ASSOCIATION BETWEEN MIR499 GENE POLYMORPHISMS AND DIABETIC NEUROPATHY IN TYPE 2 DIABETES

Background: MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression. Genetic variants (such as Single-Nucleotide Polymorphisms, SNPs) in miRNA genes may be involved in the deregulation of target gene expression. The miR499 is a novel miRNA, mainly expressed in the muscle, heart, and brain, and implicated in cardiovascular dis¬ease, cancer, rheumatoid arthritis, and metabolic syndrome. Aim: To investigate whether the miR499 A/G rs3746444 SNP is associated with susceptibility to diabetic polyneuropathy (DPN) and/or cardiovascular autonomic neuropathy (CAN) in type 2 diabetes. Methods: In 150 type 2 patients (age 63.8±8.1 years, duration 12.7±9.5 years, BMI 30.8±5.2 Kg/m2, 89 males) the rs3746444 was investigated by TaqMan genotyping assay. Cardiovascular tests, MNSI-Q and MDNS for neuropathic symptoms and signs, VPT, and Thermal Thresholds (TT) were used for CAN and DPN assessment. Results: AA, AG, and GG genotypes were present in 56%, 38%, and 6% of patients, respectively. After ANOVA analysis and adjustment for sex, age, BMI, duration, and HbA1c, GG genotype was associated with higher insulin dose (P=0.030), CAN score (P<0.0001), MDNS (P=0.010), and VPT (P=0.004) in comparison with AA and AG genotypes. Moreover, GG genotype was associated with the presence of early CAN (Chi2=9.75, P=0.006, OR 7.57, 95% C.I. 1.8-32.2), confirmed CAN (Chi2=13.1, P=0.006, OR 9.92, 95% C.I. 1.8-32.2), and abnormal TTs (Chi2=7.65, P=0.01, OR 11.4, 95% C.I. 1.3-98.1). In a logistic regression analysis, including sex, age, BMI, duration, HbA1c, insulin dose, physical activity, LDL cholesterol, systolic BP, eGFR, retinopathy, and GG genotype as independent variables, CAN was predicted by duration (OR 1.1, CI 95% 1.01-1.19, P=0.031) and GG genotype (OR 35.8, CI 95% 2.7-467, P=0.006) (r2=0.36). In a multiple regression analysis with the same variables, GG genotype was the major determinant of CAN score (P=0.001, adjusted r2=0.27). The association with DPN was lost in multivariate analyses. Conclusions: This novel association of miR499 rs3746444 SNP with CAN susceptibility, albeit requiring replication in larger cohorts, might suggest a role of miR499 in cardiovascular autonomic dysfunction in diabetes.