The transcriptomic and epigenetic alterations in type 2 diabetes mellitus patients of Chinese Tibetan and Han populations

BACKGROUND: Due to the distinctive living environment, lifestyle, and diet, the Tibetan community in China has the lowest prevalence of T2DM and prediabetes among numerous ethnic groups, while Han community shows the highest statistic. In this study, we aim to conclude the clinical manifestations of both Tibetan and Han T2DM patients and their association with transcriptomic and epigenetic alterations. METHODS: A cross-sectional study including 120 T2DM patients from Han and Tibetan ethnic groups were conducted between 2019 to 2021 at the Hospital of Chengdu University of Traditional Chinese Medicine. The various clinical features and laboratory tests were recorded and analyzed between the two groups. The genome-wide methylation pattern and RNA expression were determined by Reduced Representation Bisulfite Sequencing (RBBS) and Poly (A) RNA sequencing (RNA-seq) from leucocytes of peripheral blood samples in 6 Han and 6 Tibetan patients. GO analysis and KEGG analysis were conducted in differentially expressed genes and those with differentially methylated regions. RESULTS: Compared to Han, Tibetan T2DM individuals intake more coarse grains, meat and yak butter, but less refined grains, vegetables and fruit. They also showed increased BMI, Hb, HbA1c, LDL, ALT, GGT and eGFR, and decreased level of BUN. Among the 12 patients in the exploratory cohort, we identified 5178 hypomethylated and 4787 hypermethylated regions involving 1613 genes in the Tibetan group. RNA-seq showed a total of 947 differentially expressed genes (DEGs) between the two groups, with 523 up-regulated and 424 down-regulated in Tibetan patients. By integrating DNA methylation and RNA expression data, we identified 112 DEGs with differentially methylated regions (overlapping genes) and 14 DEGs with promoter-related DMRs. The functional enrichment analysis demonstrated that the overlapping genes were primarily involved in metabolic pathways, PI3K-Akt signaling pathway, MAPK signaling pathway, pathways in cancer and Rap1 signaling pathway. CONCLUSION: Our study demonstrates the clinical characteristics of T2DM differ subtly between various ethnic groups that may be related to epigenetic modifications, thus providing evidence and ideas for additional research on the genetic pattern of T2DM.