Search

BACKGROUND We have earlier identified a quantitative trait locus (QTL) on rat chromosome 5 that appears to be primarily under the control of the sympathetic nervous system. Because sympathetic overactivity is related to both hypertension and insulin resistance, FABP3 is a candidate gene for the link between this QTL and blood pressure regulation. In this study, therefore, we explored the role of FABP3 genetic variations in essential hypertension (EH) in humans. METHODS We evaluated two single-nucleotide polymorphisms (SNPs) (rs2279885 and rs2271072) in 758 patients with EH and 726 controls. Polymorphism-related genotypes were determined using TaqMan assays, while haplotypes were estimated from the genotype data. RESULTS The frequencies of occurrence of the G allele of rs2279885 and the C allele of rs2271072 were significantly higher in subjects with EH than in normotensive (NT) subjects (P = 0.0339, P = 0.0209, respectively). However, the genotype distributions did not exhibit any significant differences. CONCLUSION We found an association between FABP3 gene polymorphisms and EH in a Japanese population, thereby suggesting that FABP3 is a susceptibility locus for EH.

It has been shown that the systolic augmentation index (AI) in the central arteries, including the aorta and carotid arteries, changes with age. The AI can also be obtained from the peripheral arteries. The possible usefulness of AI obtained from the radial artery as an index for vascular aging was investigated.Radial arterial waveforms were obtained from 632 subjects with no cardiovascular disease, using radial tonometry. Radial AI was calculated as follows: (Second peak systolic blood pressure [SBP2] - diastolic blood pressure [DBP]) / (first peak SBP - DBP) x100 (%).Radial AI was significantly higher in women than in men (81.1% +/- 16.1% compared with 69.5% +/- 16.3%, P.001). Radial AI was positively related to age in healthy men and women (r = 0.619, P.001, and r = 0.644, P.001, respectively). When comparing subjects in their 20s to those in their 70s, radial AI increased 1.56 times (from 53.2% to 83.0%) in men and 1.49 times (from 64.6% to 96.4%) in women. Multiple regression analysis showed that age is a potent predictor of radial AI in addition to gender, DBP and pulse rate.These findings indicate that simple and easily-obtainable radial AI is age-dependent and could be a useful index of vascular aging.

A genetic epidemiologic approach is useful to elucidate the genes responsible for hypertension. Genetic analyses of the components of the renin-angiotensin system have succeeded in showing an association between their polymorphism and hypertension. Recently, two types of angiotensin II receptor were cloned and characterized. To examine the genetic contribution of angiotensin II type 1 receptor (AT 1 ) and type 2 receptor (AT 2 ) genes in human essential hypertension, a case-control study was performed in Japanese subjects. The study comprised 321 subjects with hypertension who satisfied the criteria for essential hypertension, together with 215 age and sex matched controls. The significance of the differences in genotype distribution between hypertensive and normotensive subjects was examined by χ 2 analysis. Neither AT 1 nor AT 2 gene variants were associated with human essential hypertension in the Japanese subjects. However, the AT 1 receptor gene polymorphism was associated with left ventricular mass index in normotensive subjects. The study results suggest that gene polymorphisms of both angiotensin II receptors are not directly involved in the increase of genetic risk for hypertension, but that the AT 1 receptor gene might contribute genetically to the increase of left ventricular mass.

[BACKGROUND] Central systolic blood pressure (cSBP) has been postulated to correlate closely with cardiovascular risk. Identifying factors associated with cSBP is therefore important. Prolonged QT interval is known to be associated with cardiovascular outcomes and might also be associated with the arterial waveform and cSBP. We investigated the possible associations between electrocardiogram wave interval and cSBP in general population samples. [METHODS] Brachial blood pressure and radial arterial waveform were measured simultaneously. Augmentation index (AIx) was calculated from the radial waveform as the ratio of the height of the late systolic peak to that of the first peak. cSBP was defined as the absolute pressure of the late systolic peak. [RESULTS] In the first panel (n = 8,085), QT interval was strongly association with AIx (r = 0.330; P < 0.001). This association remained significant even in the heart rate–adjusted analysis (r = 0.184; P < 0.001). Although subjects with a longer QT interval were older and had higher blood pressure, heart rate, and pulse wave velocity, multivariable analysis with adjustment for these covariables nevertheless identified longer corrected QT interval as an independent determinant of increased AIx and smaller pulse pressure amplification (PPa; brachial SBP minus cSBP) (β = −0.066; P < 0.001). This association was replicated in the independent second panel (n = 1,412) (β = −0.105; P < 0.001). In contrast, QRS interval was positively associated with PPa (β = 0.056; P < 0.001). [CONCLUSIONS] Longer QT interval and short QRS duration were significantly associated with arterial waveform and PPa. Our results provide a clue to the elucidation of unidentified mechanisms of the increased cardiovascular outcome and mortality risks in subjects with longer QT interval.

