary data were used in this work, and can be obtained from the NHGRI-EBI (National Human Genome Research Institute-European Bioinformatics Institute) Catalog of human genome-wide association studies (https://www.ebi.ac.uk/gwas/home) and deCODE (https://www.decode.com/summarydata/). The code used for this work may be obtained on request of the corresponding author. D. Gill is employed part-time by Novo Nordisk. The other author reports no conflicts.FootnotesFor Sources of Funding and Disclosures, see page e229.Correspondence to: Héléne Toinét Cronjé, PhD, Department of Public Health, Section of Epidemiology, University of Copenhagen, Oster Farimagsgade 5, Copenhagen, Denmark, 1353. Email toinet.cronje@sund.ku.dkReferences1. Stein A, Metzeler K, Kubasch AS, Rommel K-P, Desch S, Buettner P, Rosolowski M, Cross M, Platzbecker U, Thiele H. Clonal hematopoiesis and cardiovascular disease: deciphering interconnections.Basic Res Cardiol. 2022; 117:55. doi: 10.1007/s00395-022-00969-wCrossrefMedlineGoogle Scholar2. Svensson EC, Madar A, Campbell CD, He Y, Sultan M, Healey ML, Xu H, D’Aco K, Fernandez A, Wache-Mainier C, et al. TET2-driven clonal hematopoiesis and response to canakinumab: an exploratory analysis of the CANTOS randomized clinical trial.JAMA Cardiol. 2022; 7:521–528. doi: 10.1001/jamacardio.2022.0386CrossrefMedlineGoogle Scholar3. Kessler MD, Damask A, O’Keeffe S, Banerjee N, Li D, Watanabe K, Marketta A, Van Meter M, Semrau S, Horowitz J, et al; Regeneron Genetics Center. Common and rare variant associations with clonal hematopoiesis phenotypes.Nature. 2022; 612:301–309. doi: 10.1038/s41586-022-05448-9CrossrefMedlineGoogle Scholar4. Sollis E, Mosaku A, Abid A, Buniello A, Cerezo M, Gil L, Groza T, Günes¸ O, Hall P, Hayhurst J, et al. The NHGRI-EBI GWAS Catalog: knowledgebase and deposition resource.Nucleic Acids Res. 2023; 51:D977–D985. doi: 10.1093/nar/gkac1010CrossrefMedlineGoogle Scholar5. Burgess S, Davey Smith G, Davies NM, Dudbridge F, Gill D, Glymour MM, Hartwig FP, Holmes MV, Minelli C, Relton CL, et al. Guidelines for performing Mendelian randomization investigations.Wellcome Open Res. 2020; 4:186. doi: 10.12688/wellcomeopenres.15555.2CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails June 2023Vol 43, Issue 6 Advertisement Article Information Metrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.123.319259PMID: 37128918 Originally publishedApril 27, 2023 Keywordsclonal hematopoiesiscoronary artery diseaseinterleukinMendelian randomization analysisstrokePDF download Advertisement Subjects Genetic, Association Studies