MUNICH – A group of 12 genes that influence blood sugar appears to help drive the risk of heart disease, independent of type 2 diabetes.
The genome-wide association study determined that every 1 mmol/L increase in fasting glucose associated with these genes increased the risk of coronary heart disease by 43%, Jordi Merino, PhD, said at the annual meeting of the European Association for the Study of Diabetes.
“Our results quantify the causal relationship between isolated, genetically increased fasting glucose and heart disease risk beyond the genetic effect of type 2 diabetes,” said Dr. Merino of Massachusetts General Hospital, Boston. “They suggest that modulating glycemia may provide cardiovascular benefit.”
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It’s known that patients with type 2 diabetes have a higher incidence of coronary heart disease, even after accounting for traditional cardiovascular risk factors, he said. But five large prospective randomized studies – including the much-vaunted ACCORD – failed to find convincing evidence that managing blood glucose in patients with diabetes exerts any benefit on cardiovascular outcomes. In fact, patients assigned to intensive management (blood glucose targeted to below 6%) had a relative increase in all-cause mortality of 22% and an absolute increase of 1%, without any differences in cardiovascular mortality (5% vs. 4%; hazard ratio, 1.22) (N Engl J Med. 2008;358:2545-59).
However, a 2014 subanalysis of ACCORD found that outcomes for ischemic heart disease were significantly better in the intensively managed group. There was a 20% reduction in the risk of heart attack; a 19% reduction in a combined endpoint of heart attack; and similar reductions in the risk of coronary revascularization and unstable angina (Lancet. 2014;384:1936-41).
“We believed genetics might help to answer the question about this discrepancies in findings,” Dr. Merino said.
To investigate this, he and his colleagues plumbed the largest meta-analyses of genome-wide association studies of glucose and insulin regulation. MAGIC (the Meta-Analyses of Glucose and Insulin-related traits Consortium) is a collaborative effort that has combined genetic data from 55 studies.
MAGIC investigators have identified dozens of loci that influence levels of fasting glucose, fasting insulin, and hemoglobin A1c. The project includes data on 133,000 subjects without type 2 diabetes.
They used these data to conduct a Mendelian randomization analysis – a way of establishing causality between a specific gene and a specific clinical trait. Such an analysis is valid only when there are no other functional pathways between the genetic variant and the outcome and when confounding factors that could also affect the outcome can be controlled for.
MAGIC found 234 genetic variants that influence fasting glucose. Some of these also increase the risk of type 2 diabetes; after excluding those, Dr. Merino was left with 107 candidate genes. A disequilibrium analysis further pruned the group, leaving 12 genes that are independently associated with fasting glucose regulation.
He and his colleagues then applied data from the CARDIoGRAMplusC4D Consortium, which is searching for multiple risk loci for coronary artery disease and myocardial infarction in several large genetic studies. They created a five-level risk score for the glycemia-modulating genes and used to it determine how much genetically driven glucose variability affected the risk of heart disease in 5,000 subjects included in the Framingham Heart Study. The analysis controlled for lipids, blood pressure, and body mass index, he noted.
In a model that included all 12 of the variants, the investigators found that every 1 mmol/L increase in fasting glucose was associated with a significant 43% increase in the risk of heart disease.
A second analysis excluded one of the genes, but the significant association with increased risk of heart disease was preserved, at 34% per 1 mmol/L increase in fasting glucose. Individually, 10 of the genes raised the risk of coronary heart disease from a low of 6% (OR 1.06) to a high of almost 400% (OR 3.8).
The final pleiotropic analysis excluded all genes that could have more than one effect on heart disease; five genes survived to this level. Overall, they raised the risk of heart disease by 33%. Individually, the relative increased risks ranged from a low of 12% (odds ratio, 1.12) to a high of 87% (OR, 1.87). One gene was associated with a 25% risk reduction.
Dr. Merino had no financial disclosures.