Association of lipoprotein‐associated phospholipase A2 mass with asymptomatic cerebral artery stenosis

Cerebral artery stenosis (CAS) is the most important causes of ischaemic stroke. Lipoprotein‐associated phospholipase A2 (Lp‐PLA2) plays 2 diverse roles in atherosclerosis (pro‐inflammatory and anti‐inflammatory), and the association between Lp‐PLA2 mass and cardiovascular or cerebrovascular events is inconsistent among previous studies. A cross‐sectional study including 2012 North Chinese adults aged ≥40 years was performed in 2010‐2011 to investigate whether Lp‐PLA2 mass is associated with asymptomatic cerebral artery stenosis (ACAS). Serum Lp‐PLA2 mass was determined by enzyme‐linked immunosorbent assay (ELISA). All participants underwent transcranial Doppler (TCD) and bilateral carotid duplex ultrasound to evaluate intracranial artery stenosis (ICAS) and extracranial arterial stenosis (ECAS). The median serum Lp‐PLA2 mass of the participants was 140.74 ng/mL (interquartile range: 131.79‐158.07 ng/mL). The adjusted odds ratio (OR) when comparing the 4th quartile to the 1st quartile of Lp‐PLA2 was 1.98 (95% confidence interval (CI): 1.42‐2.78), 1.79 (95% CI: 1.08‐2.94) and 1.87 (95% CI: 1.28‐2.73) for the occurrence of ACAS, asymptomatic ECAS and asymptomatic ICAS, respectively, after controlling for vascular risk factors. These independently significant associations remained statistically significant in the male or elderly subgroups, but not in females or middle‐aged participants. Lp‐PLA2 mass is positively correlated with subclinical atherosclerosis determined by ACAS, ICAS and ECAS in North Chinese, particularly in male and older participants, suggesting that serum Lp‐PLA2 mass might be potential biomarker for the detection of ACAS in the adults.     

Association of Lp-PLA2 Mass and Aysmptomatic Intracranial and Extracranial Arterial Stenosis in Hypertension Patients

Background and Purpose

Intracranial arterial stenosis (ICAS) is a common cause of ischemic stroke in Asians, whereas whites tend to have more extracranial lesions. Lipoprotein-associated phospholipase A₂ (Lp-PLA₂) has been associated with ischemic stroke by a large amount of work. However, there are few studies focusing on the relationship of Lp-PLA₂ and asymptomatic ICAS or extracranial arterial stenosis (ECAS). Wehereby sought to explore the relationship of Lp-PLA₂ and ICAS, ECAS and concurrent stenosis in stroke-free hypertensive patients in Chinese population.

Methods

All the subjects were evaluated for the presence and severity of ICAS and ECAS through computerized tomographic angiography (CTA) covered the whole brain down to the level of aortic arch. Lp-PLA₂ mass was measured by enzyme linked immunoassay. The association of Lp-PLA₂ and vascular stenosis was analyzed through multivariate logistic regression.

Results

Among 414 participants, 163 (39.4%) had no ICAS or ECAS, 63 (15.2%) had ECAS only, 111 (26.8%) had ICAS only and 77 (18.6%) had concurrent extraintracranial stenosis. Lp-PLA₂ mass was significantly associated with isolated ICAS (OR: 2.3; 95% CI: 1.14-4.64), and concurrent stenosis (OR: 3.93; 95% CI: 1.62-9.51), but was not related to isolated ECAS (OR: 1.54; 95% CI: 0.68-3.48). Lp-PLA₂ mass was also associated with moderate to severe ICAS no matter how was the ECAS. Moreover, patients with higher Lp-PLA₂ mass showed more sever ICAS and had more intracranial arterial lesions.

Conclusion

This study revealed the association of Lp-PLA₂ mass with ICAS in stroke-free hypertensive patients in Chinese population. The further long-term cohort study was warranted to elucidate the concrete effect of Lp-PLA₂ on the asymptomatic ICAS.     

Association between Serum Alkaline Phosphatase Level and Cerebral Small Vessel Disease

Background

Serum alkaline phosphatase (ALP) is a marker of vascular calcification. A high serum ALP level is associated with an increase in cardiovascular events, and predicts poor functional outcome in patients with stroke. We investigated whether serum ALP was associated with cerebral small vessel disease (cSVD) and large cerebral artery stenosis (LCAS).

