Yamada 29_7

Genetic variants of the microsomal triglyceride transfer protein (MTP) have been associated with the serum concentration of low density lipoprotein-cholesterol, predisposition to coronary heart disease, or longevity. The relation of a -493G›T polymorphism in the promoter of MTP to blood pressure was examined in a population-based study. The subjects (1124 men, 1108 women) were aged 40-79 years and were randomly recruited to a population-based prospective cohort study of aging and age-related diseases in Japan. Blood pressure was measured at least twice with subjects in the sitting position. The serum lipid profile was determined after the subjects had fasted overnight. The 493G›T genotype of MTP was determined with a fluorescence-based allele-specific DNA primer assay system. There was no difference in the serum concentrations of total cholesterol, high density lipoprotein-cholesterol, low density lipoprotein-cholesterol, or triglycerides among MTP genotypes for men or for women. Systolic or diastolic blood pressure was not related to the -493G›T polymorphism in men. For women, however, systolic and diastolic blood pressures were significantly related to MTP genotype, with the T allele of the polymorphism being associated with low blood pressure. The relation between MTP genotype and the prevalence of hypertension was almost significant (P=0.055) for all women. Although MTP genotype was not associated with the prevalence of hypertension in premenopausal women, the relation between these parameters was significant (P=0.040) in postmenopausal women, with the TT genotype protecting against this condition. These results suggest that MTP genotype is a determinant of blood pressure in Japanese women. Introduction Hypertension is a complex multifactorial and polygenic disorder that is thought to result from an interaction between an individual's genetic background and various environmental factors (1). Given that hypertension is a major risk factor for coronary heart disease, stroke, and chronic renal failure, personalized prevention of hypertension is an important public health goal. One approach to personalized prevention of and selection of the most appropriate treatment for hypertension is to identify disease susceptibility genes. Although genetic linkage analyses (2-6) and candidate gene association studies (2,7-10) have implicated various loci and genes in predisposition to hypertension, the genes that confer genetic susceptibility to this condition remain to be identified definitively. In addition, because of ethnic divergence of gene polymorphisms, it is important to examine polymorphisms related to hypertension in each ethnic group. Microsomal triglyceride transfer protein is a heterodimeric lipid transfer protein that is essential for the assembly of apolipoprotein B-containing lipoproteins and their secretion from the liver and intestine (11). Mutations in the coding region of the gene for this protein (MTP) prevent the production of apolipoprotein B-containing lipoproteins, resulting in the rare genetic disorder abetalipoproteinemia (12). MTP is polymorphic, with several genetic variants existing in linkage disequilibrium (13). A common polymorphism (-493G›T) has been identified in the promoter region of MTP (located 493 base pairs upstream from the transcription start site), with the less prevalent T variant having been associated with a reduced plasma concentration of low density lipoproteincholesterol (14). The relation between MTP genotype and low density lipoprotein phenotype was confirmed in a large cohort of similar ethnic background (13), but conflicting results have been obtained with other cohorts (15,16). One possible explanation for this discrepancy might be that the phenotype associated with the -493G›T polymorphism of MTP is modulated by visceral obesity and hyperinsulinemia (17). The -493G›T polymorphism was recently shown to be associated with the prevalence of coronary heart disease (18). Furthermore, a haplotype marker of MTP was associated with longevity, suggesting that MTP might modify human life-span (19). Functional analysis of the -493G›T polymorphism with the use of promoter constructs revealed that INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 17: 83-88, 2006 83 Association of a microsomal triglyceride transfer protein gene polymorphism with blood pressure in Japanese women YOSHIJI YAMADA1, FUJIKO ANDO2 and HIROSHI SHIMOKATA2 1Department of Human Functional Genomics, Life Science Research Center, Mie University, Tsu, Mie; 2Department of Epidemiology, National Institute for Longevity Sciences, Obu, Aichi, Japan Received July 29, 2005; Accepted September 2, 2005 _________________________________________ Correspondence to: Dr Yoshiji Yamada, Department of Human Functional Genomics, Life Science Research Center, Mie University, 1577 Kurima-machiya, Tsu, Mie 514-8507, Japan E-mail: [email protected]