TY - JOUR
T1 - Altered blood gene expression in the obesity-related type 2 diabetes cluster may be causally involved in lipid metabolism
T2 - a Mendelian randomisation study
AU - de Klerk, Juliette A.
AU - Beulens, Joline W. J.
AU - Mei, Hailiang
AU - Bijkerk, Roel
AU - van Zonneveld, Anton Jan
AU - Koivula, Robert W.
AU - Elders, Petra J. M.
AU - ’t Hart, Leen M.
AU - Slieker, Roderick C.
N1 - Funding Information: This work has been funded by BBMRI-NL (Complementary project, CP2013-69), ZonMW Priority Medicine Elderly (grant no. 113102006 to LMtH). RCS, LMtH and JWJB received support from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 115881 (RHAPSODY). This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations (EFPIA) and is supported by the Swiss State Secretariat for Education‚ Research and Innovation (SERI) under contract no. 16.0097-2. The work leading to this publication has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115317 (DIRECT), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. Information on the project can be found at https://www.direct-diabetes.org/ . RB and AJvZ were supported by funding of the European Foundation for the Study of Diabetes. The opinions expressed and arguments employed herein do not necessarily reflect the official views of these funding bodies. JAdK was supported by the Medical Genomics research theme at Leiden University Medical Centre. Publisher Copyright: © 2023, The Author(s).
PY - 2023/6
Y1 - 2023/6
N2 - 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. Graphical abstract: [Figure not available: see fulltext.]
AB - 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. Graphical abstract: [Figure not available: see fulltext.]
KW - Clusters
KW - Lipid metabolism
KW - Long non-coding RNA
KW - Obesity
KW - Two-sample Mendelian randomisation
KW - Type 2 diabetes
UR - http://www.scopus.com/inward/record.url?scp=85148593587&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s00125-023-05886-8
DO - https://doi.org/10.1007/s00125-023-05886-8
M3 - Article
C2 - 36826505
SN - 0012-186X
VL - 66
SP - 1057
EP - 1070
JO - Diabetologia
JF - Diabetologia
IS - 6
ER -