Although there are some epigenome-wide association studies (EWAS) of insulin resistance, most of them did not replicate their findings and are focused in populations of European ancestry limiting the generalizability. In EPIPREG (294 Europeans and 162 South Asians), we conducted an EWAS of insulin resistance in maternal peripheral blood leukocytes, with replication in Born in Bradford (n=879; 430 Europeans and 449 South Asians), MENA (n=320) and Botnia (n=56) cohorts. In EPIPREG, we identified six CpG sites inversely associated with insulin resistance across ancestry, whereof five were replicated in independent cohorts (cg02988288, cg19693031, and cg26974062 in TXNIP, cg06690548 in SLC7A11, cg04861640 in ZSCAN26). From methylation quantitative trait loci analysis in EPIPREG, we identified gene variants related to all five replicated cross-ancestry CpG sites, which were associated with several cardiometabolic phenotypes. Mediation analyses suggested that the gene variants regulate insulin resistance through DNA methylation. To conclude, our cross-ancestry EWAS identified five CpG sites related with lower insulin resistance.
EPIPREG is supported by the South-Eastern Norway Regional Health Authority (grant number: 2019092), and the Norwegian Diabetes Association (grant number: N/A). BiB receives core infrastructure funding from the Wellcome Trust (WT101597MA), a joint grant from the UK Medical Research Council (MRC) and Economic and Social Science Research Council (ESRC) (MR/N024397/1), the British Heart Foundation (CS/16/4/32482) and the National Institute for Health Research (NIHR) under its Applied Research Collaboration (ARC) for Yorkshire and Humber and the Clinical Research Network (CRN) . DNA methylation data was funded by the UK Medical Research Council via the Integrative Epidemiology Unit (MC_UU_12013/5). HRE works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council and the University of Bristol (MC_UU_00011/5). RPB received funding form EFSD/Novo Nordisk Programme for Diabetes Research in Europe, the Swedish Research Council (2021-02623), and the Crafoord Foundation. The funders played no role in the study design and conduct, or in these analyses or the decision to submit the manuscript for publication. “The Botnia Study has been financially supported by grants from the Sigrid Juselius Foundation, Folkhalsan Research Foundation, Nordic Center of Excellence in Disease Genetics, EU (EXGENESIS), Finnish Diabetes Research Foundation, Foundation for Life and Health in Finland, Finnish Medical Society, Helsinki University Central Hospital Research Foundation, Perklén Foundation, Ollqvist Foundation, and Narpes Health Care Foundation. The study has also been supported by the Municipal Heath Care Center and Hospital in Jakobstad and Health Care Centers in Vasa, Narpes and Korsholm.”