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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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