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Researchers Tie Variant to Coronary Heart Disease Risk in Type 2 Diabetes Patients

NEW YORK (GenomeWeb News) – Researchers led by the Joslin Diabetes Center's Alessandro Doria and Lu Qi from the Harvard School of Public Health have undertaken a three-stage, genome-wide analysis that has uncovered a genetic variant linked to increased coronary heart disease risk in people with type 2 diabetes.

Their study, as reported in the Journal of the American Medical Association yesterday, included more than 4,100 diabetes patients with and without heart disease as well as some 2,400 non-diabetic people with and without heart disease. All of the study subjects were of European descent.

The rs10911021 variant, found on chromosome1q25, was consistently linked with coronary heart disease in people with type 2 diabetes, with the risk allele increasing their chance of disease by about a third, according to the researchers. In addition, the researchers noted that the variant is located close to the glutamate-ammonia, or GLUL, gene that encodes an enzyme that catalyzes the conversion of glutamic acid and ammonia to glutamine.

"It is a common genetic variant that becomes important in the presence of diabetes. You need the presence of both diabetes and the variant to increase the risk of [coronary heart disease]," Doria, an investigator at Joslin and an associate professor at Harvard Medical School, said in a statement.

As compared to people without the disease, people with type 2 diabetes have a two- to three-fold increased risk for coronary heart disease as well as similarly higher rates of morbidity and mortality due to heart disease. They also develop heart disease at younger ages than the general population does.

For this study, Doria, Qi, and their colleagues turned to a number of long-term studies — the Nurses' Health Study, the Health Professionals Follow-up Study, the Joslin Heart Study, the Gargano Heart Study, and the Catanzaro Study — to determine whether there was a genetic link to coronary heart disease that was specific to diabetes patients. From these populations, the researchers identified cases with type 2 diabetes that also had coronary heart disease, as indicated by a heart attack, a coronary artery bypass, or an angioplasty, and controls with type 2 diabetes but without heart disease.

In the first stage of their genome-wide analysis, the investigators genotyped some 2.5 million genetic variants in 350 cases and 976 controls teased out from the overall Nurses' Study and 319 cases and 665 controls from the Health Professionals Study. From this, 26 variants appeared to be linked to heart diseases.

Those 26 were then tested in cases and controls from the Joslin Study, further narrowing the field of variants to three. Of those three, one — rs10911021 — was still significant after being analyzed in the third stage that included the Gargano and Catanzaro study cohorts.

In addition, no association was found between this variant and coronary heart disease in non-diabetic cases and controls identified from the Nurses' Study and the Health Professionals Study.

The researchers noted, though, that the CARDIoGRAM consortium, which studied coronary artery disease susceptibility loci in the general population, had seen a weak significant association between the rs10911021 variant and coronary heart disease. This, Doria, Qi, and their colleagues said, was expected, given the rate of diabetes in the general population that study drew upon.

As rs10911021 falls near two genes, the researchers investigated whether their expression was affected by the presence of the variant. Indeed, they found that the expression of the gene GLUL was nearly a third lower in diabetes patients with the homozygous risk allele, as compared to those with the homozygous protective allele.

GLUL encodes glutamate-ammonia ligase, which catalyzes the conversion of glutamic acid and ammonia to glutamine. Further, the researchers noted glutamic acid plays a key role in metabolic pathways like the γ-glutamyl cycle while glutamine helps regulate cell proliferation, inhibit apoptosis, and has a role in cell signaling. Other studies, the researchers noted, have tied the metabolism of these amino acids to insulin resistance, type 2 diabetes, and cardiovascular issues.

While the researchers noted that there was no difference between glutamic acid or glutamate levels in the bloodstream between people who were homozygous for the risk alleles or the protective alleles, they found that the ratio of plasma pyroglutamic acid to glutamic acid differed, suggesting to them a possible mechanism through which the variant could have its effect.

"[O]ur finding of association between the risk variant and a lower pyroglutamic-to-glutamic acid ratio in plasma and the fact that the association between risk allele and [coronary heart disease] was attenuated after adjustment for this variable suggest an impairment of the γ-glutamyl cycle, of which pyroglutamic acid is an intermediate, as a possible mechanism," the researchers wrote. "Such alteration might increase [coronary heart disease] risk by limiting the availability of the natural antioxidant glutathione, compounding the known negative effect of diabetes on this metabolite and potentially explaining the fact that this genetic effect can be observed only among diabetic participants."

While the researchers cautioned that their findings need to be validated further — particularly to determine if they hold in non-European populations — they said that knowing such risk alleles could help prevent or treat coronary heart disease in type 2 diabetes patients.

"This finding may have particularly important implications regarding prevention and reduction of cardiovascular morbidity and mortality through dietary and lifestyle intervention in diabetic patients," Qi said.