CGM-A1c Genetics
GWAS have reported over 200 hemoglobin A1c (HbA1c)-associated genetic variants, the majority of which affect HbA1c levels independently of glucose. Individuals who carry these nonglycemic HbA1c variants may have undetected hyperglycemia if HbA1c is used to diagnose diabetes or estimate glycemic control.
Aims & Outcomes
Aims
- Estimate the effects of nonglycemic HbA1c variants on HbA1c-glucose discordance and glycated proteins, by assessing the difference between measured and predicted HbA1c using 10–14 days of continuous glucose monitoring, plus albumin and fructosamine measurements.
- Use recall-by-genotype for enriched recruitment of subjects with African or European ancestry.
Outcomes
- HbA1c correlated well with CGM glucose across genotype groups, but the relationship differed by G6PD genotype, polygenic score, and ancestry.
- HbA1c-glycemia discordance differed by polygenic score in European ancestry, and by G6PD carrier status in African ancestry.
- HbA1c and glycated albumin were higher in African ancestry vs. European ancestry despite similar CGM glucose — suggesting glycation propensity may differ by ancestry.
From a 200-variant discovery to a bedside regression equation.
Background: HbA1c is used to diagnose type 2 diabetes and monitor glycemic control; prior studies had linked 18 genetic variants to HbA1c, acting through either glycemic or erythrocytic (red blood cell) pathways.
Methods & findings: A transethnic GWAS meta-analysis of up to 159,940 individuals across four ancestries identified 60 HbA1c-associated variants (42 novel), classified as glycemic, erythrocytic, or unclassified. Glycemic-variant scores predicted incident type 2 diabetes; erythrocytic-variant scores did not. In African Americans specifically, the X-linked G6PD G202A variant lowered measured HbA1c independent of true glycemia, an effect estimated to leave roughly 2% of African American adults with diabetes undiagnosed by HbA1c-based screening.
Conclusions: The authors recommend considering G6PD genotype, or genetically-informed HbA1c thresholds, alongside HbA1c-based diagnosis in populations where G6PD deficiency is common.
Introduction: The aggregate effect of genetic variants that lower HbA1c independently of glycemia, by ancestry, had not been established.
Methods: 177 patients were recalled from the Mass General Brigham Biobank, enriching recruitment for carriers of the African-ancestry G6PD variant (rs1050828), the alpha-thalassemia 3.7kb deletion, and individuals at the tails of a European polygenic score built from HbA1c variants that act independently of glucose. Participants underwent 14 days of continuous glucose monitoring.
Conclusions: HbA1c remained a good proxy for glycemia across groups overall, but the HbA1c-glucose relationship differed by genotype and ancestry — supporting the case for considering genetic variation to promote care equity and avoid misestimating glycemia from HbA1c in diverse populations.
Introduction and Objective: HbA1c is the primary clinical measure of average glucose. The X-linked G6PD variant is associated with lower HbA1c but higher complication risk, and the extent to which it affects the HbA1c-glucose relationship, potentially leading to undetected hyperglycemia, had been unclear.
Methods: Within the GRADE Study, 1,287 participants with type 2 diabetes, including 303 non-Hispanic Black participants, underwent 10 days of continuous glucose monitoring followed by HbA1c and glycated albumin measurement.
Findings: The relationship between average glucose and HbA1c differed by G6PD genotype and race, replicating the discordance pattern in an independent, larger clinical trial cohort.
Objective: Individuals who carry genetic variants that lower HbA1c independently of glycemia may have higher real, but undetected, hyperglycemia despite achieving similar HbA1c targets, potentially raising their risk of diabetes-related complications.
Research Design and Methods: Using data from 29,828 people with type 2 diabetes of African American/African British and European ancestries, a nonglycemic HbA1c polygenic score was tested for association with retinopathy, adjusting for measured HbA1c and other risk factors.
Results: Individuals in the bottom quintile of the nonglycemic polygenic score had 20–50% higher retinopathy prevalence than those above it, despite similar measured HbA1c, in both ancestries.
Conclusions: Genetic effects on HbA1c need to be considered to personalize HbA1c targets and improve outcomes for people with diabetes across diverse ancestries.