Background <p>Type 2 diabetes mellitus (T2DM) is closely associated with both environmental and genetic factors, involving multi-gene inheritance. This study examined the association between the polymorphic locus rs10757278 in long non-coding RNA ANRIL and T2DM.</p> Methods <p>Polymerase chain reaction (PCR) was used to detect the rs10757278 polymorphism in the ANRIL gene. RT-qPCR measured ANRIL expression levels, and logistic regression identified independent risk factors for T2DM. Furthermore, the receiver operating characteristic (ROC) curve was constructed to evaluate the clinical diagnostic value of serum ANRIL levels in diagnosing T2DM.</p> Results <p>The rs10757278 polymorphism of the ANRIL was associated with the development of T2DM. Specifically, the G allele increases the risk of T2DM, and individuals carrying the GG genotype have a higher risk of developing the disease. Significant differences were found in low-density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG), and glycated hemoglobin (HbA1c) among T2DM patients with different genotypes of ANRIL rs10757278. The relative FPG and HbA1c levels were relatively lower in individuals with the AA genotype and higher in those with the GG genotype. Moreover, serum ANRIL levels in the T2DM group were lower than in the control group. Body mass index (BMI), the rs10757278 locus, and serum ANRIL levels were independent risk factors for the development of T2DM. The ROC curve showed that serum ANRIL levels have significant clinical diagnostic value for the diagnosis of T2DM.</p> Conclusion <p>The rs10757278 polymorphism in ANRIL was strongly associated with the genetic predisposition to T2DM.</p>