Methods

We evaluated vascular risk factors, brain magnetic resonance images (MRIs), and MR angiograms from 1,011 neurologically healthy participants. The presence of silent lacunar infarction (SLI) and moderate-to-severe cerebral white matter hyperintensities (MS-cWMH) were evaluated as indices of cSVD on brain MRIs. Findings of extracranial arterial stenosis (ECAS) or intracranial arterial stenosis (ICAS) were considered to be indices of LCAS on MR angiograms.

Results

Subjects with SLI (odds ratio [OR]: 2.09; 95% confidence interval [CI]: 1.27–3.42; p = 0.004) and MS-cWMH (OR: 1.48; 95% CI; 1.03–2.13, p = 0.036) were significantly more likely to have ALP levels in the third tertile (ALP ≥ 195 IU/L) than the first tertile (ALP ≤ 155 IU/L), after adjusting for cardiovascular risk factors. The mean serum ALP level was significantly higher in patients with SLI or MS-cWMH compared to patients without those findings. After adjustment for confounding factors, the multivariate model found that the statistical significance of serum ALP remained when the presence of SLI (OR: 1.05 per 10 IU/L increase in ALP; 95% CI: 1.02–1.08; p = 0.003) or MS-cWMH (OR: 1.03 per 10 IU/L increase in ALP; 95% CI: 1.00–1.06; p = 0.025) were added to the model. There were no differences in the proportions of patients with LCAS, ICAS, and ECAS across the serum ALP tertiles.

Conclusions

Our study of neurologically healthy participants found a positive association between serum ALP level and indicators of cSVD, but no association between serum ALP level and the indicators of LCAS.     

Asymptomatic Intracranial Arterial Stenosis and Metabolic Syndrome: The APAC Study

Purpose

The metabolic syndrome (MetS) is a major risk factor for cardiovascular diseases. We investigated potential associations between MetS and asymptomatic intracranial arterial stenosis (ICAS) in a general population.

Methods

The community-based “Asymptomatic Polyvascular Abnormalities in Community Study” examined asymptomatic polyvascular abnormalities in a Chinese population aged 40+ years without history of stroke and coronary heart disease. MetS was defined by the International Diabetes Federation criteria. Asymptomatic ICAS was diagnosed by transcranial color-coded Doppler sonography.

Results

Out of 5393 study participants, asymptomatic ICAS was detected in 713 (13.2%) participants, and MetS in 1323 (24.5%) individuals. Prevalence of asymptomatic ICAS increased significantly from 7.5% to 24.2% with increasing number of MetS components. After adjusting for age, gender, physical activity, body mass index, low-density lipoprotein cholesterol and high-sensitivity C-reactive protein, MetS was significantly associated with asymptomatic ICAS (OR: 1.50; 95%CI: 1.23,1.83). Compared with the subgroup without MetS, the ORs for asymptomatic ICAS increased (P<0.0001) for each of 5 components of MetS from 1.71 (95%CI: 1.27,2.30), to 2.20 (95%CI: 1.63,2.98), 2.79 (95CI: 2.01,3.88), 3.08 (95%CI: 2.11,4.51) and 4.27 (95%CI: 2.22,8.20).

Conclusions

In multivariate analysis, MetS was an independent and additional factor associated with asymptomatic ICAS. Study participants with 5 MetS components had a 4 times higher risk of asymptomatic ICAS than participants with no MetS component.     

Association between high‐sensitivity C‐reactive protein,lipoprotein‐associated phospholipase A2 and carotid atherosclerosis: A cross‐sectional study

High‐sensitivity C‐reactive protein (hs‐CRP) and lipoprotein‐associated phospholipase A2 (Lp‐PLA2) have been reported to be independent predictors of atherosclerosis. However, whether the combination of these two markers can improve the prediction of atherosclerosis is unknown. This study aimed to evaluate the association between combining hs‐CRP and Lp‐PLA2 and predicting carotid atherosclerosis. A total of 1982 participants aged ≥40 years were included in this study. Hs‐CRP and Lp‐PLA2 were measured by a high‐sensitivity nephelometry assay and quantitative sandwich enzyme‐linked immunosorbent assay, respectively. Ultrasonography was performed on the bilateral carotid arteries to evaluate stenosis and plaques. Multivariable logistic regression models were used to analyse the association between the combination of the hs‐CRP and Lp‐PLA2 levels and carotid plaques and stenosis. A total of 1579 (79.7%) and 181 (9.1%) subjects had carotid plaques and carotid stenosis, respectively. The group with high hs‐CRP and Lp‐PLA2 levels had the highest prevalence of carotid plaques (90.6%) and stenosis (20.8%). A significant association was found between high hs‐CRP and Lp‐PLA2 levels and carotid stenosis (adjusted odds ratio [OR]: 2.39; 95% confidence interval [CI]: 1.13‐5.09), but this combination was not associated with carotid plaques (OR: 2.62, 95% CI: 0.93‐7.38). The results suggested that the combination of hs‐CRP and Lp‐PLA2 were better predictors than either protein alone with regard to carotid atherosclerosis.     

