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Altered blood gene ...
Altered blood gene expression in the obesity-related type 2 diabetes cluster may be causally involved in lipid metabolism : a Mendelian randomisation study
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- de Klerk, Juliette A. (författare)
- Leiden University Medical Centre
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- Beulens, Joline W.J. (författare)
- University Medical Center Utrecht,Amsterdam Public Health
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- Mei, Hailiang (författare)
- Leiden University Medical Centre
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- Bijkerk, Roel (författare)
- Leiden University Medical Centre
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- van Zonneveld, Anton Jan (författare)
- Leiden University Medical Centre
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- Koivula, Robert W. (författare)
- Lund University,Lunds universitet,Genetisk och molekylär epidemiologi,Forskargrupper vid Lunds universitet,Genetic and Molecular Epidemiology,Lund University Research Groups,Skåne University Hospital
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- Elders, Petra J.M. (författare)
- Amsterdam Public Health
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- ’t Hart, Leen M. (författare)
- Amsterdam Public Health,Leiden University Medical Centre
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- Slieker, Roderick C. (författare)
- Leiden University Medical Centre,Amsterdam Public Health
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(creator_code:org_t)
- 2023-02-24
- 2023
- Engelska.
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 66:6, s. 1057-1070
- Relaterad länk:
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http://dx.doi.org/10... (free)
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Aims/hypothesis: The aim of this study was to identify differentially expressed long non-coding RNAs (lncRNAs) and mRNAs in whole blood of people with type 2 diabetes across five different clusters: severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), mild diabetes (MD) and mild diabetes with high HDL-cholesterol (MDH). This was to increase our understanding of different molecular mechanisms underlying the five putative clusters of type 2 diabetes. Methods: Participants in the Hoorn Diabetes Care System (DCS) cohort were clustered based on age, BMI, HbA1c, C-peptide and HDL-cholesterol. Whole blood RNA-seq was used to identify differentially expressed lncRNAs and mRNAs in a cluster compared with all others. Differentially expressed genes were validated in the Innovative Medicines Initiative DIabetes REsearCh on patient straTification (IMI DIRECT) study. Expression quantitative trait loci (eQTLs) for differentially expressed RNAs were obtained from a publicly available dataset. To estimate the causal effects of RNAs on traits, a two-sample Mendelian randomisation analysis was performed using public genome-wide association study (GWAS) data. Results: Eleven lncRNAs and 175 mRNAs were differentially expressed in the MOD cluster, the lncRNA AL354696.2 was upregulated in the SIDD cluster and GPR15 mRNA was downregulated in the MDH cluster. mRNAs and lncRNAs that were differentially expressed in the MOD cluster were correlated among each other. Six lncRNAs and 120 mRNAs validated in the IMI DIRECT study. Using two-sample Mendelian randomisation, we found 52 mRNAs to have a causal effect on anthropometric traits (n=23) and lipid metabolism traits (n=10). GPR146 showed a causal effect on plasma HDL-cholesterol levels (p = 2×10–15), without evidence for reverse causality. Conclusions/interpretation: Multiple lncRNAs and mRNAs were found to be differentially expressed among clusters and particularly in the MOD cluster. mRNAs in the MOD cluster showed a possible causal effect on anthropometric traits, lipid metabolism traits and blood cell fractions. Together, our results show that individuals in the MOD cluster show aberrant RNA expression of genes that have a suggested causal role on multiple diabetes-relevant traits.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
Nyckelord
- Clusters
- Lipid metabolism
- Long non-coding RNA
- Obesity
- Two-sample Mendelian randomisation
- Type 2 diabetes
Publikations- och innehållstyp
- art (ämneskategori)
- ref (ämneskategori)
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