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Background— Chromosome 9p21.3 (chr9p21.3) recently was identified by several genome-wide association studies as the genomic region most strongly associated with the risk of coronary artery disease. Within the chr9p21.3 locus, the single-nucleotide polymorphism rs1333049 has been demonstrated to be most strongly associated with susceptibility to developing coronary artery disease. However, the effect of rs1333049 on clinical outcomes in patients with established coronary disease has yet to be determined. Methods and Results— Coronary Disease Cohort Study (CDCS) (n=1054) and Post-Myocardial Infarction (PMI) (n=816) study participants were genotyped for rs1333049. Clinical history, circulating lipids, neurohormones, cardiac function, and discharge medications were documented. All-cause mortality and cardiovascular hospital readmissions were recorded over a median follow-up period of 4.0 years for the CDCS cohort and 9.1 years for the PMI cohort. The CDCS patients homozygous for the high-risk C allele had an age of onset 2 to 5 years earlier for coronary disease ( P =.005), angina ( P =.025), myocardial infarction ( P =.022), and percutaneous transluminal coronary angioplasty ( P =.009). Patients with the CC genotype also had higher levels of total cholesterol ( P =.033) and triglycerides ( P =.003). The PMI participants with the CC genotype were 3 years younger on admission ( P =.009). Cox proportional hazards analysis adjusting for established predictors of increased risk showed no significant association between rs1333049 genotype and mortality in either the CDCS ( P =.214) or the PMI ( P =.696) cohorts. Conclusions— The chr9p21.3 polymorphism rs1333049 was associated with an earlier age of disease onset in 2 coronary disease cohorts but not with poorer clinical outcome in either cohort.

Abstract-Angiotensinogen M235T and T174M polymorphisms have individually been associated with elevated levels of plasma angiotensinogen, hypertension, and left ventricular hypertrophy. In this study, heart failure patients (nϭ451) were genotyped for the angiotensinogen M235T and T174M polymorphisms to investigate association with survival (recorded over 4 years of follow-up) and prognostic hormone markers. Patients carrying the 235TT genotype (nϭ86) were 3 years younger at admission (Pϭ0.011), and, in those with hypertension, diagnosis was made Ϸ10 years earlier than other patients. Patients carrying Ն1 174M allele (nϭ94) were more likely to have a previous history of heart failure (Pϭ0.044) and increased mortality during follow-up (risk ratio: Key Words: angiotensinogen Ⅲ polymorphism Ⅲ single nucleotide Ⅲ mortality Ⅲ heart failure Ⅲ congestive Ⅲ association T he renin-angiotensin system (RAS) is a key element in pressure/volume homeostasis and exerts a wide range of systemic and local effects through endocrine, paracrine, and autocrine signaling. 1 In patients with cardiovascular disease, activity of the RAS is often increased and contributes to a poor prognosis. 2 Detrimental effects include promotion of inappropriate sodium and water retention, increased peripheral vascular resistance, and promotion of adverse vascular and cardiac remodeling in response to cardiac injury. 3 Gene polymorphisms that increase baseline RAS activity are, therefore, candidates for increasing risk of, and adverse outcomes in, heart disease.The gene encoding angiotensinogen (AGT) has been implicated in hypertension both through genetic linkage studies 4,5 and by allelic association. A missense mutation in exon 2 of the gene (AGT M235T) has been associated with elevated levels of AGT, with 235TT homozygotes having between 10% and 20% more plasma AGT than 235MM individuals. 4,6,7 These individuals also have increased blood pressure, 4,8 -11 although a large-scale study of 9100 men and women from the Danish general population found that this was only true in women. 7 The frequency of the 235T allele has been shown to be significantly greater in hypertensive patients than in normotensive control subjects 4,12-14 and has also been linked with pre-eclampsia, 15 left ventricular hypertrophy, 16 increased risk of coronary heart disease, 17,18 and atrial fibrillation. 19 A second variant within the AGT gene, T174M, has also been associated with hypertension, with the M allele associated with an increased risk. 4,14 The M235T and T174M variants are in linkage disequilibrium. 4,14 However, a large-scale meta-analysis found no consistent association between either AGT polymorphism and increased risk for ischemic heart disease, myocardial infarction, or ischemic cerebrovascular disease in the Danish population. 20 To date, no studies have examined the combined influence of AGT M235T and T174M variants in heart failure (HF). Neither has the influence of these variants on long-term patients survival been explored. We hypothesized that these gene ...