Serum Uric Acid Is More Strongly Associated with Impaired Fasting Glucose in Women than in Men from a Community-Dwelling Population

Serum uric acid (SUA) levels are associated with metabolic syndrome (MetS) and its components such as glucose intolerance and type 2 diabetes. It is unknown whether there are gender-specific differences regarding the relationship between SUA levels, impaired fasting glucose (IFG) and newly detected diabetes. We recruited 1,209 men aged 60±15 (range, 19–89) years and 1,636 women aged 63±12 (range, 19–89) years during their annual health examination from a single community. We investigated the association between SUA levels and six categories according to fasting plasma glucose (FPG) level {normal fasting glucose (NFG), <100 mg/dL; high NFG-WHO, 100 to 109 mg/dL; IFG-WHO, 110 to 125 mg/dL; IFG-ADA, 100 to 125 mg/dL; newly detected diabetes, ≥126 mg/dL; known diabetes} SUA levels were more strongly associated with the different FPG categories in women compared with men. In women, the associations remained significant for IFG-WHO (OR, 1.23, 95% CI, 1.00–1.50) and newly detected diabetes (OR, 1.33, 95% CI, 1.03–1.72) following multivariate adjustment. However, in men all the associations were not significant. Thus, there was a significant interaction between gender and SUA level for newly detected diabetes (P = 0.005). SUA levels are associated with different categories of impaired fasting glucose in participants from community-dwelling persons, particularly in women.     

Elevated Plasma Total Cholesterol Level Is Associated with the Risk of Asymptomatic Intracranial Arterial Stenosis

Background

Intracranial arterial stenosis (ICAS) is one of the most common causes of stroke, and dyslipidemia was one of the most common risk factors related to ICAS. However, the correlation between the plasma total cholesterol level (PTC) and ICAS, especially asymptomatic ICAS (AICAS) is not clear.

Materials and Methods

5,300 participants were enrolled in this study. The diagnosis of AICAS was made by transcranial Doppler ultrasonography. The participants were then divided into 5 essentially equal-sized groups based on their PTC levels. The multivariate logistic regression was used to analyze the correlation between the PTC level and the prevalence of AICAS.

Results

13.0% of the participants were diagnosed with AICAS. The prevalence of AICAS gradually increased with the increasing PTC level. After adjusted by the possible confounding factors, the Odds Ratios (OR) of the AICAS prevalence between the 1st quintile group and the other 4 groups were 1.13, 1.23, 1.63 and 1.75 with 95% confident intervals (CI) of 0.84–1.52, 0.91–1.66, 1.20–2.22 and 1.23–2.47, respectively. The further subgroup analysis revealed that the PTC level was stronger for males (OR 1.42 95%CI 1.23–1.64), regarding the prevalence of AICAS.

Conclusions

In this large community-based study, the prevalence of AICAS is 13.0%, subjects with higher PTC levels showed a mild increase in the prevalence of AICAS. The PTC level is an independent risk factor of AICAS. Males seem to be significantly more vulnerable to the risk of AICAS.     

Computational Fluid Dynamics Modeling of Symptomatic Intracranial Atherosclerosis May Predict Risk of Stroke Recurrence

Background

Patients with symptomatic intracranial atherosclerosis (ICAS) of ≥70% luminal stenosis are at high risk of stroke recurrence. We aimed to evaluate the relationships between hemodynamics of ICAS revealed by computational fluid dynamics (CFD) models and risk of stroke recurrence in this patient subset.