BACKGROUND: Recent studies have reported the association between advanced arterial stiffness and brain small vessel diseases (SVDs). Two possible hemodynamic mechanisms, increases in central blood pressure (BP) and pulsatile flow load to the brain, have been speculated to link arterial stiffness and SVD. The carotid flow augmentation index (AI) has been proposed as an index of pulsatile flow to the brain. We compared its association with brain SVD with that of central BP in a general population. METHODS: Subjects were 500 individuals free from symptomatic cardiovascular diseases with a mean age of 66.9 +/- 8.4 years. Brachial-ankle pulse wave velocity (baPWV) was measured as an index of arterial stiffness. Carotid flow AI was obtained by Doppler ultrasonography. The presence of silent cerebral lacunar infarcts (SCI) was determined as a manifestation of SVD by 3-tesla magnetic resonance imaging (MRI). Second peak radial systolic BP (SBP2) and pulse pressure (PP2) were used as estimates of central BP. RESULTS: baPWV was significantly associated with radial BP2 (r = 0.55, P < 0.0001) but not with carotid flow AI (r = 0.03, P = 0.51). Radial BPs and baPWV, but not flow AI, were significantly higher in subjects with SCI. Radial SBP2 had higher odds ratio for the presence of SCI than brachial SBP, PP, and radial PP2. Logistic regression analysis showed that radial SBP2, but not flow AI, was independently related to the presence of SCI. CONCLUSION: These findings indicate that the SBP2, an estimate of central SBP, is significantly associated with the presence of SVD in an apparently healthy general population.

Hyperhomocysteinemia is reported to be associated with an increase in the incidence of ischemic heart disease and cerebrovascular disease. Genetic aberrations in methylenetetrahydrofolate reductase (MTHFR) may account for reduced enzyme activity and elevated plasma homocysteine level. A recent report revealed that a common mutation (677C to T; Ala to Val) in the MTHFR gene is associated with decreased specific MTHFR activity and with increased risk for coronary artery disease in the homozygous state (Val/Val). In the present study, we investigated whether the MTHFR gene is a genetic risk factor for cerebrovascular disease (CVD). To undertake a case-control study, we selected the patients with cerebral infarction (n = 48) or cerebral hemorrhage (n = 35) and examined the association between MTHFR gene polymorphism and CVD. The genotype distribution of the MTHFR gene was not significantly different between cases and controls. Because the possibility of matching the morbidity of the effects of hypertension, the lack of association could not be excluded in the first study; however, we also examined whether the MTHFR mutation was associated with any clinical risk factor for CVD or with hypertension. It turned out that the subjects with the Val allele of the MTHFR gene had significantly lower blood pressure than the subjects with other genotypes in the general population (P = .02), and that the frequency of the Val/Val genotype in hypertensive subjects (n = 173) was significantly lower than in control subjects (n = 184) (P = .03). From these results, we conclude that the Val/Val homozygous state of the MTHFR gene increased the risk of thrombosis, but reduced the blood pressure, which resulted in the lack of increased risk for CVD.

The homozygous deletion allele of the angiotensin converting enzyme gene (ACE/DD), homozygous threonine allele of the angiotensinogen gene (AGN/TT), and the epsilon4 allele of the apolipoprotein E gene (apoE/epsilon4) are reported to be associated with ischemic heart disease. Cerebrovascular disease (CVD) is another atherosclerotic disease; and the effects of these polymorphisms on CVD have been confusing. In this study, we investigated whether ACE/DD, AGN/TT, and apoE/epsilon4 genotypes are associated with CVD and whether genetic risk is enhanced by the effect of one upon another. We ascertained these genotypes in patients with cerebral infarction (n = 55) and cerebral hemorrhage (n = 38), diagnosed by brain computed tomography. Control subjects for the infarction group and the hemorrhage group were randomly selected from 583 subjects matched for age, gender, and history of hypertension with patients. Frequency of ACE/DD genotype was higher in the patients with infarction than in the controls (chi2 = 6.1, P.05). The AGN/TT genotype was not associated with either infarction or hemorrhage, but it increased the relative risk for cerebral infarction in the subjects with ACE/DD genotype (chi2 = 8.0, P.01, odds ratio; 11.7, 95% confidence intervals: 1.4 to 96.0). There was no significant association between apoE/epsilon4 and CVD. These results suggest that ACE/DD predicts cerebral infarction, but not cerebral hemorrhage, and that AGN/TT enhances the risk for cerebral infarction associated with ACE/DD.

OR-5 Key Words: Genome-Wide Search, Case-Control Approaches, Millennium Projects