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Plasma aldosterone levels post-MI are independent predictors of survival and hospitalization for heart failure over a 5-year-follow-up period.

Background— Genome-wide association studies have identified gene variants associated with coronary artery disease risk; however, whether they affect disease progression is largely unknown. This study investigated associations between polymorphisms at 1p13.3 (rs599839), 1q41 (rs17465637), and 3q22.3 (rs9818870) and cardiovascular outcomes in healthy volunteers and in patients with established heart disease. Methods and Results— Canterbury Healthy Volunteer study (HV) (n=1649), Coronary Disease Cohort Study (CDCS) (n=1797), and Post-Myocardial Infarction study (PMI) (n=906) participants (New Zealand), were genotyped for rs599839, rs9818870, and rs17465637. Associations between genotype and anthropometric characteristics, neurohormonal analysis, echocardiography, and clinical outcomes over medium-long-term follow-up (median HV, 5.9 years; CDCS, 3.7 years; PMI, 11.3 years) were tested. At 1p13.3, HV and CDCS participants carrying 1 or more rs599839 G allele had a lower prevalence of dyslipidemia ( P ≤0.005) or lower levels of low-density lipoprotein ( P =0.031) and total ( P =0.004) cholesterol and/or less history of myocardial infarction ( P ≤0.04) compared with AA participants. Moreover, CDCS and PMI AG/GG participants had better cardiac function as indicated by echocardiography ( P ≤0.026), and fewer CDCS AG/GG participants were readmitted for a non-ST-segment elevation MI ( P =0.012) during follow-up. The polymorphism at 1q41 (rs17465637) was associated with better cardiovascular outcomes in the HV ( P =0.028) and PMI ( P =0.008) cohorts, and 3q22.3 (rs9818870) was a predictor of death/admission in the HV cohort ( P =0.045). Conclusions— These data suggest that coronary artery disease genomic risk variants at 1p13.3 and 1q41 are associated with subsequent clinical outcome in heart patients and confirm rs9818870 at 3q22.3 as a predictor of cardiovascular risk in individuals free of overt heart disease.

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Specific chromosomal abnormalities are increasingly recognised to be associated with particular tumour subtypes. These cytogenetic abnormalities define the sites of specific genes, the alteration of which is implicated in the neoplastic process. We used comparative genomic hybridisation (CGH) to examine DNA from different breast and ovarian cancer cell lines for variations in DNA sequence copy number compared with the same normal control. We also compared different sources of the MCF7 breast line by both CGH and cDNA expression arrays. Some of the differences between the subcultures were extensive and involved large regions of the chromosome. Differences between the four subcultures were observed for gains of 2q, 5p, 5q, 6q, 7p, 7q, 9q, 10p, 11q, 13q, 14q, 16q, 18p and 20p, and losses of 4q, 5p, 5q, 6q, 7q, 8p, 11p, 11q, 12q, 13q, 15q, 19p, 19q, 20p, 21q, 22q and Xp. However, few variations were found between two subcultures examined, 5 months apart, from the same initial source. The RNA arrays also demonstrated considerable variation between the three different subcultures, with only 43% of genes expressed at the same levels in all three. Moreover, the patterns of the expressed genes did not always reflect our observed CGH aberrations. These results demonstrate extensive genomic instability and variation in RNA expression during subculture and provide supportive data for evidence that cell lines do evolve in culture, thereby weakening the direct relevance of such cultures as models of human cancer. This work also reinforces the concern that comparisons of published analyses of cultures of the same name may be dangerous.