Blood lipid levels are highly heritable and modifiable risk factors for coronary artery disease (CAD), and are the leading cause of death worldwide. These facts have motivated human genetic association studies that have the substantial potential to define the risk factors that are causal and to identify pathways and therapeutic targets for lipids and CAD.
The success of the HapMap project that provided an extensive catalog of human genetic variations and the development of microarray based genotyping chips (typically containing variations with allele frequencies ＞5%) facilitated common variant association study (CVAS; formerly termed genome-wide association study, GWAS) identifying disease-associated variants in a genome-wide manner. To date, 157 loci associated with blood lipids and 46 loci with CAD have been successfully identified, accounting for approximately 12%–14% of heritability for lipids and 10% of heritability for CAD. However, there is yet a major challenge termed “missing heritability problem,” namely the observation that loci detected by CVAS explain only a small fraction of the inferred genetic variations. To explain such missing portions, focuses in genetic association studies have shifted from common to rare variants. However, it is challenging to apply rare variant association study (RVAS) in an unbiased manner because such variants typically lack the sufficient number to be identified statistically.
In this review, we provide a current understanding of the genetic architecture mostly derived from CVAS, and several updates on the progress and limitations of RVAS for lipids and CAD.

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Although many clinical studies have shown that a low testosterone level is associated with cardiovascular diseases, the role of androgens in cardiovascular physiology and pathophysiology remains controversial. Androgens exert various actions in their target organs, and the androgen receptor (AR) is widely distributed in several tissues, including endothelial cells, smooth muscle cells, and fibroblasts, in the vascular system. Biological activities of androgens are predominantly mediated through the AR by the transcriptional control of target genes and interaction with multiple signaling pathways. To clarify the molecular mechanisms of androgens in cardiovascular disease, we examined a pathological model using AR knockout mice and showed that the androgen–AR system has protective effects on cardiovascular remodeling against cardiovascular stress. In this review, we focus on the role of the androgen–AR system in angiogenesis after ischemic stress.

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Both hyperthyroidism and hypothyroidism affect the cardiovascular system. Hypothyroidism is known to be associated with enhanced atherosclerosis and ischemic heart diseases. The accelerated atherosclerosis in the hypothyroid state has been traditionally ascribed to atherogenic lipid profile, diastolic hypertension, and impaired endothelial function. However, recent studies indicate that thyroid hormone has direct anti-atherosclerotic effects, such as production of nitric oxide and suppression of smooth muscle cell proliferation. These data suggest that thyroid hormone inhibits atherogenesis through direct effects on the vasculature as well as modification of risk factors for atherosclerosis. This review summarizes the basic and clinical studies on the role of thyroid hormone in vascular remodeling. The possible application of thyroid hormone mimetics to the therapy of hypercholesterolemia and atherosclerosis is also discussed.

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Adverse blood pressure (BP) is a major independent risk factor for epidemic cardiovascular diseases affecting almost one-quarter of the adult population worldwide. Dietary intake is a major determinant in the development and progression of high BP. Lifestyle modifications, including recommended dietary guidelines, are advocated by the American Society of Hypertension, the International Society of Hypertension, the Japanese Society of Hypertension, and many other organisations for treating all hypertensive people, prior to initiating drug therapy and as an adjunct to medication in persons already on drug therapy. Lifestyle modification can also reduce high BP and prevent development of hypertension. This review synthesizes results from the International Study of Macro/Micronutrients and Blood Pressure (INTERMAP), a cross-sectional epidemiological study of 4,680 men and women aged 40-59 years from Japan, the People's Republic of China, the United Kingdom, and the United States, published over the past few years on cross cultural BP differences. INTERMAP has previously reported that intakes of vegetable protein, glutamic acid, total and insoluble fibre, total polyunsaturated fatty acid and linoleic acid, total n-3 fatty acid and linolenic acid, phosphorus, calcium, magnesium, and non-heme iron were inversely related to BP. Direct associations of sugars (fructose, glucose, and sucrose) and sugar-sweetened beverages (especially combined with high sodium intake), cholesterol, glycine, alanine, and oleic acid from animal sources with BP were also reported by the INTERMAP Study.

