Association of the TNF-{alpha}-C-857T polymorphism with resistance to the cholesterol-lowering effect of HMG-CoA reductase inhibitors in type 2 diabetic subjects.
OBJECTIVE An association of the C-857T polymorphism of the tumor necrosis factor-alpha (TNF-alpha) gene promoter region with LDL cholesterol levels has been reported. This study was designed to evaluate the relationship between the TNF-alpha-C-857T polymorphism and LDL cholesterol levels according to statin treatment in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS DNA was obtained from 322 Japanese subjects (160 male and 162 female) with type 2 diabetes, and TNF-alpha-C-857T polymorphisms were determined by direct sequencing. Serum LDL cholesterol was measured by a direct method. RESULTS Although serum LDL cholesterol levels were significantly higher in the T carriers (C/T + T/T) than in the non-T carriers (C/C) (3.14 +/- 0.86 vs. 2.89 +/- 0.75 mmol/l, P < 0.05), there was no difference in LDL cholesterol levels between the non-T carriers and the T carriers in statin-untreated subjects (2.87 +/- 0.73 vs. 2.89 +/- 0.76 mmol/l, NS), whereas in statin-treated subjects, LDL cholesterol levels were significantly higher in the T carriers than in the non-T carriers (3.43 +/- 0.89 vs. 2.90 +/- 0.78 mmol/l, P = 0.0007). There were no differences in HDL cholesterol and triglyceride levels between the non-T carriers and the T carriers in both statin-treated and -untreated subjects. The percent decrease in LDL cholesterol levels after administration of statins was significantly smaller in the T carriers compared with the non-T carriers (27.6 vs. 36.4%, P = 0.031). CONCLUSIONS The mutant allele of the C-857T promoter polymorphism of the TNF-alpha gene may predispose to resistance to the LDL cholesterol-lowering effect of statins and could be one of the markers used to predict the efficacy of statins.
Takahashi
Toru
T
Division of Diabetes and Metabolism, Department of Internal Medicine, Iwate Medical University School of Medicine, Iwate, Japan.
Takahashi
Kazuma
K
Yamashina
Mitsuhiro
M
Maesawa
Chihaya
C
Kajiwara
Takashi
T
Taneichi
Haruhito
H
Takebe
Noriko
N
Kaneko
Yoshihito
Y
Masuda
Tomoyuki
T
Satoh
Jo
J
D000368:Aged; D000483:Alleles; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological / Q000032:analysis / Q000378:metabolism; D008078:Cholesterol, LDL / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D006580:Genetic Carrier Screening; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D000924:Anticholesteremic Agents; D054316:Biomarkers, Pharmacological; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D014409:Tumor Necrosis Factor-alpha