Methods

Patients with a symptomatic ICAS lesion of 70–99% luminal stenosis were screened and enrolled in this study. CFD models were reconstructed based on baseline computed tomographic angiography (CTA) source images, to reveal hemodynamics of the qualifying symptomatic ICAS lesions. Change of pressures across a lesion was represented by the ratio of post- and pre-stenotic pressures. Change of shear strain rates (SSR) across a lesion was represented by the ratio of SSRs at the stenotic throat and proximal normal vessel segment, similar for the change of flow velocities. Patients were followed up for 1 year.

Results

Overall, 32 patients (median age 65; 59.4% males) were recruited. The median pressure, SSR and velocity ratios for the ICAS lesions were 0.40 (−2.46–0.79), 4.5 (2.2–20.6), and 7.4 (5.2–12.5), respectively. SSR ratio (hazard ratio [HR] 1.027; 95% confidence interval [CI], 1.004–1.051; P = 0.023) and velocity ratio (HR 1.029; 95% CI, 1.002–1.056; P = 0.035) were significantly related to recurrent territorial ischemic stroke within 1 year by univariate Cox regression, respectively with the c-statistics of 0.776 (95% CI, 0.594–0.903; P = 0.014) and 0.776 (95% CI, 0.594–0.903; P = 0.002) in receiver operating characteristic analysis.

Conclusions

Hemodynamics of ICAS on CFD models reconstructed from routinely obtained CTA images may predict subsequent stroke recurrence in patients with a symptomatic ICAS lesion of 70–99% luminal stenosis.     

TAP1 I333V gene polymorphism and type 1 diabetes mellitus: a meta‐analysis of 2248 cases

Transporter associated with antigen processing 1 (TAP1) I333V gene polymorphism has been suggested to be associated with type 1 diabetes mellitus (T1DM) susceptibility. However, the results from individual studies are inconsistent. To explore the association of TAP1 I333V gene polymorphisms with T1DM, a meta‐analysis involving 2246 cases from 13 individual studies was conducted. The pooled odd ratios (ORs) and their corresponding 95% confidence intervals (95% CIs) were evaluated by a fixed‐effect model. A significant relationship was observed between TAP1 I333V gene polymorphism and T1DM in allelic (OR: 1.35, 95% CI: 1.08–1.68, P = 0.007), dominant (OR: 1.462, 95% CI: 1.094–1.955, P = 0.010), homozygous (OR: 1.725, 95% CI: 1.082–2.752, P = 0.022), heterozygous (OR: 1.430, 95% CI: 1.048–1.951, P = 0.024) and additive (OR: 1.348, 95% CI: 1.084–1.676, P = 0.007) genetic models. No significant association between TAP1 I333V gene polymorphism and T1DM was detected in a recessive genetic model (OR: 1.384, 95% CI: 0.743–2.579, P = 0.306) in the entire population, especially among Caucasians. No significant association between them was found in an Asian or African population. TAP1 I333V gene polymorphism was significantly associated with increased T1DM risk. V allele carriers might be predisposed to T1DM susceptibility.     

Association of the variants in the BUD13‐ZNF259 genes and the risk of hyperlipidaemia

The single nucleotide polymorphisms (SNPs) in the BUD13 homolog (BUD13) and zinc finger protein 259 (ZNF259) genes have been associated with one or more serum lipid traits in the European populations. However, little is known about such association in the Chinese populations. Our objectives were to determine the association of the BUD13/ZNF259 SNPs and their haplotypes with hypercholesterolaemia (HCH)/hypertriglyceridaemia (HTG) and to identify the possible gene–gene interactions among these SNPs. Genotyping of 6 SNPs was performed in 634 hyperlipidaemic and 547 normolipidaemic participants. The ZNF259 rs2075290, ZNF259 rs964184 and BUD13 rs10790162 SNPs were significantly associated with serum lipid levels in both HCH and non‐HCH populations (P < 0.008–0.001). On single locus analysis, only BUD13 rs10790162 was associated with HCH (OR: 2.23, 95% CI: 1.05, 4.75, P = 0.015). The G‐G‐A‐A‐C‐C haplotype, carrying rs964184‐G‐allele, was associated with increased risk of HCH (OR: 1.35, 95% CI: 1.10, 1.66, P = 0.005) and HTG (OR: 1.75, 95% CI: 1.39, 2.21, P = 0.000). The A‐C‐G‐G‐C‐C and A‐C‐A‐G‐T‐C haplotypes, carrying rs964184‐C‐allele, were associated with reduced risk of HCH (OR: 0.77, 95% CI: 0.61, 0.99, P = 0.039 and OR: 0.66, 95% CI: 0.47, 0.94, P = 0.021 respectively). On multifactor dimensionality reduction analyses, the two‐ to three‐locus models showed a significant association with HCH and HTG (P < 0.01–0.001). The BUD13/ZNF259 SNPs, which were significant in the European populations, are also replicable in the Southern Chinese population. Moreover, inter‐locus interactions may exist among these SNPs. However, further functional studies are required to clarify how these SNPs and genes actually affect the serum lipid levels.     

