Effect of ScrF I polymorphism in the 2nd intron of the HMGCR gene on lipid-lowering response to simvastatin in Chinese diabetic patients.
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 polymorphism 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 (20mg day-1 p.o.) for 12 weeks. Serum lipid levels were determined before and after simvastatin 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 20mg 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.


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 20mg 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+/-4.96, P<0.05). These results suggest that the HMGCR gene may serve as a modifier gene for hypercholesterolemia in Chinese diabetic patients.
Ying
Su
S
Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
Sun
Yan-Ming
YM
Liu
Xiao-Min
XM
An
Chi-Ying
CY
Gao
Yin-Yuan
YY
D000214:Acyl Coenzyme A / Q000235:genetics*; D000368:Aged; D002681:China / Q000453:epidemiology; D004252:DNA Mutational Analysis; D015252:Deoxyribonucleases, Type II Site-Specific / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D008055:Lipids / Q000097:blood*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D019821:Simvastatin / Q000008:administration & dosage*
D000214:Acyl Coenzyme A; D008055:Lipids; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; D019821:Simvastatin; C045297:CCNGG-specific type II deoxyribonucleases; D015252:Deoxyribonucleases, Type II Site-Specific