Regulation of nc886 (vtRNA2-1) RNAs is associated with cardiometabolic risk factors and diseases
Rajić, Sonja; Delerue, Thomas; Ronkainen, Justiina; Zhang, Ruiyuan; Ciantar, Joanna; Kostiniuk, Daria; Mishra, Pashupati P; Lyytikäinen, Leo-Pekka; Mononen, Nina; Kananen, Laura; Peters, Annette; Winkelmann, Juliane; Kleber, Marcus E; Lorkowski, Stefan; Kähönen, Mika; Lehtimäki, Terho; Raitakari, Olli; Waldenberger, Melanie; Gieger, Christian; März, Winfried; Harville, Emily W; Sebert, Sylvain; Marttila, Saara; Raitoharju, Emma (2025-04-29)
Springer
29.04.2025
Rajić, S., Delerue, T., Ronkainen, J. et al. Regulation of nc886 (vtRNA2-1) RNAs is associated with cardiometabolic risk factors and diseases. Clin Epigenet 17, 68 (2025). https://doi.org/10.1186/s13148-025-01871-7
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© The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
https://creativecommons.org/licenses/by/4.0/
© The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
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Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:oulu-202505023038
https://urn.fi/URN:NBN:fi:oulu-202505023038
Tiivistelmä
Abstract
Non-coding 886 (nc886, vtRNA2-1) is a polymorphically imprinted gene. The methylation status of this locus has been shown to be associated with periconceptional conditions, and both the methylation status and the levels of nc886 RNAs have been shown to associate with later-life health traits. We have previously shown that nc886 RNA levels are associated not only with the methylation status of the locus, but also with a genetic polymorphism upstream from the locus. In this study, we describe the genetic and epigenetic regulators that predict lifelong nc886 RNA levels, as well as their association with cardiometabolic disease (CMD) risk factors and events. We utilised six population cohorts and one CMD cohort comprising 9058 individuals in total. The association of nc886 RNA levels, as predicted by epigenetic and genetic regulators, with CMD phenotypes was analysed using regression models, with a meta-analysis of the results. The meta-analysis showed that individuals with upregulated nc886 RNA levels have higher diastolic blood pressure (β = 0.07, p = 0.008), lower HDL levels (β = − 0.07, p = 0.006) and an increased incidence of type 2 diabetes (OR = 1.260, p = 0.013). Moreover, CMD patients with upregulated nc886 RNA levels have an increased incidence of stroke (OR = 1.581, p = 0.006) and death (OR = 1.290, p = 0.046). In conclusion, we show that individuals who are predicted to present elevated nc886 RNA levels have poorer cardiovascular health and are at an elevated risk of complications in secondary prevention. This unique mechanism yields metabolic variation in human populations, constituting a CMD risk factor that cannot be modified through lifestyle choices.
Non-coding 886 (nc886, vtRNA2-1) is a polymorphically imprinted gene. The methylation status of this locus has been shown to be associated with periconceptional conditions, and both the methylation status and the levels of nc886 RNAs have been shown to associate with later-life health traits. We have previously shown that nc886 RNA levels are associated not only with the methylation status of the locus, but also with a genetic polymorphism upstream from the locus. In this study, we describe the genetic and epigenetic regulators that predict lifelong nc886 RNA levels, as well as their association with cardiometabolic disease (CMD) risk factors and events. We utilised six population cohorts and one CMD cohort comprising 9058 individuals in total. The association of nc886 RNA levels, as predicted by epigenetic and genetic regulators, with CMD phenotypes was analysed using regression models, with a meta-analysis of the results. The meta-analysis showed that individuals with upregulated nc886 RNA levels have higher diastolic blood pressure (β = 0.07, p = 0.008), lower HDL levels (β = − 0.07, p = 0.006) and an increased incidence of type 2 diabetes (OR = 1.260, p = 0.013). Moreover, CMD patients with upregulated nc886 RNA levels have an increased incidence of stroke (OR = 1.581, p = 0.006) and death (OR = 1.290, p = 0.046). In conclusion, we show that individuals who are predicted to present elevated nc886 RNA levels have poorer cardiovascular health and are at an elevated risk of complications in secondary prevention. This unique mechanism yields metabolic variation in human populations, constituting a CMD risk factor that cannot be modified through lifestyle choices.
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