KCNQ1 rs2237892 C→T gene polymorphism and type 2 diabetes mellitus in the Asian population: a meta‐analysis of 15,736 patients

The KCNQ1 rs2237892 C→T gene polymorphism is reportedly associated with T2DM susceptibility, but various studies show conflicting results. To explore this association in the Asian population, a meta‐analysis of 15,736 patients from 10 individual studies was performed. The pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were evaluated using random‐effect or fixed‐effect models. A significant relationship between the KCNQ1 rs2237892 C→T gene polymorphism and T2DM was observed in the Asian population under the allelic (OR, 1.350; 95% CI, 1.240–1.480; P < 0.00001), recessive (OR: 0.650; 95% CI: 0.570–0.730; P < 0.00001), dominant (OR: 1.450; 95% CI: 1.286–1.634; P < 0.00001), and additive (OR: 1.346; 95% CI: 1.275–1.422; P < 0.00001) genetic models. In the subgroup analysis by race, a significant association was found in Chinese, Korean and Malaysia population, but not in Indian population. KCNQ1 rs2237892 C→T gene polymorphism was found to be significantly associated with increased T2DM risk in the Asian population, except Indian population. The C allele of the KCNQ1 rs2237892 C→T gene polymorphism may confer susceptibility to T2DM.     

Sex-related differences in plasma amino acids of patients with ST-elevation myocardial infarction and glycine as risk marker of acute heart failure with preserved ejection fraction

Nowadays, the problem of preventing acute heart failure (AHF) in patients with ST-elevation myocardial infarction (STEMI) and preserved left-ventricular ejection fraction (pLVEF) is still not completely resolved, especially in late-presented patients. The purpose of study was: (1) assessment of free plasma amino acid (PAA) alterations in STEMI patients [not receiving reperfusion therapy (RT)], depending on sex and LVEF; (2) analysis of development of late/persistent AHF more than 48 h after admission (pAHF) in STEMI patients with pLVEF depending on PAA levels. This prospective cohort study included 92 STEMI patients (33 women and 59 men), not receiving RT. The free PAA were investigated by ion-exchange liquid-column chromatography. The women had significantly higher PAA levels than men in general cohort and cohort with pLVEF (n?=?69). There were associations between female sex and pAHF in general cohort (OR 3.7, p?=?0.004) and cohort with pLVEF (OR 11.4, p?=?0.0001) by logistic regression. The association between pAHF and glycine level [OR 2.5, p?<?0.0001; AUC 0.84, p?<?0.0001; 86.7% sensitivity and 77.8% specificity for?>?2.6 mg/dL] was revealed in cohort with pLVEF (including female and male). Glycine remained a predictor of pAHF with pLVEF by multivariable logistic regression adjusting for comorbidities, demographic and clinical variables. Higher rate of pAHF in female than in male STEMI patients with pLVEF is associated with higher plasma glycine in women. The glycine level may be genetically determinated by female sex. The plasma glycine?>?2.6 mg/dL is a predictor of pAHF in STEMI with pLVEF (including female and male).

     

Uric Acid as a Risk Factor for Cardiovascular Disease and Mortality in Overweight/Obese Individuals

Background

The predictive value of serum uric acid (SUA) for adverse cardiovascular events among obese and overweight patients is not known, but potentially important because of the relation between hyperuricaemia and obesity.

Methods

The relationship between SUA and risk of cardiovascular adverse outcomes (nonfatal myocardial infarction, nonfatal stroke, resuscitated cardiac arrest or cardiovascular death) and all-cause mortality, respectively, was evaluated in a post-hoc analysis of the Sibutramine Cardiovascular OUTcomes (SCOUT) trial. Participants enrolled in SCOUT were obese or overweight with pre-existing diabetes and/or cardiovascular disease (CVD). Cox models were used to assess the role of SUA as an independent risk factor.

