Showing papers by "Simon G. Gregory published in 2011"

A stress response pathway regulates DNA damage through β2-adrenoreceptors and β-arrestin-1.

Abstract: The human mind and body respond to stress, a state of perceived threat to homeostasis, by activating the sympathetic nervous system and secreting the catecholamines adrenaline and noradrenaline in the 'fight-or-flight' response. The stress response is generally transient because its accompanying effects (for example, immunosuppression, growth inhibition and enhanced catabolism) can be harmful in the long term. When chronic, the stress response can be associated with disease symptoms such as peptic ulcers or cardiovascular disorders, and epidemiological studies strongly indicate that chronic stress leads to DNA damage. This stress-induced DNA damage may promote ageing, tumorigenesis, neuropsychiatric conditions and miscarriages. However, the mechanisms by which these DNA-damage events occur in response to stress are unknown. The stress hormone adrenaline stimulates β(2)-adrenoreceptors that are expressed throughout the body, including in germline cells and zygotic embryos. Activated β(2)-adrenoreceptors promote Gs-protein-dependent activation of protein kinase A (PKA), followed by the recruitment of β-arrestins, which desensitize G-protein signalling and function as signal transducers in their own right. Here we elucidate a molecular mechanism by which β-adrenergic catecholamines, acting through both Gs-PKA and β-arrestin-mediated signalling pathways, trigger DNA damage and suppress p53 levels respectively, thus synergistically leading to the accumulation of DNA damage. In mice and in human cell lines, β-arrestin-1 (ARRB1), activated via β(2)-adrenoreceptors, facilitates AKT-mediated activation of MDM2 and also promotes MDM2 binding to, and degradation of, p53, by acting as a molecular scaffold. Catecholamine-induced DNA damage is abrogated in Arrb1-knockout (Arrb1(-/-)) mice, which show preserved p53 levels in both the thymus, an organ that responds prominently to acute or chronic stress, and in the testes, in which paternal stress may affect the offspring's genome. Our results highlight the emerging role of ARRB1 as an E3-ligase adaptor in the nucleus, and reveal how DNA damage may accumulate in response to chronic stress.

Replication of TCF4 through Association and Linkage Studies in Late-Onset Fuchs Endothelial Corneal Dystrophy

Abstract: Fuchs endothelial corneal dystrophy (FECD) is a common, late-onset disorder of the corneal endothelium. Although progress has been made in understanding the genetic basis of FECD by studying large families in which the phenotype is transmitted in an autosomal dominant fashion, a recently reported genome-wide association study identified common alleles at a locus on chromosome 18 near TCF4 which confer susceptibility to FECD. Here, we report the findings of our independent validation study for TCF4 using the largest FECD dataset to date (450 FECD cases and 340 normal controls). Logistic regression with sex as a covariate was performed for three genetic models: dominant (DOM), additive (ADD), and recessive (REC). We found significant association with rs613872, the target marker reported by Baratz et al.(2010), for all three genetic models (DOM: P = 9.33×10−35; ADD: P = 7.48×10−30; REC: P = 5.27×10−6). To strengthen the association study, we also conducted a genome-wide linkage scan on 64 multiplex families, composed primarily of affected sibling pairs (ASPs), using both parametric and non-parametric two-point and multipoint analyses. The most significant linkage region localizes to chromosome 18 from 69.94cM to 85.29cM, with a peak multipoint HLOD = 2.5 at rs1145315 (75.58cM) under the DOM model, mapping 1.5 Mb proximal to rs613872. In summary, our study presents evidence to support the role of the intronic TCF4 single nucleotide polymorphism rs613872 in late-onset FECD through both association and linkage studies.

The S1103Y Cardiac Sodium Channel Variant Is Associated With Implantable Cardioverter-Defibrillator Events in Blacks With Heart Failure and Reduced Ejection Fraction

Abstract: Background— Risk-stratifying heart failure patients for primary prevention implantable cardioverter-defibrillators (ICDs) remains a challenge, especially for blacks, who have an increased incidence of sudden cardiac death but have been underrepresented in clinical trials. We hypothesized that the S1103Y cardiac sodium channel SCN5A variant influences the propensity for ventricular arrhythmias in black patients with heart failure and reduced ejection fraction. Methods and Results— Blacks (n=112) with ejection fractions <35% receiving primary prevention ICDs were identified from the Duke Electrophysiology Genetic and Genomic Studies (EPGEN) biorepository and followed for appropriate ICD therapy (either anti tachycardia pacing or shock) for documented sustained ventricular tachycardia or fibrillation. The S1103Y variant was overrepresented in patients receiving appropriate ICD therapy compared with subjects who did not (35% versus 13%, P =0.03). Controlling for baseline characteristics, the adjusted hazard ratio using a Cox proportional hazard model for ICD therapy in Y1103 allele carriers was 4.33 (95% confidence interval, 1.60 to 11.73, P =<0.01). There was no difference in mortality between carriers and noncarriers. Conclusions— This is the first report that the S1103Y variant is associated with a higher incidence of ventricular arrhythmias in blacks with heart failure and reduced ejection fraction.

Polymorphic variants in tenascin-C (TNC) are associated with atherosclerosis and coronary artery disease

Abstract: Tenascin-C (TNC) is an extracellular matrix protein implicated in biological processes important for atherosclerotic plaque development and progression, including smooth muscle cell migration and proliferation. Previously, we observed differential expression of TNC in atherosclerotic aortas compared with healthy aortas. The goal of this study was to investigate whether common genetic variation within TNC is associated with risk of atherosclerosis and coronary artery disease (CAD) in three independent datasets. We genotyped 35 single nucleotide polymorphisms (SNPs), including 21 haplotype tagging SNPs, in two of these datasets: human aorta tissue samples (n = 205) and the CATHGEN cardiovascular study (n = 1,325). Eleven of these 35 SNPs were then genotyped in a third dataset, the GENECARD family study of early-onset CAD (n = 879 families). Three SNPs representing a block of linkage disequilibrium, rs3789875, rs12347433, and rs4552883, were significantly associated with atherosclerosis in multiple datasets and demonstrated consistent, but suggestive, genetic effects in all analyses. In combined analysis rs3789875 and rs12347433 were statistically significant after Bonferroni correction for 35 comparisons, p = 2 × 10−6 and 5 × 10−6, respectively. The SNP rs12347433 is a synonymous coding SNP and may be biologically relevant to the mechanism by which tenascin-C influences the pathophysiology of CAD and atherosclerosis. This is the first report of genetic association between polymorphisms in TNC and atherosclerosis or CAD.