In the largest study of its kind, an international research team has identified 60 gene variants - 42 for the first time - that can influence blood levels of hemoglobin A1c, measurements of which are used both to diagnose type 2 diabetes and to monitor blood sugar control.

While these variants together produce just a modest increase in the risk of developing type 2 diabetes, one variant found only in African Americans significantly reduces the accuracy of A1c blood testing.

This may contribute to underdiagnosis in a population known to have a higher risk for the disease.

“Large-scale genetic discoveries about the increasingly common type 2 diabetes have not yet had much impact on prevention,” said James Meigs, HMS professor of medicine at Massachusetts General Hospital and co-corresponding author of the paper published in the journal PLOS Medicine.

“In this huge study that analyzed data from 82 cohort studies from around the world, we found dozens of gene regions affecting A1c levels and were able to show how genetic discoveries could help improve type 2 diabetes detection and reduce health disparities,” he added.

Previous studies have identified 18 gene variants associated with higher or lower A1c levels, which could be classified based on whether they directly influenced blood glucose or factors related to red blood cells. The latter types of variants, including ones that reduce the lifespan of red blood cells, could lead to A1c results that do not accurately reflect actual blood sugar levels.

Because the earlier studies were conducted in individuals of either European or Asian ancestry, the current study was designed to identify new A1c-influencing variants by analyzing data from larger, more diverse population samples.

The team, comprised of more than 200 investigators from around the world, analyzed genetic data from almost 160,000 individuals of European, African American and Asian ancestries who had not been diagnosed with diabetes at the time they entered their respective studies.

The 60 A1c-influencing variants that were identified were classified as either acting through blood glucose, through red blood cells or through other means. That data revealed that inheriting any of the 20 variants that influenced A1c levels by raising blood glucose increased the risk of developing type 2 diabetes by around 5 percent per inherited variant.

While the ability of these variants to predict future diabetes was similar in those of European, Asian and African ancestry, the influence of variants on the ability to diagnose diabetes by A1c testing was significantly different in African Americans. This difference was attributable to one specific variant in a gene called 6GPD, which is located on the X chromosome and codes for an important red blood cell protein.

This 6GPD variant, which has been seen only in individuals of African ancestry, impairs function of the 6GPD protein, can shorten the lifespan of red blood cells and thereby can reduce A1c independent of blood sugar levels.

Individuals with the G6PD variant could have apparently normal A1c results despite chronically elevated blood sugar.

The research team estimates that the variant - which is relatively common in individuals of African ancestry, affecting about 11 percent - could lead to missing a diabetes diagnosis in around 660,000 African Americans in the U.S.

The presence of the 6GPD gene on the X chromosome means that inheriting only a single variant copy would be required to produce misleading A1c results in men, while two copies of the variant gene would be needed to do so in women, who have two copies of the X chromosome.