Investigators presented research at the 89th annual meeting of the Endocrine Society showing that patients with heart failure who had particular allelic variants did worse than those who did not have such genetic profiles.
"We know that there is a genetic element to heart disease," says Anna Pilbrow, PhD, a postdoctoral research fellow with the Cardioendocrine Research Group at the University of Otago, in Christchurch, New Zealand. "We are looking at candidate genes associated with [adverse] outcomes in heart-failure patients."
Pilbrow and colleagues genotyped patients for particular polymorphisms — angiotensinogen (AGT) M235T and T174M — to assess, over a 4-year period, whether the presence of these polymorphisms is linked to survival in patients with heart failure. The 451 patients had a mean age of 74 years. A total of 51% were male and 91% were of European origin.
Dr. Pilbrow noted that the 2 polymorphisms, (AGT) M235T and T174M, have been linked individually to elevated levels of plasma angiotensinogen. Pilbrow and colleagues established that (AGT) M235T and T174M provide prognostic information about long-term survival in research that was published in Hypertension (2007;49:322-327). In that research, patients were classified as having high-risk genotype combinations if they had the 235TT genotype and/or 1 or more copies of the 174M allele. This high-risk group, which represented 32% of the total cohort, had a 2-fold greater risk for mortality during the follow-up period (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.3 to 3.0; P = .001).
Pilbrow discussed further research that explored the additive effects of several polymorphisms in the same cohort. Specifically, investigators sought to examine synergies between renin-angiotensin hormone system polymorphisms in the same cohort of patients who were genotyped for several polymorphisms: AGT M235T and T174M, angiotensin II type I receptor (AT1R) A1166C, and angiotensin converting-enzyme insertion-deletion (ACE I/D) polymorphisms.
After controlling for age, sex, ethnicity, medical history, use of medications, kidney function, and neurohormonal and echocardiography markers, investigators found an additive effect of AGT and AT1R genotype risk groups in conferring heightened risk for mortality (OR and 95% CI, 2.2 [1.5-3.2]; P = .001).
Investigators found that for patients who carried high-risk AGT genotypes, the AT1R CC genotype significantly elevated risk for death. Moreover, they found an additive effect among 3 RAS genes; the risk for mortality heightened with the number of high-risk genotypes patients had (n = 0, 1, 2, or 3; P = .002).
"We have controlled for as many factors as we can, but there are shortcomings with association studies," said Dr. Pilbrow. "We don't know, for example,...why and how these polymorphisms are having an impact on survival."
Still, the findings raise new directions for research, according to Richard Auchus, MD, PhD, an associate professor of endocrinology and internal medicine at the University of Texas Southwestern Medical Center, in Dallas, Texas.
"The implications are that certain allelic variants may change the activity of the renin-angiotensin-aldosterone system and put people at risk of worse outcomes," said Dr. Auchus, who moderated the oral session in which the study was presented. "The next step would be to look at the mechanisms and then we may understand how we can tailor treatments to subgroups of patients with heart failure to achieve better outcomes. This is a first stage of this type of work to look at associations. They are trying to get a toehold on genetic parameters that may change outcomes."
Dr. Auchus noted that investigators reported that subjects were matched, but the types of drug therapies they took was not detailed, nor was the type of heart failure (systolic or diastolic).
Dr. Pilbrow reports no relevant financial relationships.
The study was supported by the Health Research Council of New Zealand; the National Heart Foundation of New Zealand; the New Zealand Foundation for Research, Science and Technology; the Lottery Grants Board of New Zealand; and the Canterbury Medical Research Foundation. Dr. Auchus is a member of the scientific advisory board for Cougar Biotechnology and a member of the scientific advisory board for QuatRx Pharmaceuticals.
ENDO 2007 Annual Meeting: Abstract OR14-3. Presented June 2, 2007.
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