Gene Could Cause Missed Diabetes Diagnosis in African Americans

Veronica Hackethal, MD

September 13, 2017

The largest study of its kind has discovered a genetic variant found only in African Americans that may lead to inaccurate measurements of HbA1c. Results were published online September 12 in PLoS Medicine.

HbA1c is used to diagnose diabetes and monitor blood glucose levels, and having the gene variant could result in missing diagnoses of diabetes.

"Knowing whether African American individuals carry this gene variant would help reduce the underdiagnosis of type 2 diabetes in a population in which diabetes is known to be disproportionately common and devastating," co–corresponding author James B Meigs, MD, MPH, of the division of general internal medicine at Massachusetts General Hospital, Boston, said in a press release from his institution.

"In this huge study that analyzed data from 82 cohort studies from around the world, we found dozens of gene regions affecting HbA1c levels and were able to show how genetic discoveries could help improve type 2 diabetes detection and reduce health disparities," he added.

HbA1c to Diagnose Diabetes Gives Longer-Term View, Is Convenient

Past studies in people of European and Asian descent have found 18 genetic variants associated with HbA1c. Some of these are related to blood glucose control, while others are associated with red blood cells.

Glucose binds irreversibly to hemoglobin on red blood cells, and HbA1c testing measures this. In contrast to a blood glucose test, which represents one point in time, HbA1c testing reflects average levels of blood glucose over a period of about 3 months, the usual lifespan of red blood cells.

Long used as tool for managing diabetes, HbA1c testing has been recommended for diagnosing diabetes and prediabetes since 2009. In addition to giving a longer-term view of an individual's blood glucose levels, HbA1c testing does not need to be conducted after an 8- to 10-hour fast, potentially making it more convenient for patients as well as being more accurate for diabetes detection.

But genetic variants that affect the life span of red blood cells could result in HbA1c levels that do not accurately reflect blood glucose levels, in turn leading to misdiagnosis or undertreatment.

To evaluate genetic variants associated with HbA1c, the researchers analyzed genetic data from 159,940 participants in 82 cohort studies. Participants were of European, African, East Asian, and South Asian descent and were free of diabetes when they entered the studies.

Using meta-analytic techniques, the researchers found 60 common genetic variants linked to HbA1c, 42 of which were previously unknown. Then they grouped these variants according to whether they were linked to HbA1c through blood glucose control (22 variants), red blood cells (19 variants), or other means (19 variants).

Next they used genetic risk scores to see whether blood glucose or red blood cell variants were linked to an increased type 2 diabetes incidence in a subset of 33,241 people of multiple ethnicities.

Results showed that having more red blood cell variants was not linked to increased risk for type 2 diabetes (odds ratio, 1.00; = .60).

Overall results for blood glucose control variants showed that having more of these was associated with a higher risk for type 2 diabetes, and the risk increased by about 5% for each inherited variant (incidence OR 1.05 per HbA1c-raising allele; = 3×10−29).

However, this was not true in African Americans.

Blacks With G6PD Variant: Normal HbA1c Despite High Blood Glucose

That led to further studies in African Americans, which revealed a genetic variant of the X-linked glucose-6-phosphate dehydrogenase (G6PD) gene that explained 14.4% of variance in HbA1c in this group.

Mutating the G6PD gene can shorten the life span of the red blood cell and thus lower HbA1c levels no matter the blood glucose level, meaning that individuals with the G6PD variant could have apparently normal HbA1c results despite chronically elevated blood sugar.

The G6PD gene is found only on the X chromosome. Because men have only one X chromosome, inheriting just one copy of the gene might be enough to produce misleading results in males. Women would need to inherit two copies of the gene to experience such an effect.

The G6PD variant is also found almost exclusively in people of African descent, among whom about 11% carry it. That translates to about one in 10 African American men with one copy and one in 100 African American women with two copies of the variant.

Lower Treatment Targets, Screen With Blood Glucose in Blacks With Variant

Compared with people without the G6PD variant, HbA1c was 0.68% lower in women with two copies of the variant, and 0.81% lower in men with one copy.

The standard HbA1c threshold for diagnosing diabetes, 6.5%, could therefore result in about 650,000 missed diagnoses among African Americans who carry the G6PD variant.

The findings may also have "important implications for the management of diabetes," say the authors, "with carriers of the G6PD allele requiring adjusted [lower] HbA1c treatment targets."

The authors calculate that in those carrying the G6PD variant, HbA1c thresholds of 5.8% and 5.7% in women and men, respectively, should be probably used to diagnose diabetes.

Or to avoid missed diagnoses, they recommend screening for diabetes using blood glucose measurements rather than HbA1c in blacks.

Alternatively, genetically informed diagnostic thresholds could be used.

But before that can happen, more work is needed on how to tailor diagnostic thresholds for people who have the variant.

Dr Meigs concluded: "We now plan to directly study, rather than estimate, the impact of HbA1c genetics on type 2 diabetes diagnosis in different minority communities to determine the correct diagnostic HbA1c thresholds for different ancestry groups. We also plan to look for other clinically important variants associated with HbA1c in the gene regions we have discovered."

Dr Meigs reports no relevant financial relationships. Disclosures for the coauthors are listed in the paper.

PLoS Med. Published online September 12, 2017. Article

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