Altered blood gene expression in the obesity-related type 2 diabetes cluster may be causally involved in lipid metabolism: a Mendelian randomisation study

Abstract

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

Epigenetic modifications in obesity‐associated diseases

“…This varied lncR-NAs expression may be associated with the expression of genes involved in lipid metabolism and white blood cell fractions. 129 The lncRNA noncoding repressor of NFAT (NRON) plays a crucial role in regulating glucose and lipid metabolism. Its deficiency has been associated with enhanced insulin sensitivity and improved serum lipid status, making it a potential target for obesity treatment.…”

“…Diabetes can be categorized based on clinical characteristics, and the expression levels of lncRNAs in different clusters of diabetes vary significantly. This varied lncRNAs expression may be associated with the expression of genes involved in lipid metabolism and white blood cell fractions 129 . The lncRNA noncoding repressor of NFAT (NRON) plays a crucial role in regulating glucose and lipid metabolism.…”

Unraveling the links between circulating bioactive factors and epilepsy: A bidirectional Mendelian randomization study

“…Subsequently, to guarantee sufficient SNPs for subsequent MR analysis, a higher cutoff of P < 5 × 10 −6 was applied to the remaining cytokines. All F-statistic values exceeded 10, suggesting insignificant, weak instrumental bias [33] (Table S1, Supplemental Digital Content, http://links.lww.com/MD/ M633).…”

Causality between Peripheral Immune Cell Counts and Membranous Nephropathy: A Bidirectional Mendelian Randomization Study

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