Oxidative stress as pathogenesis of cardiovascular risk associated with metabolic syndrome

Metabolic syndrome (MetS) is characterized by accumulation of visceral fat associated with the clustering of metabolic and pathophysiological cardiovascular risk factors: impaired glucose tolerance, dyslipidemia, and hypertension. Although the definition of MetS is different among countries, visceral obesity is an indispensable component of MetS. A growing body of evidence suggests that increased oxidative stress to adipocytes is central to the pathogenesis of cardiovascular disease in MetS. Increased oxidative stress to adipocytes causes dysregulated expression of inflammation-related adipocytokines in MetS, which contributes to obesity-associated vasculopathy and cardiovascular risk primarily through endothelial dysfunction. The purpose of present review is to unravel the mechanistic link between oxidative stress and cardiovascular risk in MetS, focusing on insulin resistance, hypertension, and atherosclerosis. Then, therapeutic opportunities translated from the bench to bedside will be provided to develop novel strategies to cardiovascular risk factors in MetS.     

Genome-wide haplotype association analysis and gene prioritization identify CCL3 as a risk locus for rheumatoid arthritis

Rheumatoid arthritis (RA) is a common autoimmune disease caused by a complex interaction of multiple genetic variants and environmental factors. The association between RA and genetic susceptibility loci has been observed in many different populations, and most studies have focused on univariate analyses of single nucleotide polymorphisms. We performed a genome-wide haplotype association study and prioritized RA-related genes within 100 kb in either direction of significant haplotypes (P < 0.0001), based on their similarity to known RA susceptibility genes. The results showed that the chemokine CCL3 was associated with susceptibility to RA. A haplotype that located CCL3 on chromosome 17q12 had significant correlation with RA (P = 7.56E-05), and the global similarity score of CCL3 was ranked in the top of all RA-related genes, excluding known susceptibility genes (P = 8.42E-07). Our findings provide further evidence for the potential importance of the chemokine CCL3 in RA, and will facilitate the further understanding of its role in immunological regulation and the pathogenesis of RA.     

A genome-wide shRNA screen identifies GAS1 as a novel melanoma metastasis suppressor gene

Metastasis suppressor genes inhibit one or more steps required for metastasis without affecting primary tumor formation. Due to the complexity of the metastatic process, the development of experimental approaches for identifying genes involved in metastasis prevention has been challenging. Here we describe a genome-wide RNAi screening strategy to identify candidate metastasis suppressor genes. Following expression in weakly metastatic B16-F0 mouse melanoma cells, shRNAs were selected based upon enhanced satellite colony formation in a three-dimensional cell culture system and confirmed in a mouse experimental metastasis assay. Using this approach we discovered 22 genes whose knockdown increased metastasis without affecting primary tumor growth. We focused on one of these genes, Gas1 (Growth arrest-specific 1), because we found that it was substantially down-regulated in highly metastatic B16-F10 melanoma cells, which contributed to the high metastatic potential of this mouse cell line. We further demonstrated that Gas1 has all the expected properties of a melanoma tumor suppressor including: suppression of metastasis in a spontaneous metastasis assay, promotion of apoptosis following dissemination of cells to secondary sites, and frequent down-regulation in human melanoma metastasis-derived cell lines and metastatic tumor samples. Thus, we developed a genome-wide shRNA screening strategy that enables the discovery of new metastasis suppressor genes.     

Genetic and functional analyses identify DISC1 as a novel callosal agenesis candidate gene

Agenesis of the corpus callosum (AgCC) is a congenital brain malformation that occurs in approximately 1:1,000-1:6,000 births. Several syndromes associated with AgCC have been traced to single gene mutations; however, the majority of AgCC causes remain unidentified. We investigated a mother and two children who all shared complete AgCC and a chromosomal deletion at 1q42. We fine mapped this deletion and show that it includes Disrupted-in-Schizophrenia 1 (DISC1), a gene implicated in schizophrenia and other psychiatric disorders. Furthermore, we report a de novo chromosomal deletion at 1q42.13 to q44, which includes DISC1, in another individual with AgCC. We resequenced DISC1 in a cohort of 144 well-characterized AgCC individuals and identified 20 sequence changes, of which 4 are rare potentially pathogenic variants. Two of these variants were undetected in 768 control chromosomes. One of these is a splice site mutation at the 5' boundary of exon 11 that dramatically reduces full-length mRNA expression of DISC1, but not of shorter forms. We investigated the developmental expression of mouse DISC1 and find that it is highly expressed in the embryonic corpus callosum at a critical time for callosal formation. Taken together our results suggest a significant role for DISC1 in corpus callosum development.     

