Weihua Song

Genetic variants of the monocyte chemoattractant protein-1 gene and its receptor CCR2 and risk of coronary artery disease: A meta-analysis

OBJECTIVE Monocyte chemoattractant protein-1 (MCP-1) and its receptor chemokine (C-C motif) receptor 2 (CCR2) are implicated in promoting atherosclerosis. Many studies have searched the association between variants of the MCP-1 gene or CCR2 gene and risk of coronary artery disease (CAD), but the results are inconsistent. METHODS We conducted a meta-analysis of 20 publications including 24 studies on 2 genetic variants [A-2518G in the MCP-1 and V64I in the CCR2] published before January 2011, including a total of 9844 patients with CAD and 11,821 controls. Publication bias and heterogeneity among studies were explored. RESULTS In a combined analysis, the pooled OR for CAD of the -2518G allele was 1.42 (95%CI: 1.06-1.92) compared to wild-type A allele under a recessive model in Caucasian group, but there is an indication of publication bias and heterogeneity among the 9 studies. When the analyses were restricted to 2 large studies (n≥500 cases), the pooled OR was 1.08 (95%CI: 0.85-1.37). Our analyses detected a possibility of publication bias with an overestimate of the true association by smaller studies. A meta-analysis of studies on the CCR2 V64I variant showed no significant association with CAD, the pooled OR of 64I was 1.27 (95%CI: 0.81-1.99) in recessive model and 1.06 (95%CI: 0.95-1.19) in dominant model, respectively. CONCLUSIONS The results indicate that MCP-1-2518G allele had probably increased risk of CAD in Caucasian but this is likely to be due to publication bias and insufficient sample size. The CCR2 V64I has not been found any association with CAD.

Angiopoietin-2 promoter haplotypes confer an increased risk of stroke in a Chinese Han population

Angiopoietin-2 is an important mediator of angiogenesis, and we hypothesized that genetic variants of ANGPT2 (the gene encoding angiopoietin-2) would result in abnormal angiogenesis and contribute to stroke susceptibility. To test our hypothesis, we investigated the association of variants in the promoter of ANGPT2 with stroke in a multi-centre case-control study. We found that the C allele of rs3739390 conferred a 1.42-fold risk of lacunar infarction {adjusted OR (odds ratio), 1.42 [95% CI (confidence interval), 1.08-1.87]; P=0.012} and a 2.10-fold higher transcriptional activity than did the corresponding G allele rs3739390G. The haplotype G-G-T conferred a 1.54-fold risk of atherothrombotic stroke and a 1.64-fold risk for haemorrhagic stroke, whereas the haplotype G-C-C conferred approx. a 2.0-fold risk of each subtype of stroke. In conclusion, our results indicate that haplotypes in the promoter of ANGPT2 confer a high risk of stroke in a Chinese population.

Association of Kallikrein gene polymorphisms with sporadic intracranial aneurysms in the Chinese population

OBJECT Variants of Kallikreins have been shown to be risk factors for intracranial aneurysm (IA) in a Finnish population. In the present study, the authors investigated the correlation between polymorphisms in the Kallikrein gene cluster and IAs in the Chinese population. METHODS The association of Kallikrein variants (rs1722561 and rs1701946) with sporadic IAs was tested in 308 cases and 443 controls. The differences in allelic frequencies between patients and the control group were evaluated with the chi-square test. RESULTS The C allele of rs1722561 showed a significant reduction in the risk of sporadic IA (OR 0.71, 95% CI 0.53-0.95; p = 0.023). However, no association of the variant rs1701946 with sporadic IA was found (OR 0.78, 95% CI 0.57-1.06; p = 0.115). CONCLUSIONS The variant rs1722561 of Kallikreins might reduce the risk of sporadic IAs among individuals of Chinese Han ethnicity. This study confirms the association between Kallikreins and IAs.

A functional variant in the coding region of CAMTA2 is associated with left ventricular hypertrophy by affecting the activation of Nkx2.5-dependent transcription.

