HMGCR genetic variation and risk of new-onset type 2 diabetes in statin users

Statins are widely prescribed lipid-lowering agents, but their use is associated with an increased risk of new-onset type 2 diabetes mellitus (NO-T2DM) ranging from 9% to 13%. While genetic variants in 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the pharmacological target of statins, and the solute carrier organic anion transporter family, member 1B1 (SLCO1B1), a key hepatic transporter, have been implicated in statin response and toxicity, their role in statin-associated diabetogenesis remains unclear. To investigate the association of four common HMGCR variants (rs17671591, rs12916, rs17238484, and rs2303152) and the SLCO1B1 (rs4149056) with the risk of NO-T2DM among statin-treated cohort. In a matched case-control study, 194 adults receiving atorvastatin or rosuvastatin were enrolled. The cases were patients who developed NO-T2DM within four years of initiating statin therapy (n = 97), while controls remained diabetes-free after four years of use (n = 97). Participants were matched for age, sex, ethnicity, BMI, and statin intensity. Genotyping was performed using TaqMan assays, and associations were evaluated using genetic models, linkage disequilibrium (LD), and haplotype analyses. The HMGCR rs17238484 variant showed a nominal association with NO-T2DM in statin users. Carriers of the T allele (GT + TT) showed a lower risk compared with the GG genotype (OR = 0.56, 95% CI: 0.36–0.99, P = 0.044); however, this association did not remain significant after correction for multiple testing. Haplotype analysis identified that the T–T–T haplotype of rs17671591–rs17238484–rs12916 was significantly associated with reduced risk of NO-T2DM (OR = 0.12, 95% CI: 0.02–0.58, P = 0.009). Other HMGCR SNPs and SLCO1B1 rs4149056 showed no significant associations. These findings suggest that HMGCR haplotypes may be associated with NO-T2DM risk among statin users, further studies in larger and more diverse populations are needed to validate these results.