From candidate gene to genome-wide association studies in cardiovascular disease.

Continuous updating of the genotyping technology has led to improvement of genetic study design. The recent advances in technology coupled with the advances in our understanding of the molecular mechanisms have allowed a more comprehensive examination of the role of genetics, environment and their interaction in determining the individual risk of cardiovascular disease (CVD). Initial candidate gene studies identified a limited number of polymorphisms associated with disease, explaining only a minor part of trait variance. Furthermore, results were not often concordant, with meta-analyses not reaching the statistical power to confirm an association in many cases. The advent of the genome-wide design furnished an enormous quantity of information and decreased time of genotyping, while increased complexity of analyses and costs. Their results were more concordant, even when they suggested associations between CVD and polymorphisms distant from codifying regions or in genes involved in previously unsuspected pathways. Future results from genome-wide studies coupled with results from functional studies and investigation on gene-environment interactions will allow improvement of cardiovascular risk assessment and discovery of new targets for therapy and prevention. In this review, a brief history of cardiovascular genetics is reported, from candidate gene to genome wide association studies, that led to the identification of association between CVD and SNPs in the 9p21 region, firstly thought a gene desert without importance

From candidate gene to genome-wide association studies in cardiovascular disease.

Continuous updating of the genotyping technology has led to improvement of genetic study design. The recent advances in technology coupled with the advances in our understanding of the molecular mechanisms have allowed a more comprehensive examination of the role of genetics, environment and their interaction in determining the individual risk of cardiovascular disease (CVD). Initial candidate gene studies identified a limited number of polymorphisms associated with disease, explaining only a minor part of trait variance. Furthermore, results were not often concordant, with meta-analyses not reaching the statistical power to confirm an association in many cases. The advent of the genome-wide design furnished an enormous quantity of information and decreased time of genotyping, while increased complexity of analyses and costs. Their results were more concordant, even when they suggested associations between CVD and polymorphisms distant from codifying regions or in genes involved in previously unsuspected pathways. Future results from genome-wide studies coupled with results from functional studies and investigation on gene-environment interactions will allow improvement of cardiovascular risk assessment and discovery of new targets for therapy and prevention. In this review, a brief history of cardiovascular genetics is reported, from candidate gene to genome wide association studies, that led to the identification of association between CVD and SNPs in the 9p21 region, firstly thought a gene desert without importance

Type 2 diabetes and polymorphisms on chromosome 9p21: a meta-analysis.

BACKGROUND AND AIMS: Genome-wide association studies found some variants on chromosome 9p21 associated with type 2 diabetes (T2D). We performed a meta-analysis to estimate strength, accuracy and feature of the association of polymorphisms in 9p21 with T2D. METHODS AND RESULTS: Articles were retrieved screening electronic databases and cross references. Twenty-two publications were identified, for a total of 38,455 T2D patients and 60,516 controls. Twenty-one studies investigated the role of the SNP rs10811661; in some studies three additional SNPs (rs564398, rs10757278, rs1333040) were genotyped. Population attributable risk (PAR) was computed as: risk allele frequency 17(OR-1)/OR, using the per-allele odds ratio (OR). The risk allele (T) of rs10811661 was associated with T2D in most of the studies. In meta-analysis the overall per-allele OR was 1.24 (95% CI: 1.21-1.27; P < 10(-15)), with no difference according to ethnicity (P = 0.45), and low heterogeneity (P = 0.040) across studies partly explained by sample size. Modeling of inheritance suggested an additive effect of the T allele. PAR of T2D related to this polymorphism was 15% for Caucasians and 13% for Asians. The overall odds ratio for the T allele of the SNP rs564398 was 1.08 (95% CI: 1.05-1.12; PAR = 6%). The other SNPs showed negligible associations. CONCLUSIONS: This meta-analysis provides accurate and comprehensive estimates of the association of some genetic variants at chromosome 9p21 and T2D. A relatively small but significant role of the T allele of the rs10811661 SNP in increasing by 21-27% the risk of T2D in an additive way was apparent

Inhibition of the renin-angiotensin system downregulates tissue factor and vascular endothelial growth factor in human breast carcinoma cells.