Results

9742 subjects were included in the study; 83.6% had diabetes, and 75.1% had CVD. During an average follow-up time of 4.2 years, 1043 subjects had a primary outcome (myocardial infarction, resuscitated cardiac arrest, stroke, or cardiovascular death), and 816 died. In a univariate Cox model, the highest SUA quartile was associated with an increased risk of cardiovascular adverse outcomes compared with the lowest SUA quartile in women (hazard ratio [HR]: 1.59; 95% confidence interval [CI]: 1.20–2.10). In multivariate analyses, adjusting for known cardiovascular risk factors the increased risk for the highest SUA quartile was no longer statistically significant among women (HR: 0.99; 95% CI: 0.72–1.36) nor was it among men. Analyses of all-cause mortality found an interaction between sex and SUA. In a multivariate Cox model including women only, the highest SUA quartile was associated with an increased risk in all-cause mortality compared to the lowest SUA quartile (HR: 1.51; 95% CI: 1.08–2.12). No relationship was observed in men (HR: 1.06; 95% CI: 0.82–1.36).

Conclusion

SUA was not an independent predictor of cardiovascular disease and death in these high-risk overweight/obese people. However, our results suggested that SUA was an independent predictor of all-cause mortality in women.     

Serum level of soluble Hsp70 is associated with vascular calcification

It has been previously reported that serum levels of 70-kDa heat shock protein (Hsp70) are elevated in peripheral artery disease. The aim of the present study was to examine whether increased serum Hsp70 levels are related to the extent of arterial calcification and standard laboratory parameters of patients with peripheral artery disease, as well as to markers of inflammation (C-reactive protein), atherosclerosis (homocysteine), and calcification (fetuin-a). One hundred eighty chronic atherosclerotic patients with significant carotid stenosis and/or lower extremity vascular disease were enrolled in this cross-sectional study. Systemic atherosclerosis and calcification was assessed by ultrasound (carotid intima–media thickness (IMT), presence of calcification at the abdominal aorta, carotid and femoral bifurcations, and aortic and mitral cardiac valves). Standard serum markers of inflammation, diabetes, renal function, ankle-brachial indexes, and traditional risk factors for atherosclerosis were noted. Serum Hsp70 levels were measured with enzyme-linked immunosorbent assay. Standard laboratory parameters (clinical chemistry), C-reactive protein (CRP), and homocysteine levels were determined by an autoanalyzer using the manufacturer’s kits. Fetuin-a levels were measured by radial immunodiffusion. Patients’ median age was 64 (57–71) years, 69% were men, and 34.5% had diabetes. Serum heat shock protein 70 levels were significantly higher in patients with more severe arterial calcification (p < 0.02) and showed significant positive correlations with serum bilirubin (r = 0.23, p = 0.002) and homocysteine levels (r = 0.18, p = 0.02). Serum Hsp70 did not correlate with body mass index, IMT, CRP, or fetuin-a levels in this cohort. Logistic regression analysis confirmed the association between sHsp70 and calcification score (OR, 2.189; CI, 1.156–4.144, p = 0.016) and this correlation remained significant (OR, 2.264; CI, 1.021–5.020, p = 0.044) after the adjustment for age, sex, eGFR, smoking, CRP, and homocysteine levels. Our data show that serum Hsp70 levels correlate with the severity of atherosclerosis in patients with carotid artery disease and chronic lower limb ischemia. These data support a putative role for plasma Hsp70 in the development of arterial calcification. Nevertheless, further studies are required to investigate the usefulness of circulating Hsp70 level as a marker of atherosclerotic calcification.     

High red blood cell distribution width and preclinical carotid atherosclerosis

Abstract

Background: Preclinical carotid atherosclerosis is associated with future risk of stroke. Data regarding the correlation between carotid atherosclerosis and biomarkers, which might predict the risk for the disease has been inconsistent and conflicting. Red blood cell distribution width (RDW) is also related to adverse clinical outcomes. Studies examining the relationship between RDW and preclinical and clinical carotid atherosclerosis were non-conclusive.

Objective: To study the association between RDW and preclinical carotid atherosclerosis in a large heterogeneous cohort.

Methods: Patients underwent Doppler ultrasound of the common carotid artery and Carotid Intima Media Thickness (CIMT). Advanced CIMT software analyzed over 100 samples in each exam. Blood samples for RDW were obtained on the same day. Logistic regression was used to evaluate the correlation between RDW and preclinical carotid atherosclerosis.

