Objective: To investigate whether ScrF I polymorphism in the 2nd intron of the HMG-COA reductase gene (HMGCR) influences serum lipid levels and whether this polyrnorphism affects the efficiency of the cholesterol lowering HMG-CoA reductase inhibitor, simvastatin. Methods: One hundred sixty-eight patients with type 2 diabetes mellitus (T2DM) prospectively received simvastatin as a single-agent therapy (20 mg day-1 p.o.) for 12 weeks. Serum lipid levels were determined before and after sinivastatin treatment. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: Subjects with the AA homozygotes had significantly higher serum very low-density lipoprotein cholesterol (VLDL-C) levels than those with the aa homozygotes. In addition, in 168 patients with T2DM who took 20 mg simvastatin, the VLDL-C lowering effect by sinivastatin in subjects with the aa homozygotes was significantly lower than in those with the Aa heterozygotes and AA homozygotes. Conclusions: Simvastatin treatment significantly decreased plasma lipids in all patients (P < 0.01). Importantly, we demonstrate that ScrF I polymorphism of the HMGCR gene in patients with T2DM groups is associated with significant elevation of serum VLDL-C levels. Subjects with the AA homozygotes had significantly higher serum high VLDL-C levels than those with the Aa heterozygotes and aa homozygotes (AA: 2.18 +/- 0.51; Aa: 2.04 +/- 0.59, aa: 1.86 +/- 0.43, P < 0.05 for comparison among three genotypes and P < 0.01 for difference between AA and aa). Furthermore, this polymorphism tends to show an enhanced response to an HMG-CoA reductase inhibitor in terms of the cholesterol-lowering effect. In 168 patients with T2DM who took 20 mg simvastatin, the VLDL-C lowering effect by simvastatin in subjects with the AA homozygotes was significantly lower than in those with the Aa heterozygotes and aa homozygotes (the reduction in serum VLDL-C levels; 37.03 +/- 5.67 versus 28.97 +/- 4.96, P < 0.01; 34.62 +/- 5.87 versus 28.97 +/- 14.96, P < 0.05). These results suggest that the HMGCR gene may serve as a modifier gene for hypercholesterolemia in Chinese diabetic patients. (C) 2007 Elsevier Inc. All rights reserved.