Combined Effect of Hemostatic Gene Polymorphisms and the Risk of Myocardial Infarction in Patients with Advanced Coronary Atherosclerosis

BACKGROUND: Relative little attention has been devoted until now to the combined effects of gene polymorphisms of the hemostatic pathway as risk factors for Myocardial Infarction (MI), the main thrombotic complication of Coronary Artery Disease (CAD). The aim of this study was to evaluate the combined effect of ten common prothrombotic polymorphisms as a determinant of MI. METHODOLOGY/PRINCIPAL FINDINGS: We studied a total of 804 subjects, 489 of whom with angiographically proven severe CAD, with or without MI (n = 307; n = 182; respectively). An additive model considering ten common polymorphisms [Prothrombin 20210G>A, PAI-1 4G/5G, Fibrinogen beta -455G>A, FV Leiden and "R2", FVII -402G>A and -323 del/ins, Platelet ADP Receptor P2Y12 -744T>C, Platelet Glycoproteins Ia (873G>A), and IIIa (1565T>C)] was tested. The prevalence of MI increased linearly with an increasing number of unfavorable alleles (chi(2) for trend = 10.68; P = 0.001). In a multiple logistic regression model, the number of unfavorable alleles remained significantly associated with MI after adjustment for classical risk factors. As compared to subjects with 3-7 alleles, those with few (/=8) alleles had an increased MI risk (OR 2.49, 95%CIs 1.03-6.01). The number of procoagulant alleles correlated directly (r = 0.49, P = 0.006) with endogenous thrombin potential. CONCLUSIONS: The combination of prothrombotic polymorphisms may help to predict MI in patients with advanced CAD

The Role of Repetitive Negative Thoughts in the Vulnerability for Emotional Problems in Non-Clinical Children

The current study examined the role of repetitive negative thoughts in the vulnerability for emotional problems in non-clinical children aged 8–13 years (N = 158). Children completed self-report questionnaires for assessing (1) neuroticism and behavioral inhibition as indicators of general vulnerability (2) worry and rumination which are two important manifestations of repetitive negative thoughts, and (3) emotional problems (i.e., anxiety, depression, and sleep difficulties). Results demonstrated that there were positive correlations between measures of general vulnerability, repetitive negative thoughts, and emotional problems. Further, support was found for a model in which worry and rumination acted as partial mediators in the relation between neuroticism and symptoms of anxiety and depression. In the case of sleep difficulties, no evidence was obtained for such a mediation model. In fact, data suggested that sleeping difficulties are better conceived as an epiphenomenon of high symptom levels of anxiety and depression or as a risk factor for the development of other types of psychopathology. Finally, besides neuroticism, the temperamental trait of behavioral inhibition appeared to play a unique direct role in the model predicting anxiety symptoms but not in the models predicting depressive symptoms or sleep difficulties. To conclude, the current findings seem to indicate that worry and rumination contribute to children’s vulnerability for anxiety and depression

Fine-mapping of common genetic variants associated with colorectal tumor risk identified potential functional variants

Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s).National Institutes of Health; National Cancer Institute; U.S. Department of Health and Human Services