Gene-Environment Interaction through single-cell transcriptomics in Type 2 diabetes

Background: Type 2 diabetes mellitus (T2DM) arises from the interplay between inherited genetic factors and environmental influences such as lifestyle, metabolic challenges, and inflammation. Objective: To provide a systematic review and meta-analysis of human studies that use single-cell transcriptomic methods to examine gene–environment interactions in T2DM, focusing on the integration of genome-wide association studies (GWAS), polygenic risk scores (PRS), environmental exposures, and comprehensive multi-omics analysis frameworks. Methods: We conducted a systematic literature search of PubMed/MEDLINE, EMBASE, Web of Science, Scopus, and Google Scholar for eligible human studies published from January 2021 to December 2025. Studies were included if they applied single-cell transcriptomics to tissues relevant to T2DM and combined genetic risk assessment with environmental or clinical data. Study quality was evaluated using modified STROBE and QUADAS-2 tools. When suitable, random-effects meta-analyses were conducted, and heterogeneity was estimated using the I² statistic. Results: Seven studies of high methodological quality were included. Single-cell transcriptomic analyses consistently revealed significant cellular diversity in pancreatic, immune, and peripheral tissues, with disease-related gene expression changes restricted to specific cell populations. The integration of PRS showed that genetic risk was distributed unevenly across various cell types, identifying subsets of cells with heightened genetic susceptibility. Environmental exposures were found to influence the relationship between genetic variations and gene expression, indicating genuine gene–environment interactions at the single-cell level. The meta-analysis revealed a significant overall association between molecular dysregulation and T2DM-related traits, with moderate heterogeneity (I² ≈ 48%). Conclusion: The available evidence demonstrates that gene–environment interactions in T2DM are highly specific to individual cell types and are best elucidated through single-cell transcriptomic studies. Combining genetic risk, environmental exposures, and multi-omics analysis yields valuable mechanistic insights and informs the advancement of precision medicine for T2DM.