Results: Five hundred and twenty-two consecutive patients were included, with a mean age of 6.6?±?11. A cut-off value of 14.1% was used to differentiate between high and low RDW groups. The higher RDW group (RDW above 14.1%) was significantly older and with more cardiovascular risk factors. In a multivariate analysis, in all the patients including those treated by lipid modifying therapies, high RDW was significantly associated with advanced CIMT (OR?=?2.35, CI 95% 1.28–4.30, p?=?0.006). This association remained significant in subgroups of non-diabetic patients as well as patients not treated by lipid modifying drugs. RDW was also associated with significant carotid artery stenosis (OR?=?1.77, CI 95% 1.12–2.82, p?=?0.015).

Conclusions: High RDW correlates with increased risk for preclinical and clinical carotid atherosclerosis.     

Association of congenital cardiovascular malformations with 33 single nucleotide polymorphisms of selected cardiovascular disease–related genes

INTRODUCTION: Clark ( 1996 ) proposed that abnormal blood flow is related to some congenital cardiovascular malformations (CCVMs), particularly CCVM with obstruction to blood flow. Our hypothesis is that CCVMs may relate to genes that affect blood coagulation or flow. We studied whether polymorphisms of such genes are related to CCVMs; previous association of these SNPs to conotruncal CCVMs is described. METHODS: We assessed risk of pulmonary stenosis (PS, N = 120), atrial septal defect (ASD, N = 108), aortic stenosis (AS, N = 36), and coarctation of the aorta (CoAo, N = 64), associated with 33 candidate genes, selected for their relationship to blood flow affected by homocysteine metabolism, coagulation, cell‐cell interaction, inflammation, or blood pressure regulation. RESULTS: Effects were specific to cardiac phenotype and race. CoAo was associated with MTHFR (?667) C>T (odds ratio [OR] for TT 3.5, 95% confidence limits [CI] 1.4–8.6). AS was associated with a polymorphism of SERPINE1, G5>G4, OR = 5.6 for the homozygote with 95% CI 1.4–22.9. Unique polymorphisms were associated with increased risk of ASD and PS: NPPA 664G>A with ASD (OR of 2.4, 95%CI 1.3–4.4) and NOS3 (?690) C>T with PS (OR 6.1; 95% CI 1.6–22.6 in the African American population only). For ASD, the NPPA (?664) G>A SNP there was increased risk from the variant genotype only in maternal smokers (OR 2.6; 95% CI 1.0–7.2). CONCLUSIONS: Genes affecting vascular function and coagulation appear to be promising candidates for the etiology of cardiac malformations and warrant further study. Birth Defects Research (Part A), 2010. © 2009 Wiley‐Liss, Inc.     

Association between FABP2 Ala54Thr polymorphisms and type 2 diabetes mellitus risk: a HuGE Review and Meta‐Analysis

Many studies have examined the association between the FABP2 (rs1799883) Ala54Thr gene polymorphism and type 2 diabetes mellitus risk (T2DM) in various populations, but their results have been inconsistent. To assess this relationship more precisely, A HuGE review and meta‐analysis were performed. The PubMed and CNKI database was searched for case‐control studies published up to April 2014. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. Ultimately, 13 studies, comprising 2020 T2DM cases and 2910 controls were included. Overall, for the Thr carriers (Ala/Thr and Thr/Thr) versus the wild‐type homozygotes (Ala/Ala), the pooled OR was 1.18 (95% CI = 1.04–1.34, P = 0.062 for heterogeneity), for Thr/Thr versus Ala/Ala the pooled OR was 1.17 (95% CI = 1.05–1.41 P = 0.087 for heterogeneity). In the stratified analysis by ethnicity, the significantly risks were found among Asians but not Caucasians. This meta‐analysis suggests that the FABP2 (rs1799883) Ala54Thr polymorphisms are associated with increased susceptibility to T2DM risk among Asians but not Caucasians.     

Hyperuricemia as an Independent Predictor of Vascular Complications and Mortality in Type 2 Diabetes Patients: A Meta-Analysis

Background

Recent data have suggested that serum uric acid (SUA) level is positively associated with the development of type 2 diabetes (T2DM). Whether SUA is also independently associated with the development of vascular complications and mortality in T2DM is controversial.

