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

• Medical Terminologies

  This document provides a comprehensive list of medical terms related to patient statuses, conditions, tools, procedures, and commonly used prefixes in medical terminology. It serves as a reference for understanding various medical concepts and their meanings.

• Absolutely. I based this on the 4th edition of Essentials of

  Absolutely. I based this on the 4th edition of Essentials of Nursing Informatics that you uploaded. The book identifies Chapter 17 as “Theories, Models, and Frameworks” and Chapter 32 as “The Nursing

• Anatomy and Physiology of the Respiratory System

  This document provides a detailed overview of the anatomy and functions of the respiratory system, including structures, gas exchange mechanisms, and respiratory physiology. It covers both upper and lower respiratory tract components, physiological processes involved in breathing, and the impacts of various factors on respiratory health.

• Blood Vessels and Circulatory System Functions

  This document provides an extensive overview of blood vessel functions, classifications, structures, and the circulatory system's physiology. It details systemic and pulmonary circulation, highlighting the anatomy and roles of various arteries and veins.

• Functions and Anatomy of the Lymphatic and Immune Systems

  This document provides an overview of the lymphatic system's functions, anatomy, and its role in immunity, detailing structures such as lymphatic vessels, nodes, and organs. It also covers innate and adaptive immunity, including responses to foreign substances and the production of immune cells.