Non-glycemic genetic effects on HbA1c and clinical glycemic status in African ancestry: VA Million Veteran Program

ABSTRACT IMPORTANCE Clinical guidelines recommend against using glycated hemoglobin A1c (HbA1c) to assess glycemia in patients with two erythropoietic conditions: glucose-6-phosphate dehydrogenase (G6PD) deficiency or sickle cell disease. What remains elusive is quantifying the impact of genetic variants underlying these and other erythropoietic conditions on HbA1c levels as a clinical indicator of glycemic status. OBJECTIVE To evaluate the impact of five erythropoietic (non-glycemic) genetic variants on HbA1c levels as a clinical indicator of glycemic status in a population with African genetic ancestry. DESIGN Retrospective cohort study conducted January 2011 to November 2022. SETTING Veterans Health Administration’s (VHA’s) Million Veteran Program (MVP), a genetic biobank representative of the U.S.’s largest integrated healthcare system, including the longest-running electronic health record system. PARTICIPANTS 84,987 MVP participants with African genetic ancestry, excluding those with type 1 or secondary diabetes or G6PD, sickle cell, or other erythropoietic conditions. EXPOSURE Any one of five erythropoietic genetic variants known or suspected to affect HbA1c levels in African ancestry. MAIN OUTCOMES AND MEASURES Clinically measured HbA1c, random blood glucose, triglyceride to HDL-cholesterol ratio, body mass index, blood pressure, diagnosis of and medications for type 2 diabetes (T2D). RESULTS All the variants had significant differences in HbA1c compared to non-carriers with the same sex, age, glucose and BMI. Males with X-linked G202A variant for G6PD deficiency (11% of males in cohort) had HbA1c levels reduced by 0.8 percentage points compared to non-carriers; female carriers had reductions over 0.3 percentage points. Overall, G202A carriers had worse dysglycemia but were less likely to be diagnosed with or prescribed medication for dysglycemia than non-carriers. Due to this variant, an estimated 1.5 million (6%) African American adults without T2D may have dysglycemia in the pre-diabetes or T2D range, but their HbA1c indicate normoglycemia. CONCLUSIONS AND RELEVANCE By lowering HbA1c without lowering glucose level, G202A variant for G6PD deficiency—a condition common to African ancestry and largely asymptomatic and undiagnosed—could be misguiding clinical management for 9% of African American Veterans without T2D and 6% of African American adults without T2D in the U.S. and contributing to racial disparities in T2D management. KEY POINTS QUESTION What is the impact of non-glycemic genetic variants on HbA1c levels as a clinical indicator of glycemic status? FINDINGS In patients with African ancestry within a U.S. healthcare setting, carriers of G202A variant for glucose-6-phosphate dehydrogenase (G6PD) deficiency have significantly lower HbA1c—0.9% points in males—and lower rates of type 2 diabetes diagnosis and medication but higher glucose compared to non-carriers. Four additional erythropoietic variants also had significant effects on HbA1c but none on glucose. MEANING HbA1c can underestimate dysglycemia in carriers of G202A variant, which is common in African, and very rare in European, ancestry.