Genetic risk for metabolic syndrome: examination of candidate gene polymorphisms related to lipid metabolism in Japanese individuals

Yoshiji Yamada ^1*, Kimihiko Kato ², Tetsuro Yoshida ², Kiyoshi Yokoi ², Hitoshi Matsuo ³, Sachiro Watanabe ³, Norifumi Metoki ⁴, Hidemi Yoshida ⁵, Kei Satoh ⁵, Sahoko Ichihara ¹, Yukitoshi Aoyagi ⁶, Akitomo Yasunaga ⁶, Hyuntae Park ⁶, Masashi Tanaka ⁶, Wan Lee ⁷ and Yoshinori Nozawa ⁸

¹ Life Science Research Center, Mie University, Japan
² Department of Cardiovascular Medicine, Gifu Prefectural Tajimi Hospital, Japan
³ Department of Cardiology, Gifu Prefectural General Medical Center, Japan
⁴ Department of Internal Medicine, Hirosaki Stroke Center, Japan
⁵ Department of Vascular Biology, Institute of Brain Science, Hirosaki University School of Medicine, Japan
⁶ Department of Genomics for Longevity and Health, Tokyo Metropolitan Institute of Gerontology, Japan
⁷ Department of Biochemistry, College of Medicine, Dongguk University, Kyungju, Korea, Republic of
⁸ Gifu International Institute of Biotechnology, Japan

^* To whom correspondence should be addressed. E-mail: yamada{at}gene.mie-u.ac.jp.

Accepted 21 August 2007

Abstract

Background: The etiology of metabolic syndrome is complex, being determined by the interplay of both genetic and environmental factors. The aim of the present study was to identify gene polymorphisms that confer susceptibility to metabolic syndrome in order to allow prediction of genetic risk for this condition.

Methods: The study population comprised 2417 unrelated Japanese individuals, including 1522 subjects with metabolic syndrome and 895 controls. The genotypes for 44 polymorphisms of 31 candidate genes related to lipid metabolism were determined with a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology.

Results: The chi-square test and subsequent multivariable logistic regression analysis with adjustment for age, sex, and smoking status revealed that the -3AG and 553GT (Gly185Cys) polymorphisms of APOA5, the 2052TC (Val653Val) and 1866CT (Asn591Asn) polymorphisms of LDLR, the 13989AG (Ile118Val) polymorphism of CYP3A4, and the 1014TA polymorphism of C1QTNF5 were significantly (false discovery rate < 0.05) associated with the prevalence of metabolic syndrome, with the variant alleles of APOA5 and C1QTNF5 representing risk factors for and those of LDLR and CYP3A4 being protective against this condition. Serum concentrations of triglycerides and HDL-cholesterol differed significantly (P < 0.05) among APOA5 genotypes; the serum concentration of HDL-cholesterol differed among LDLR genotypes; and the fasting plasma glucose level and body mass index differed between CYP3A4 and C1QTNF5 genotypes, respectively.

Conclusions: APOA5, LDLR, CYP3A4, and C1QTNF5 are susceptibility loci for metabolic syndrome in Japanese individuals. Genotypes for these polymorphisms may prove informative for prediction of genetic risk for metabolic syndrome.

Keywords: APOA5, C1QTNF5, CYP3A4, LDLR, metabolic syndrome

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