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Gene related to high stress also linked to elevated MI, death risk
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A gene variant that causes a hyperactive reaction to stress has been linked to a 38% increased risk for MI or death in patients with heart disease.
In 2011, researchers identified a variant of the 5HTR2C gene, rs6318 Ser23 C allele — located on the X chromosome — that was associated with hypothalamic-pituitary-adrenal axis response to a stress recall task and with endophenotypes associated with CVD. In the current study, they examined the variant as a predictor of CAD severity and of a composite of MI and all-cause mortality.
“We have added a potentially important candidate to the list of genes that have been shown to increase risk [for] and/or influence the course of CHD,” Redford B. Williams Jr., MD, of Duke University Medical Center, told Cardiology Today.
The researchers studied the gene and clinical outcomes in 6,126 white patients (65.9% men) at the Duke University Hospital cath lab. Median follow-up time was 5.3 years. During that period, 1,544 deaths and 225 MIs occurred.
Carriers of C allele at risk
In unadjusted time-to-event models, men hemizygous and women homozygous for the Ser23 C allele were at increased risk for the composite endpoint of MI and all-cause death (HR=1.47; 95% CI, 1.17-1.84) vs. carriers of the Cys23 G allele. Event rates were 35%.1 for men hemizygous for the Ser23 C allele vs. 28.9% for men hemizygous for the Cys23 G allele. Event rates were 36.5% for women homozygous for the Ser23 C allele vs. 26.9% for women homozygous for the Cys23 G allele and 25.4% for heterozygous women.
After adjustment for age, the genotype was not related to BMI, diabetes, hypertension, dyslipidemia, smoking history, number of diseased coronary arteries or left ventricular ejection fraction.
After adjusting for those factors, the differences between the groups remained (HR=1.38; 95% CI, 1.1-1.73).
“The increased risk of dying or having a heart attack in patients with the C allele was similar to that associated with having three coronary arteries blocked (48%), having a history of smoking (40%) or being 10 years older (47%),” Williams said in an interview. “The effect of this risk allele appears similar to that of biomarkers that have been shown to adversely affect prognosis in CHD patients.”
More research needed
The next step, Williams said, is to confirm the findings. The allele will need to be tested in large samples of healthy people to see whether it predicts increased risk for CHD in healthy people.
Then, he said, researchers must “begin the process of evaluating behavioral and pharmacological interventions that could reduce risk in CHD patients — and, ultimately, healthy persons — carrying the C allele. There are drugs that block the serotonin 2C receptor, and these could be tested to see if they reduce the large cortisol response to acute stress in C carriers.
“If these initial trials of behavioral and pharmacological approaches are encouraging, ie, they reduce cortisol hyperreactivity, then it would be possible to undertake larger randomized clinical trials in CHD patients carrying the C allele to see if they are effective in reducing the 38% excess mortality in C carriers,” Williams said. – by Erik Swain
Disclosure: Williams is a founder of and stockholder in Williams LifeSkills Inc.
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