Telomere-Independent Associations of hTERT Promoter Polymorphisms with Metabolic Phenotypes and Diabetic Complications

This study investigated association of three hTERT promoter polymorphisms (rs2735940, rs7712562, rs2853669) with leukocyte relative telomere length (RTL) and clinical characteristics, in patients with type 1 (T1DM) and type 2 (T2DM) diabetes. Covariate-adjusted ANCOVA revealed no significant direct association between hTERT variants and leukocyte RTL in either cohort. However, nominally significant, RTL-independent clinical associations emerged in T2DM patients. Multivariate logistic regression associated the rs2853669 CC genotype with lower odds of diabetic neuropathy (OR = 0.324, 95% CI: 0.106–0.989, raw p = 0.048). Furthermore, the rs2735940 TT genotype was associated with a favorable lipid profile (lower TC, LDL, and non-HDL; raw p < 0.05), while rs7712562 CC carriers exhibited higher waist circumference (raw p = 0.016). While hTERT variants were not directly associated with RTL under severe metabolic stress, they exhibited clinically relevant phenotypic associations. Although these exploratory secondary findings did not survive False Discovery Rate (FDR) correction, the nominal association of rs2853669 CC with lower neuropathy odds suggests potential non-telomeric pathways associated with mitochondrial protection. These hypothesis-generating observations warrant independent validation in larger, prospective cohorts.