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Aim: To investigate the relationships among carotid wall shear stress (WSS), carotid intima-media thickness (IMT), and total plaque area (TPA) using ultrasound (US) in the common carotid artery (CCA) in patients with suspected coronary artery disease (CAD).
Methods: Carotid artery US was performed in 950 patients with suspected CAD, and mean IMT, TPA, and hemodynamic parameters of CCA, including peak and mean WSS, were measured. We analyzed the carotid parameters according to the presence of CAD and the predictive values of WSS and TPA for the presence of significant CAD.
Results: Compared with patients without CAD (n=667), patients with CAD (n=283) demonstrated significantly higher mean IMT (0.66 vs. 0.74 mm, p＜0.001), TPA (0.13 vs. 0.20 cm², p=0.002), and beta stiffness index (5.12 vs. 5.60, p=0.045) and lower mean WSS (2.59 vs. 2.23 dyne/cm², p＜0.001). Mean WSS revealed significant negative correlations with the beta stiffness index (r=－0.116, p＜0.001), mean IMT (r=－0.193, p=0.007), and TPA (r=－0.296, p＜0.001). Mean WSS, mean IMT and TPA revealed significant difference with respect to CAD severity (for all p＜0.001). Age [OR, 1.038 (95% CI, 1.010–1.066), p=0.007], diabetes mellitus [1.606 (1.194–1.807), p= 0.011], smoking [1.758 (1.564–1.866), p＜0.001], carotid TPA [2.615 (1.320–5.183), p=0.006], and mean WSS [0.554 (0.371–0.838), p=0.005] were significant CAD predictors.
Conclusions: In patients with chest pain, low local shear stress and high plaque burden in the carotid arteries were significant CAD predictors. These findings indicate that carotid WSS has a role as an index of atherosclerosis and serves as a predictor of significant coronary atherosclerosis.

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Aim: Visceral fat accumulation contributes to the development of metabolic syndrome. As visceral fat accumulation increases, adiponectin levels decrease; therefore, adiponectin provides a link between visceral fat accumulation and metabolic disorders. Genome-wide association studies (GWASs) have identified genetic variations in the cadherin 13 (CDH13) gene that are associated with adiponectin levels.
Methods: We investigated whether single nucleotide polymorphisms (SNPs) in CDH13 was associated with adiponectin levels and metabolic syndrome traits independent of the visceral fat area (VFA), as measured using computed tomography (CT) in 945 Japanese individuals.
Results: We found that three CDH13 SNPs reported by recent GWASs (i.e., rs3865188, rs4783244, and rs12051272) were significantly associated with higher adiponectin levels (P＜1×10 ^－14 ), even after adjustment for VFA. However, these adiponectin-inducing alleles of CDH13 SNPs were significantly associated with traits consistent with deteriorating metabolic symptoms, such as higher fasting insulin, homeostasis model assessment–insulin resistance (HOMA-IR) scores, and triglycerides and lower high-density lipoprotein (HDL)-cholesterol levels, similar to increasing VFA and decreasing adiponectin levels.
Conclusion: These results suggested that CDH13 SNPs cause an adiponectin-resistant status to compensate for increasing adiponectin levels and could result in the deterioration of metabolic syndrome traits.

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Aim: To determine the best anthropometric index among body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-stature ratio (WSR) and to derive optimal thresholds for predicting CVD risk factors in Chinese children.
Methods: A total of 2563 children aged 8–12 years were recruited in Guangzhou, China. Anthropometric indices were measured in all participants. Systolic and diastolic blood pressure (SBP and DBP, respectively), glucose, triglyceride (TG), total cholesterol, high-density lipoprotein cholesterol (HDLC) and low-density lipoprotein cholesterol (LDL-C) were measured in a subsample of 1609 children.
Results: In partial correlation analyses, the highest coefficients were found for WC in four risk factors in both genders. The receiver operating characteristic (ROC) analyses showed that WC was comparably consistent among the best in predicting BP and risk factor clustering, WC and WSR were the best in predicting HDL-C and TG in boys; WC, slightly better than BMI, was the best in distinguishing high BP and risk factor clustering in girls. In contrast, WHR was consistently the poorest index in both genders. Optimal age- and gender-specific thresholds to identify individual and clustering risk factors were provided; the thresholds for WC were 57.4–80.4 cm and 55.8–69.6 cm in boys and girls, respectively.
Conclusions: WC was the comparatively consistent and best predictor of CVD risk factors compared with WSR and BMI, although the differences were small and depended on the type of risk factor and gender, and WHR was consistently the poorest predictor in Chinese children.

