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Type 2 Diabetes Test May Miss Some Cases in African-Americans With Common Genetic Variant

NEW YORK (360Dx) – New research suggests that at least one of the 60 genetic variants implicated in blood sugar control may interfere with the ability to detect type 2 diabetes with a blood test that measures glycated hemoglobin (HbA1c), which forms when blood glucose binds hemoglobin in red blood cells and provides a look at individuals' glycemic control.

Researchers from the UK and the US led a large team searching for genetic contributors to HbA1c profiles through a genome-wide association study meta-analysis involving almost 160,000 individuals of European, African, East Asian, or South Asian ancestry. As they reported in PLOS Medicine today, they narrowed in on 60 HbA1c-associated variants and subsequently searched for ties between glycemic pathways, red blood cell biology, and T2D itself in more than 33,200 individuals from a range of ethnic backgrounds.

In particular, the team reported, the search led to 19 glycemic control-related variants with significant HbA1c associations and another 22 variants influencing erythrocytic processes and HbA1c outcomes. While the glycemic processes appeared to impact T2D risk, the erythrocytic variants did not, the authors explained, though a variant in the X-linked gene G6PD dialed down levels in HbA1c in African-Americans in a manner that might producing misleading T2D test results.

"The issue with the G6PD genetic variant is it artificially lowers the value of blood sugar in the HbA1c test, and can lead to underdiagnosis of people with type 2 diabetes," co-corresponding author Inês Barroso, a human genetics researcher affiliated with the Wellcome Trust Sanger Institute and the University of Cambridge, said in a statement.

"We estimate that if we tested all Americans for diabetes using the HbA1c test, we would miss type 2 diabetes in around 650,000 African-Americans," Barroso explained, though she went on to say that the test "remains a suitable test for diagnosing and monitoring diabetes for the majority of people."

There were prior clues that variants related to red blood cell biology or glycemic control could influence HbA1c, the researchers explained. To explore these processes in more detail, they amalgamated Affymetrix or Illumina array-based genotypes for 159,940 individuals enrolled in dozens of prior genetic studies who had not been diagnosed with T2D.

Along with analyses focused on finding HbA1c-associated variants in the individuals, from European, African American, East Asian, and South Asian ancestry groups, the team attempted to tease apart variants involved in glycemic or erythrocytic aspects of the test.

The search led to 42 new and 18 known variants with apparent ties to HbA1c, the researchers reported. Of those, they predicted that 22 variants had an impact on erythrocytic functions, while 19 had a glycemic influence. Another 19 did not fall distinctly into either group.

In the African-American individuals in particular, the researchers estimated that the presence of the G6PD variant led to a 2 percent dip in T2D diagnoses using the HbA1c test, apparently due to muted HbA1c levels relative to other glycemic measures.

The authors cautioned that further research is needed to continue teasing apart the influence of other HbA1c-associated variants in various human populations. They also urged additional studies focused on the potential benefits of genotyping G6PD in individuals being tested for T2D with the HbA1c test who might be prone to carrying the newly described variant or other genetic changes that alter G6PD levels.

"[A]n option would be to genetically screen African-Americans for the G6PD variant alongside the HbA1c test in order to accurately diagnose type 2 diabetes, or use other diagnostic tests such as fasting glucose measurements," co-corresponding author James Meigs, a researcher affiliated with Massachusetts General Hospital, Harvard Medical School, and the Broad Institute, said in a statement. "We suggest moving towards precision medicine to take people’s genetics into account and improve diagnosis and monitoring for diabetes."