Gene variant may underlie diabetes disparities

A genetic variation common in people of African descent is associated with an increased risk of complications from diabetes, including diabetic retinopathy, according to a report published June 25 in the journal. Nature Medicine.

The investigators found that the diagnosis of diabetes and the treatment needed to prevent diabetes complications may be delayed in people who carry the variant, G6PDdef, because it is associated with reduced levels of HbA1c, a widely used clinical marker of blood glucose levels.

Testing for genetic variations that cause G6PD deficiency could lead to improvements in how doctors diagnose and treat diabetes, thereby helping to reduce the long-observed disparity in diabetes complications between individuals of European and African descent, the paper concluded.

The multi-institutional study was led by Vanderbilt University Medical Center (VUMC), VA Tennessee Valley Health Care System and the Million Veteran Program (MVP) of the US Department of Veterans Affairs, Emory University School of Medicine and Joseph Maxwell Cleland Atlanta VA The health care system.

“This discovery could lead to changes in the way diabetes is managed for millions of patients in the US and around the world,” said Todd Edwards, Ph.D., MS, co-corresponding author of the paper with Ayush Giri, Ph.D. . Both are VUMC faculty members affiliated with the VA Tennessee Valley Health Care System.

“More needs to be done, such as health economics and policy studies, and clinical trials, to establish how best to use this knowledge to prevent diabetes complications,” said Edwards, associate professor of Medicine. “Now that process can begin.”

More than 400 million people worldwide have G6PD deficiency. Although most MVP participants are men, millions of women are also at increased risk of diabetes complications if they carry one copy of the G6PDdef variant.

“While this discovery may impact how millions of individuals manage their diabetes, it also highlights the importance of including diverse populations in biomedical research,” said the paper’s first author, Joseph Breeyear, Ph.D., MS. , a postdoctoral researcher at the National Institute of Environmental Health Sciences of the National Institutes of Health (NIH).

“By including underrepresented individuals, we can identify genetic variations that influence health outcomes,” said Breeyear, who earned his Ph.D. in Human Genetics in the Edwards lab at VUMC in 2023.

Diabetic retinopathy, damage to the retinal blood vessels and nerves in the back of the eye that can cause permanent vision loss, has previously been linked to genetic variations called single nucleotide polymorphisms, or SNPs, but these links have been largely studied 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.

To better understand why some people with diabetes develop retinopathy but others do not, researchers conducted a combined genome-wide association study (GWAS) of more than 197,000 individuals with diabetes, including more than 68,000 who had also diabetic retinopathy.

The study was the largest pedigree-stratified, SNP-based assessment of the heritability of diabetic retinopathy performed to date and included an unprecedented number of individuals of non-Hispanic African descent—more than 46,000.

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

They also investigated the effect of G6PDdef on the risk of diabetes complications among participants in the NIH-sponsored Clinical Trial to Control Cardiovascular Risk in Diabetes (ACCORD), which assessed the impact of tight diabetes control on cardiovascular events in more than 10,000 adults with type 2 diabetes.

Their analysis found that individuals of non-Hispanic African descent with G6PDdef in the ACCORD trial had a significantly higher probability of two diabetes complications—diabetic retinopathy and diabetic nephropathy—compared to individuals without the variant, despite receiving standard-of-care treatment to reduce . HbA1c levels.

The current study uncovered nine previously unreported loci, or positions on chromosomes, that were associated with diabetic retinopathy, including an evolutionary adaptive genetic variant that may explain some of the racial disparities in diabetes complications.

The G6PDdef variant results in a lack of the enzyme glucose 6-phosphate dehydrogenase. Common only in Africans and some Asian populations, this genetic variation may have evolved as a defense against severe malaria.

It is associated with a shorter lifespan of red blood cells, which lowers HbA1c levels but not blood glucose levels. This “discrepancy” may mask the true extent of hyperglycemia: in individuals carrying the G6PDdef mutation, HbA1c levels systematically underestimate blood glucose levels.

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 descent in the United States who have diabetes may have some level of G6PD deficiency.

These numbers are broadly consistent with a previous study, which estimated that diabetes may be diagnosed late, or remain undiagnosed, in about 650,000 people of non-Hispanic African descent in the United States because of the G6PDdef variant.

“With comprehensive screening … and subsequent standard-of-care treatment, possibly targeting glucose rather than HbA1c targets, nearly 12% of diabetic retinopathy cases and 9% of diabetic neuropathy cases in individuals of non-Hispanic African descent could be avoided.” in the US alone,” the researchers concluded.

HbA1c works well as a marker for hyperglycemia in most people, but not as well in individuals with genetic disorders that affect enzyme function such as G6PD deficiency, noted Giri, assistant professor of Obstetrics and Gynecology at VUMC.

“If HbA1c wasn’t widely used for diabetes screening and management, we probably wouldn’t have observed such a finding,” he said.

Eighteen research groups, including six affiliated with the VA, contributed to the study.