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Aim: Cytochrome P450s (CYP450) enzymes regulate inflammation and atherosclerosis and can affect carotid plaque stability in patients with ischemic stroke (IS). This study aimed to investigate the association of CYP450 genetic variants with CYP plasma metabolite levels and plaque stability in patients with IS.
Methods: Eleven single nucleotide polymorphisms (SNPs) of CYP genes and their plasma metabolite [20-hydroxyeicosatetraenoic acid (HETE), total epoxyeicosatrienoic acids (EETs), and dihydroxyeicosatrienoic acids (DiHETEs)] levels were measured in 396 patients with IS who underwent high-resolution B-mode ultrasound carotid plaque detection and were stratified into the following groups: non-carotid plaque and carotid plaque groups. The carotid plaque was further classified into subgroups of echolucent plaque (ELP) and echogenic plaque (EGP).
Results: Among the 396 patients with IS, 294 cases (74%) had plaques. The frequency of rs17110453CC, rs751141 GG, and rs9333025 GG genotypes was significantly higher in patients with plaque than those without plaque. The CC, GG, GG, and GG genotypes of rs17110453, rs776746, rs751141, and rs9333025 polymorphisms were independently associated with ELP (OR, 2.62 [1.34–5.26]; OR, 1.89 [1.16–3.58]; OR, 3.12 [1.27–7.13]; and OR, 2.06 [1.34–6.33], respectively). These polymorphisms were also associated with CYP plasma metabolite levels. Patients with ELP have also shown significantly higher levels of 20-HETE and DiHETEs, but lower levels of EETs.
Conclusions: Our data demonstrates that CYP450 SNPs are associated with plasma CYP450 metabolite levels and echolucent plaques, indicating that these SNPs may be potential markers for plaque instability.

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Aim: In animals, dietary energy restriction is reported to increase longevity, whereas in humans, all cohort studies from Western countries have not shown an association between the low energy intake and longevity. We examined the association between total energy intake and longevity in Japan where dietary pattern is different from that in the West.
Methods: A total of 7,704 Japanese aged 30–69 years were followed from 1980 to 2009. Participants were divided into the quintiles of total energy (kcal/day) based on data collected from the National Nutrition Survey. Hazard ratios and 95% confidence intervals (CIs) were derived through the use of Cox proportional hazards models to compare the risk of death across and between the quintiles.
Results: There was a significant association between increased energy intake and all-cause mortality risk in only men (P for linear trend=0.008). In cause-specific analysis, compared with the lowest quintile, there was rise in coronary heart disease (CHD) mortality among men (HR; 2.63, 95%CI; 0.95–7.28, P for linear trend 0.016) and women (HR; 2.91, 95%CI; 1.02–8.29, P for linear trend 0.032) and cancer mortality among men (HR; 1.50, 95%CI; 0.999–2.24, P for linear trend 0.038) in the top quintile.
Conclusion: We observed significant associations of high energy intake with all-cause and cancer mortality among men and with CHD mortality among men and women. Further studies are needed to confirm the benefits of caloric restriction.

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Aim: Flow-mediated vasodilation (FMD) of the brachial artery measures the ability of the artery to dilate after a forearm ischemia lasting for 5 min. During ischemia, and therefore in conditions of low flow, constriction of the brachial artery (L-FMC) has sometimes been reported. The meaning of L-FMC is still unclear. The aims of our study were to establish the prevalence of subjects with L-FMC, to determine whether the magnitude of L-FMC correlates with magnitude of FMD, and to determine whether L-FMC can be used to predict FMD timing.
Methods: A total of 179 outpatients were studied, and the brachial artery diameter was measured every minute during the 5 min forearm ischemia. Subjects who had at least one measurement showing a constriction of ＞1% during ischemia were defined as constrictors. FMD was evaluated at 50 s, 2 min, and 3 min after cuff release. On the basis of time, the subjects in whom maximal dilation had occurred were divided into Early, Late, or No dilators.
Results: The brachial artery diameter of 70 subjects (39%) constricted during ischemia. Higher the constriction during ischemia, lower was the dilation after ischemia. Constrictors were more likely to have Late (OR 2.6; ICs 95% 1.19-5.81, p=0.02) or No dilation (OR 4.8; ICs 95% 1.90-12-16, p=0.02) compared with no constrictors.
Conclusions: The present study reveals that almost 40% of the subjects had brachial artery L-FMC and a more pronounced constriction during ischemia correlated with a lower dilation after ischemia. Finally, the prevalence of subjects showing L-FMC was significantly higher among subjects with delayed or no vasodilation, suggesting that L-FMC may be a marker of endothelial dysfunction.

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