Study finds gene variant may underlie diabetes disparities

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A multi-institutional study has found that a genetic variation common in people of African ancestry is linked with an increased risk of complications from diabetes, including diabetic retinopathy.

The report was published today in the journal Nature Medicine.¹

According to a Vanderbilt University Medical Center (VUMC) news release, multi-institutional study was led by VUM), the VA Tennessee Valley Healthcare System and Million Veteran Program (MVP) of the U.S. Department of Veterans Affairs, Emory University School of Medicine, and the Joseph Maxwell Cleland Atlanta VA Healthcare System.²

VUMC noted in its news release researchers noted that the diagnosis of diabetes and treatment needed to prevent diabetes complications may be delayed in people who carry the variant, G6PDdef, because it is linked with reduced levels of HbA1c, a widely used clinical marker of blood glucose levels.

The researchers noted that testing for genetic variations that cause G6PD deficiency may lead to improvements in the way physicians diagnose and treat diabetes, thereby helping to reduce the known disparity in diabetes complications between individuals of European and African ancestries, the paper concluded.

“This discovery could lead to changes in the way diabetes is managed for millions of patients in the U.S. and around the world,” Todd Edwards, PhD, MS, the paper’s co-corresponding author with Ayush Giri, PhD, said in the news release.

Both are VUMC faculty members and affiliation with the VA Tennessee Valley Healthcare System.

Edwards pointed out in the news release that more needs to be done, with options including health economics and policy studies, and clinical trials, to establish the best way to use this knowledge to prevent diabetes complications.²

“Now that process can begin,” he said.

According to the news release, more than 400 million people globally have G6PD deficiency. While most MVP participants are men, millions of women find themselves at increased risk of diabetes complications if they carry a copy of the G6PDdef variant.

Joseph Breeyear, PhD, MS, a postdoctoral research fellow at the National Institute of Environmental Health Sciences of the National Institutes of Health (NIH), pointed out in the VUMC news release that while the findings could ultimately impact how millions of individuals manage their diabetes, it also highlights the importance of including diverse populations in biomedical research.

“By including underrepresented individuals, we can identify genetic variations that affect health outcomes,” said Breeyear, who earned his PhD in Human Genetics in the Edwards lab at VUMC in 2023, and was the first author of the paper.

Diabetic retinopathy has previously been linked to genetic variations called single nucleotide polymorphisms, or SNPs, but these associations have been studied primarily in individuals of European and Asian ancestry.

The estimated prevalence of diabetic retinopathy in the United States ranges from 24% in non-Hispanic white people to 34% in non-Hispanic Black people.²

In an effort to gain a better understanding of why some individuals diagnosed with diabetes develop retinopathy but others don’t, the researchers 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.¹

VUMC noted in its news release the study was the largest ancestry-stratified, SNP-based 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.

Researchers used electronic health records and genomic data from the Million Veteran Program, the United Kingdom Biobank, VUMC’s biorepository, called BioVU, the Mass General Brigham Biobank in Boston, and summary statistics from a 2019 study.

The researchers also examined the effect of G6PDdef on the risk of diabetes complications among participants in the NIH-sponsored Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial, which assessed the impact of tight diabetes control on cardiovascular events in more than 10,000 adults with Type 2 diabetes.

The researchers’ work found that individuals of non-Hispanic African ancestry with G6PDdef in the ACCORD trial had a higher likelihood of 2 diabetes complications — diabetic retinopathy and diabetic nephropathy — compared to individuals without the variant, despite receiving standard-of-care treatment to lower HbA1c levels.

Moreover, according to the VUMC news release, the current study detected 9 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 researchers noted the G6PDdef variant results in deficiency of the enzyme glucose 6-phosphate dehydrogenase. Common only in African and in some Asian populations, this genetic variation may have evolved as a protection against severe malaria.

This, according to the news release, is linked with a shorter red blood cell lifespan, which lowers HbA1c levels but not blood glucose levels. This “mismatch” can mask the true extent of hyperglycemia: in individuals who carry the G6PDdef mutation, HbA1c levels systematically underestimate blood glucose levels.²

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^.1

According to the news release, the numbers are broadly consistent with an earlier study, which that diabetes could be diagnosed late, or remain undiagnosed, in as many as 650,000 people of non-Hispanic African ancestry in the United States due to the G6PDdef variant.²

“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 concluded in the study.

Eighteen research groups, including 6 affiliated with the VA, contributed to the study. The research was supported by NIH grants as well as grants from the VA Office of Research & Development.

Co-authors from VUMC and the VA Tennessee Valley Healthcare System were Jacklyn Hellwege, PhD, Hanna Poisner, Sabrina Mitchell, PhD, Til Basnet, PhD, Alexander Bick, MD, PhD, Otis Wilson, Adriana Hung, MD, MPH, and Milam Brantley Jr., MD, PhD.

Other sources of support were the Doris Duke Foundation, American Diabetes Association, Research to Prevent Blindness, and the Intramural Research Program of the National Institute of Environmental Health Sciences.

References

1. Breeyear, J.H., Hellwege, J.N., Schroeder, P.H. et al. Adaptive selection at G6PD and disparities in diabetes complications. Nat Med. Published June 25, 2024. Accessed June 25, 2024. https://doi.org/10.1038/s41591-024-03089-1

2. Gene variant may underlie diabetes disparities: study. EurekAlert! Accessed June 25, 2024. https://www.eurekalert.org/news-releases/1049282