9PMID: 22188725 [noneNapoleone E; Cutrone A; Cugino D; Amore C; Di Santo A; Iacoviello L; de Gaetano G; Donati MB; Lorenzet RNapoleone, E; Cutrone, A; Cugino, D; Amore, C; Di Santo, A; Iacoviello, Licia; de Gaetano, G; Donati, Mb; Lorenzet, R

Polymorphisms of matrix metalloproteinase gene and adiposity indices in European children: results of the IDEFICS study

Objective: We investigated the relationship between matrix metalloproteinase 3 (MMP3) polymorphisms and adiposity indices in European children of the IDEFICS (Identification and Prevention of Dietary- and Lifestyle-Induced Health Effects in Children and Infants) project.&lt;p&gt;&lt;/p&gt; Subjects: A total of 16 224 Caucasian children (2–9 years) were recruited into a population-based survey from eight European countries. In all, 4540 children were randomly selected for genetic studies (T0); 3238 children were re-examined 2 years later (T1). Anthropometric measures were collected by standardized protocols at T0 and T1.&lt;p&gt;&lt;/p&gt; Results: Six variants of MMP3 gene were genotyped. Homozygotes for the variant A allele of rs646910 and for the H3 haplotype had higher hip circumference (P=0.002 and 0.001; age, sex and country adjusted) at T0. The association remained significant after false discovery rate (FDR) correction. At T1, subjects carrying rs646910 A/A genotype or H3/H3 diplotype showed significantly higher values of body mass index, waist and hip circumference and sum of tricipital and subscapular skinfolds, all associations remaining significant after FDR correction (P=0.020–0.048).&lt;p&gt;&lt;/p&gt; Conclusions: We showed for the first time an association between the MMP3 rs646910 variant and indices of adiposity in European children, highlighting the involvement of metalloproteinase genes in adipose tissue remodeling and growth.&lt;p&gt;&lt;/p&gt

White blood cell count, sex and age are major determinants of heterogeneity of platelet indices in an adult general population: results from the MOLI-SANI project

BACKGROUND: The understanding of non-genetic regulation of platelet indices--platelet count, plateletcrit, mean platelet volume, and platelet distribution width--is limited. The association of these platelet indices with a number of biochemical, environmental and clinical variables was studied in a large cohort of the general population. DESIGN AND METHODS: Men and women (n=18,097, 52% women, 56\ub112 years) were randomly recruited from various villages in Molise (Italy) in the framework of the population-based cohort study "Moli-sani". Hemochromocytometric analyses were performed using an automatic analyzer (Beckman Coulter, IL, Milan, Italy). Associations of platelet indices with dependent variables were investigated by multivariable linear regression analysis. RESULTS: Full models including age, sex, body mass index, blood pressure, smoking, menopause, white and red blood cell counts, mean corpuscular volume, D-dimers, C-reactive protein, high-density lipoproteins, low-density lipoproteins, triglycerides, glucose, and drug use explained 16%, 21%, 1.9% and 4.7% of platelet count, plateletcrit, mean platelet volume and platelet distribution width variability, respectively; variables that appeared to be most strongly associated were white blood cell count, age, and sex. Platelet count, mean platelet volume and plateletcrit were positively associated with white blood cell count, while platelet distribution width was negatively associated with white blood cell count. Platelet count and plateletcrit were also positively associated with C-reactive protein and D-dimers (P&lt;0.0001). Each of the other variables, although associated with platelet indices in a statistically significant manner, only explained less than 0.5% of their variability. Platelet indices varied across Molise villages, independently of any other platelet count determinant or characteristics of the villages. CONCLUSIONS: The association of platelet indices with white blood cell count, C-reactive protein and D-dimers in a general population underline the relation between platelets and inflammation