Letter to the Editor in response to the article “Associations between peripheral blood mitochondrial genomic variants and gestational diabetes mellitus and postpartum abnormal glucose metabolism”

To the Editor, We have read with great interest the article titled “Associations between peripheral blood mitochondrial genomic variants and gestational diabetes mellitus and postpartum abnormal glucose metabolism,”1 which explores the associations between peripheral blood mitochondrial genomic variants and both gestational diabetes mellitus (GDM) and postpartum abnormal glucose metabolism (AGM). The authors conducted a well-designed case–control study, yielding valuable insights into the potential genetic susceptibility factors underlying GDM and postpartum AGM. Their findings are particularly noteworthy: specific single-nucleotide polymorphisms (SNPs) in the mitochondrial DNA (mtDNA) D-loop region (e.g., 249 days as a risk factor, 309 + C and 16,193 + C as protective factors for GDM), distinct haplogroup associations (e.g., R9 linked to increased GDM risk and M* to reduced risk), and the differential dynamics of mtDNA copy number between whole blood and plasma. These observations meaningfully advance our understanding of mitochondrial involvement in glucose metabolism disorders during and after pregnancy. However, we wish to highlight a key limitation that may impact the generalizability of the findings and the validity of causal inferences. The study population was restricted to a single geographic region with Han Chinese participants exclusively. Mitochondrial DNA haplogroups are known to exhibit marked racial variability and geographic specificity—for example, haplogroups R9 and M7b, identified as significant in this analysis, are highly prevalent in East Asian populations1. This regional homogeneity raises concerns about population stratification bias, which may lead to overestimated effect sizes for these specific haplogroups. Importantly, the findings may not be directly translatable to populations with divergent mtDNA haplogroup distributions (e.g., individuals of European or African ancestry), thereby constraining the external validity of the results. Furthermore, while the cross-sectional case–control design employed for the primary GDM analysis is valuable for identifying associations2, it inherently limits the ability to establish causality between the reported mtDNA variants and GDM development. The observed associations could be confounded by unmeasured factors or may represent epiphenomena. The authors appropriately acknowledge this limitation and call for longitudinal cohort studies and functional experiments to address it. To strengthen causal inference, future research should prioritize multi-ethnic cohorts to validate these associations across diverse genetic backgrounds. Additionally, longitudinal designs that assess mtDNA variants prior to pregnancy and track subsequent GDM incidence would provide more robust evidence for a temporal relationship—and thus potential causality. In conclusion, while Qing Luo et al.'s study provides important preliminary evidence, the geographic restriction of the cohort and the cross-sectional nature of the design warrant cautious interpretation. We believe that addressing these limitations in future work will be critical to confirming the role of mitochondrial genomic variants in the pathogenesis of GDM and postpartum AGM, as well as evaluating their potential as biomarkers across diverse populations. Sincerely, This research did not receive any specific grant from funding agencies in the public, commercial, or not-for profit sectors. The authors declare no conflict of interest. Approval of the research protocol: N/A. Informed consent: N/A. Registry and the registration no. of the study/trial: N/A. Animal studies: N/A. The data that support the findings of this study are available from the corresponding author upon reasonable request.