Methods

A computerized literature search of MEDLINE, Embase and PubMed database was conducted and the odds ratio (OR) or hazard ratio (HR) for per 0.1mmol/l increase in SUA in each study was calculated. Cochrane’s Q and I² statistics were used to evaluate heterogeneity among studies and pooling OR and HR with 95% confidence intervals (CIs) were calculated using random-effects models and fixed-effects models. The pooled analysis was performed using Stata 10.0.

Results

Our search yielded 9 eligible articles (16 ORs and HRs) including 20,891 T2DM patients. Pooled estimates for the relationship suggested that each 0.1 mmol/l increase in SUA resulted in a 28% increase in the risk of diabetic vascular complications and a 9% increase in the risk of diabetic mortality. In stratification-analysis, the positive relationship between SUA and vascular complications remained significant irrespective of mean age, adjustment for metabolic variables and medications. However, it was inconsistent in different populations (significantly positive in the Asian but not in Australian and Italian population) and sample sizes (significantly positive in the relatively large sample size [≥1000] but non-significant in the small sample size [<1000]).

Conclusions

Results of this meta-analysis supported elevated SUA as an independent predictor of vascular complications and mortality in T2DM patients. SUA-lowering therapies might be helpful for prevention and treatment of vascular complications in this population.     

A common variant on chromosome 9p21 affects the risk of early-onset coronary artery disease

Background Two single nucleotide polymorphisms (SNPs, rs10757278 and rs2383207) on chromosome 9p21 have been proved to be associated with myocardial infarction. We investigated whether these two genetic markers are determinants of early-onset coronary artery disease. Methods and results A total of 444 consecutive patients were studied including 212 cases with coronary stenosis ≥50% or previous myocardial infarction and 232 controls without documented coronary artery disease. Ligase detection reaction was performed to detect two SNPs. After adjustment of clinical parameters, significant associations were identified for the rs2383207 and rs10757278 SNPs, with A/G and G/G genetypes at rs10757278 and G/G genetype carriers at rs2383207 having a higher risk of early-onset coronary artery disease than carriers of A/A genotype (odds ratio [OR] 2.207, 95% CI: 1.069–4.394, P = 0.028; OR 3.051, 95% CI: 1.086–8.567, P = 0.004; OR 2.964, 95% CI: 1.063–8.265, P = 0.038, respectively). There were no associations between rs10757278 and rs2383207 genotypes and the severity of coronary artery disease (both P > 0.05). Conclusions The rs10757278 and rs2383207 variants are determinants for early-onset coronary artery disease. These markers may help the identification of patients at increased risk for early-onset coronary artery disease. Zhong Chen and Qi Qian contributed equally to this paper.     

PD‐1 mRNA expression in peripheral blood mononuclear cells as a biomarker for different stages of primary gouty arthritis

There is currently a lack of biomarkers to assist the diagnosis and prediction of primary gouty arthritis (PG). Therefore, we evaluated the clinical value of programmed cell death protein 1 (PD‐1) mRNA expression in peripheral blood mononuclear cells (PBMCs) of patients with PG. This study included 36 patients with acute phase PG (APPG), 48 with non‐acute phase PG (NAPPG), 42 with asymptomatic hyperuricemia (AH) and 79 normal controls (NCs). PD‐1 mRNA expression levels were detected by qRT‐PCR. PD‐1 mRNA expression was statistically analysed by ANOVA or t tests, while correlations between PD‐1 mRNA and clinical variables were assessed using Pearson correlation tests. Receiver operator characteristic (ROC) curve analysis was used to evaluate the diagnostic value of PD‐1 in different PG stages. PD‐1 mRNA expression was significantly lower in patients with APPG than that in NAPPG, AH and NCs (P < 0.01). Correlation analysis revealed that PD‐1 mRNA levels correlated negatively with T‐score (r = ?0.209, P < 0.01). ROC curve analysis showed that serum uric acid (SUA), PD‐1 mRNA and both combined displayed higher diagnostic value in patients with PG, NAPPG and APPG compared to that in NCs and patients with non‐PG arthritis (NPG). Moreover, ROC curve analysis showed that SUA and PD‐1 mRNA had good diagnostic value in APPG, with the greatest diagnostic power when combined. PD‐1 mRNA could be a clinical auxiliary diagnostic biomarker for APPG, and the combined use of PD‐1 mRNA and SUA is better than that of SUA alone.