Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis

Summary

Background Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes. Methods & findings Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04–1.06, per HbA1c-raising allele, p = 3 × 10−29); whereas GS-E was not (OR = 1.00, 95% CI 0.99–1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66–0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38–0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55–0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants. Conclusions As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

Key Points

• 1Sixty common genetic variants associated with HbA1c were identified across diverse ancestries
• 2Glycemic variants increased diabetes risk, whereas erythrocytic variants did not
• 3The glucose-6-phosphate dehydrogenase variant affects HbA1c levels in African Americans
• 4Failure to consider genetic factors may lead to undiagnosed diabetes in certain populations
• 5The study suggests improved screening strategies for individuals with specific genetic backgrounds.

Related articles

• How to Assess the Quality of Qualitative Research

  This article serves as a guide for health care practitioners, educators, and researchers on how to evaluate the quality of qualitative research. It discusses essential characteristics that make a qualitative study high-quality and trustworthy, as well as standards specific to this type of research.

• CHOLEGRAPHY Easy Visual Reviewer - Terms & Definitions Matrix Based on Module

  This document serves as an educational resource on cholegraphy, outlining procedures, indications, contraindications, and care related to the imaging of the biliary system. It is designed as a visual reviewer for learners in health sciences.

• Routine CT Procedures and Related Anatomy Visual Study Reviewer Matrix

  This document serves as a comprehensive reviewer for technologists involved in routine CT examinations, detailing essential procedures, patient preparations, and anatomical landmarks essential for accurate imaging.

• Investigating Genetic Counselors' Inclusion of Sponsored Genetic Testing Programs

  This study aims to investigate genetic counselors' awareness and attitudes toward sponsored genetic testing programs, as well as the factors influencing their decisions to offer these tests to patients. The importance of understanding these dynamics arises amid the growing availability of biopharmaceutical-sponsored genetic tests and the impact of financial considerations on patient access to care.

• Nature-Based Mindfulness: A Qualitative Study of the Experience of Support for Self-Regulation

  This qualitative study investigates how a five-day residential mindfulness program in a natural setting supports self-regulation among university students experiencing stress. Through interviews, the study explores participants' lived experiences and the perceived benefits of the mindfulness retreat.