A genome-wide study of panic disorder suggests the amiloride-sensitive cation channel 1 as a candidate gene

Panic disorder (PD) is a mental disorder with recurrent panic attacks that occur spontaneously and are not associated to any particular object or situation. There is no consensus on what causes PD. However, it is recognized that PD is influenced by environmental factors, as well as genetic factors. Despite a significant hereditary component, genetic studies have only been modestly successful in identifying genes of importance for the development of PD. In this study, we conducted a genome-wide scan using microsatellite markers and PD patients and control individuals from the isolated population of the Faroe Islands. Subsequently, we conducted a fine mapping, which revealed the amiloride-sensitive cation channel 1 (ACCN1) located on chromosome 17q11.2-q12 as a potential candidate gene for PD. The further analyses of the ACCN1 gene using single-nucleotide polymorphisms (SNPs) revealed significant association with PD in an extended Faroese case-control sample. However, analyses of a larger independent Danish case-control sample yielded no substantial significant association. This suggests that the possible risk alleles associated in the isolated population are not those involved in the development of PD in a larger outbred population.     

European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene

Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 × 10(-11). SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the 'urogenous contact hypothesis' that urine production and voiding frequency modify the risk of UBC.     

Gene–gene interaction analysis of personality traits in a Japanese population using an electrochemical DNA array chip analysis

It has been suggested that genes involved in the central dopaminergic pathway may contribute to personality traits. However, the results of association studies for these genes have not been consistent. The present study investigated the relationship between the specific polymorphisms of MAO-A, COMT, DRD2, DRD3 and personality traits in Japanese women using a novel genotyping method involving electrochemical DNA array (ECA) chip analysis. Single marker association analysis for each mutation revealed no significant association between scores for Neuroticism Extraversion Openness-Five Factor Inventory (NEO-FFI) items. Gene–gene interaction analysis showed that a MAO-A 30-bp repeat × COMT (Val158Met) × DRD3 (Ser9Gly) had a marginally significant association with Agreeableness (P = 0.0547). The present results suggest that a combination of polymorphisms of MAO-A, COMT, and DRD3 might affect personality traits in Japanese women.     

Hypertension, hypercoagulability and the metabolic syndrome: a cluster of risk factors for cardiovascular disease

Cardiovascular disease (CVD) is one of the main causes of mortality in the world representing around 30% of all deaths. It constitutes also an important factor in morbidity and incapacity. There are several related CVD risk factors such as hypertension, metabolic syndrome (MetS) and hypercoagulability. The exact mechanisms that underlie the relation between those factors and CVD are not sufficiently known yet; pathogenic explanations are lacking also for the mechanisms relating metabolic factors to insulin resistance (IR) and the association with the development of atherosclerosis and thrombosis. The possible links between hypertension, hemostasis alterations and MetS are examined in this report.     

Predicted 10-year risk of cardiovascular disease is influenced by the risk equation adopted: a cross-sectional analysis

Background

Validated risk equations are currently recommended to assess individuals to determine those at ‘high risk’ of cardiovascular disease (CVD). However, there is no longer a risk ‘equation of choice’.

Aim

This study examined the differences between four commonly-used CVD risk equations.

Design and setting

Cross-sectional analysis of individuals who participated in a workplace-based risk assessment in Carmarthenshire, south Wales.

Method

Analysis of 790 individuals (474 females, 316 males) with no prior diagnosis of CVD or diabetes. Ten-year CVD risk was predicted by entering the relevant variables into the QRISK2, Framingham Lipids, Framingham BMI, and JBS2 risk equations.