Objective: The calmodulin-binding transcription activator 2 (CAMTA2) promotes transcription of genes involved in cardiac hypertrophy through its interaction with Nkx2.5 and is an indispensable transcription coactivator for cardiac hypertrophy. We hypothesized that variants in the coding region of CAMTA2 would affect its function and confer a risk of cardiac hypertrophy. Methods: The effects of the variant rs238234 on the activity of the atrial natriuretic factor promoter and on the cardiomyocytes hypertrophy were assessed in the H9C2 cell line and primary neonatal rat cardiomyocytes, respectively. Furthermore, the association of this variant with left ventricular hypertrophy (LVH) was tested in hypertensive patients with and without hypertrophy (N = 325 and 697), and this analysis was replicated in an independent population of 987 hypertensive patients without hypertrophy and 463 hypertensive patients with hypertrophy. Results: We found that the G allele of rs238234 activated the atrial natriuretic factor promoter more strongly than the C allele. The cell size of cardiomyocytes was larger in the presence of the Ad-CAMTA2 G allele, and the G allele was associated with significantly increased susceptibility to LVH in hypertensive [odds ratio (OR), 1.29; P = 0.009]. In the discovery cohort, after adjusting for age and sex, the GG genotype was significantly associated with increased LVH risk (OR, 1.75; P = 0.015). There was little attenuation of the ORs (1.62; P < 0.05) when adjusting for BMI, heart rate, blood pressure, smoking, and drinking and further adjusting all covariates including lipid levels and other major risk factors. However, the GC genotype did not show any association with LVH using three regressive models. Replication in the second study yielded similar results. Conclusion: Our results provide evidence that the rs238234 GG genotype in the coding region of CAMTA2 may increase the risk of LVH by affecting the activation of Nkx2.5-dependent transcription.

A Variant in the Endoglin Gene is Associated with the Development of Sporadic Intracranial Aneurysms

Intracranial aneurysms (IAs) are acquired lesions in the brain and can pose potential risk of rupture leading to subarachnoid hemorrhage. Endoglin plays a pivotal role in the vascular development and disease. Variations of endoglin gene have been shown to be risk factors for IAs in different racial population. In the present study, we investigated the correlation between polymorphism in the endoglin gene with IAs in Chinese Han population. The association of endoglin D366H variant (rs1800956) with sporadic IAs was tested in 313 patients with intracranial aneurysms, and 450 controls. The difference in allelic frequency between patients and control group was evaluated with the chi-square test. The frequency of the GG+CG genotype of rs1800956 was significantly higher in patients with IAs than in controls [22.0% vs 15.3%, P = .018; crude OR(odds ratio), 1.56; 95% CI(confidence interval), 1.08-2.26]. Multivariate analysis showed that rs1800956G conferred a risk to IAs [adjusted OR, 1.56 [95% CI, 1.08-2.26]; P=.019], independent of conventional factors, including age, sex, blood pressure, smoking, and alcohol consumption. The variant rs1800956 of endoglin might raise the risk of sporadic IAs among individuals of Chinese Han ethnicity.

The Human Myotrophin Variant Attenuates MicroRNA-Let-7 Binding Ability but Not Risk of Left Ventricular Hypertrophy in Human Essential Hypertension.

Myotrophin, known as a myocardial hypertrophy-inducing factor, is responsible for the initiation of cardiac hypertrophy that transits to heart failure. MicroRNAs are small noncoding RNAs that down-regulate posttranscriptional expression of target molecules. We investigated the role of variants of the microRNA-binding site in myotrophin in affecting its expression and any association with cardiac hypertrophy. Bioinformatics demonstrated that variant rs17168525 was identified to be located in the let-7/miR-98-binding site of myotrophin. We further experimentally test to effects of the identified variant on myotrophin translation using luciferase reporter assay and Western blotting. We found that the C allele of rs17168525 suppressed myotrophin translation by facilitating let-7c binding, but not the T allele. Let-7c overexpression caused a significant decrease in the level of myotrophin protein. Next, we investigated the association of the variant with cardiac hypertrophy in 1614 hypertensive patients, including 552 with left ventricular hypertrophy and 1062 without left ventricular hypertrophy, as well as 591 healthy control subjects from a Han Chinese population. No significant association between the variant rs17168525 and left ventricular hypertrophy in hypertensive patients in a Han Chinese population (P>0.05). In conclusion, our experimental results provide evidence that the T allele of rs17168525 in the 3′-UTR of myotrophin might influence the level of myotrophin protein by interfering with let-7/miR-98 binding.