Gene variant may underlie diabetes disparities

Key Takeaways

• A genetic variation common in people of African ancestry is associated with an increased risk of complications from diabetes, including diabetic retinopathy.
• The diagnosis of diabetes and treatment needed to prevent diabetes complications may be delayed in people who carry the variant, which causes HbA1C tests to underestimate blood sugar levels. 

Diabetic retinopathy has been linked to genetic variations, but these associations have been studied primarily in individuals of European and Asian ancestry. To better understand why some people with diabetes develop retinopathy but others don’t, researchers from eighteen research groups conducted a combined-ancestry genome-wide association study (GWAS) of more than 197,000 individuals with diabetes, including more than 68,000 who also had diabetic retinopathy. (Genome-wide association studies involve rapidly scanning markers across the complete sets of DNA, or genomes, of many people to find genetic variations associated with a particular disease.) The study was the largest ancestry-stratified estimation of the heritability of diabetic retinopathy conducted to date and included an unprecedented number of individuals of non-Hispanic African ancestry—more than 46,000.

The study, published in the journal Nature Medicine, detected nine previously unreported loci, or positions on the chromosomes, which were associated with diabetic retinopathy, including an evolutionarily adaptive genetic variant that potentially may explain some of the racial disparity in diabetes complications. The G6PDdef variant, common only in African and some Asian populations, may have evolved as a protection against severe malaria. It is associated with a shorter red blood cell lifespan. Unfortunately, because of this, the variant also lowers HbA1c levels, a widely used clinical marker of blood glucose levels, without lowering blood glucose levels. This “mismatch” can mask the true extent of high blood sugar: in individuals who carry the G6PDdef mutation, HbA1c levels systematically underestimate blood glucose levels. Thus, the diagnosis of diabetes and treatment needed to prevent diabetes complications may be delayed in people who carry the variant.

Based on the prevalence of this genetic variant, the researchers estimated that more than 250,000 men and 500,000 women of non-Hispanic African ancestry in the United States who have diabetes may have some level of G6PD deficiency. “With comprehensive screening … and subsequent standard-of-care treatment, possibly aimed at glucose rather than HbA1c targets, nearly 12% of diabetic retinopathy cases and 9% of diabetic neuropathy cases in individuals of non-Hispanic African ancestry could be avoided in the U.S. alone,” the researchers said. Testing for genetic variations that cause G6PD deficiency could lead to improvements in the way clinicians diagnose and treat diabetes, thereby helping to reduce the long-observed disparity in diabetes complications between individuals of European and African ancestries, the paper concluded. 

Edited by Miriam Kaplan, PhD

Source: Vanderbilt University Medical Center, Medical Xpress, June 25, 2024; see source article