Results

The Framingham BMI and JBS2 risk equations predicted a higher absolute risk than the QRISK2 and Framingham Lipids equations, and CVD risk increased concomitantly with age irrespective of which risk equation was adopted. Only a small proportion of females (0–2.1%) were predicted to be at high risk of developing CVD using any of the risk algorithms. The proportion of males predicted at high risk ranged from 5.4% (QRISK2) to 20.3% (JBS2). After age stratification, few differences between isolated risk factors were observed in males, although a greater proportion of males aged ≥50 years were predicted to be at ‘high risk’ independent of risk equation used.

Conclusions

Different risk equations can influence the predicted 10-year CVD risk of individuals. More males were predicted at ‘high risk’ using the JBS2 or Framingham BMI equations. Consideration should also be given to the number of isolated risk factors, especially in younger adults when evaluating CVD risk.     

Evaluating gene by sex and age interactions on cardiovascular risk factors in Brazilian families

Background  

In family studies, it is important to evaluate the impact of genes and environmental factors on traits of interest. In particular, the relative influences of both genes and the environment may vary in different strata of the population of interest, such as young and old individuals, or males and females.     

Interaction between metabolic syndrome and PON1 polymorphisms as a determinant of the risk of coronary artery disease

Abstract The enzyme serum paraoxonase plays an important role in antioxidant defences and prevention of atherosclerosis. Metabolic syndrome (MS) is a clinical condition associated with increased oxidant stress and cardiovascular mortality. Two common polymorphisms of serum paraoxonase, PON1 Leu₅₅Met and Gln₁₉₂Arg, have been postulated to modulate the cardiovascular risk. We studied 915 subjects with angiographic documentation: 642 subjects with coronary atherosclerosis and 273 with normal coronary arteries. Two hundred and twenty-four subjects met the diagnostic criteria of MS. We found a significant interaction between MS and both the PON1 polymorphisms in determining the risk of coronary artery disease (P<0.05 by likelihood-ratio test). The 55Leu and the 192Arg alleles, associated with reduced protection against lipid peroxidation, were associated with coronary artery disease only in the MS subgroup. Subjects with MS and both 55Leu and 192Arg alleles had significantly increased risk (OR=9.38 with 95% CI=3.02–29.13 after adjustment by multiple logistic regression) as compared to subjects without MS and with 55Met/Met-192Gln/Gln genotype. No increased risk was found for subjects with MS and the 55Met/Met-192Gln/Gln genotype. This study highlights a potential example of genetic (paraoxonase polymorphisms)-clinical (MS) interaction influencing cardiovascular risk.     

Interaction between metabolic syndrome and PON1 polymorphisms as a determinant of the risk of coronary artery disease

The enzyme serum paraoxonase plays an important role in antioxidant defences and prevention of atherosclerosis. Metabolic syndrome (MS) is a clinical condition associated with increased oxidant stress and cardiovascular mortality. Two common polymorphisms of serum paraoxonase, PON1 Leu(55)Met and Gln(192)Arg, have been postulated to modulate the cardiovascular risk. We studied 915 subjects with angiographic documentation: 642 subjects with coronary atherosclerosis and 273 with normal coronary arteries. Two hundred and twenty-four subjects met the diagnostic criteria of MS. We found a significant interaction between MS and both the PON1 polymorphisms in determining the risk of coronary artery disease (P<0.05 by likelihood-ratio test). The 55Leu and the 192Arg alleles, associated with reduced protection against lipid peroxidation, were associated with coronary artery disease only in the MS subgroup. Subjects with MS and both 55Leu and 192Arg alleles had significantly increased risk (OR=9.38 with 95% CI=3.02-29.13 after adjustment by multiple logistic regression) as compared to subjects without MS and with 55Met/Met-192Gln/Gln genotype. No increased risk was found for subjects with MS and the 55Met/Met-192Gln/Gln genotype. This study highlights a potential example of genetic (paraoxonase polymorphisms)-clinical (MS) interaction influencing cardiovascular risk.