Researchers from Harvard TH Chan School of Public Health have found that specific genetic variations may have increased cardiovascular mortality among participants of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial receiving intensive diabetes medication.
The ACCORD trial, which began in 2008 and aimed to compare intensive and standard glycemic control among type 2 diabetes patients at risk of cardiovascular disease, had to be stopped due to an increased mortality risk in the intensive-control arm of the study.
Until now, no subsequent research was able to identify why more intensive diabetes treatments were linked to a higher cardiovascular mortality rate.
In this study, published recently in the journal Diabetes Care, Dr Hetal S Shah and her colleagues explored whether differences in the participants’ genome might be responsible.
They analysed data from 8,174 volunteers out of the 10,251 involved in the original ACCORD study and examined the association of nearly seven million common DNA variants extracted from white blood cells with cardiovascular mortality.
By crossing data from a second study called the Joslin Kidney Study in Type 2 Diabetes (JSK), the researchers noticed that two common DNA sequence variations, known as single nucleotide polymorphisms (SNPs), were associated with a more than twofold increase in cardiovascular mortality risk within the intensive glycemic control group.
According to the researchers, these SNPs – located on chromosome 10 and 5 – may regulate physiological responses when glucose levels are intensively lowered, hence why they are not linked to increased mortality in patients on standard glycemic control.
Inherited differences in DNA sequences, or SNPs, are distributed throughout the human genome and influence an individual’s risk of disease. Mapping SNPs allow the researchers to identify important genes for diagnosis and therapy.
The researchers also developed a genetic risk score to measure gene expression changes based on these two genetic markers in order to determine CV mortality risks more accurately.
After controlling for other known risk factors such as the presence of neuropathy or the use of aspiri, the scientists noted that patients with the highest gene expression score had a threefold increased mortality risk, while those with the lowest score had a fourfold reduction in mortality with intensive glycemic therapy.
The authors believe that these results suggest that testing for these two SNPs could be used as screening tools to identify subjects with type 2 diabetes on intensive glycemic therapy that are at risk of adverse cardiovascular outcomes.

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