Leptin receptor polymorphism is associated with serum lipid levels and impairment of cholesterol lowering effect by simvastatin in Japanese men.
OBJECTIVE
To investigate whether leptin receptor (Ob-R) Arg223Gln polymorphism influences serum lipid levels and whether this polymorphism affects the efficiency of the cholesterol lowering HMG-CoA reductase inhibitor, simvastatin [Clin. Cardiol. 16 (1993) 317].


METHODS
Case-control association study.


METHODS
We studied 201 Japanese men without medical care, and 78 Japanese who took simvastatin.


METHODS
Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Serum lipid and leptin levels were determined.


RESULTS
Subjects with the Arg/Arg homozygotes had significantly higher serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels than those with the Arg/Gln heterozygotes and Gln/Gln homozygotes (TC: Arg/Arg: 213+/-3, Arg/Gln: 196+/-6, Gln/Gln: 184+/-5, P=0.004 for comparison among three genotypes, P=0.008 for difference between Arg/Arg and Arg/Gln, and P=0.025 for difference between Arg/Arg and Gln/Gln, LDL-C: Arg/Arg: 127+/-3, Arg/Gln: 112+/-6, Gln/Gln: 114+/-8, P=0.027) for comparison among three genotypes and P=0.011 for difference between Arg/Arg and Arg/Gln. Subjects with the Arg/Arg homozygotes had significantly lower serum high density lipoprotein cholesterol (HDL-C) levels than those with the Arg/Gln heterozygotes and Gln/Gln homozygotes (Arg/Arg: 55+/-1, Arg/Gln: 62+/-3, Gln/Gln: 57+/-7, P=0.046) for comparison among three genotypes and P=0.013 for difference between Arg/Arg and Arg/Gln. In addition, in 78 patients with hypercholesterolemia who took 5 mg simvastatin, the TC lowering effect by simvastatin in subjects with the Arg/Arg homozygotes was significantly lower than in those with the Arg/Gln heterozygotes and Gln/Gln homozygotes (the reduction in serum TC levels; 62+/-4 vs. 79+/-6, P=0.044).


CONCLUSIONS
We demonstrate that Ob-R Arg223Gln polymorphism in Japanese men is associated with significant elevation of serum TC and LDL-C levels. Our data also show that the Arg/Arg homozygotes tend to show lowered level of serum HDL-C. Furthermore, this polymorphism tends to show an attenuated response to an HMG-CoA reductase inhibitor in terms of the cholesterol lowering effect. These results suggest that the Ob-R gene may serve as a novel modifier gene for hypercholesterolemia in Japanese men.
Takahashi-Yasuno
Akiko
A
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Masuzaki
Hiroaki
H
Miyawaki
Takashi
T
Ogawa
Yoshihiro
Y
Matsuoka
Naoki
N
Hayashi
Tatsuya
T
Hosoda
Kiminori
K
Inoue
Gen
G
Yoshimasa
Yasunao
Y
Nakao
Kazuwa
K
D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D005838:Genotype; D006720:Homozygote; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood* / Q000188:drug therapy; D007564:Japan; D008055:Lipids / Q000097:blood*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D011110:Polymorphism, Genetic / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics*; D054411:Receptors, Leptin; D019821:Simvastatin / Q000627:therapeutic use*
D000924:Anticholesteremic Agents; D001786:Blood Glucose; C515448:LEPR protein, human; D008055:Lipids; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D019821:Simvastatin