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

Abstract

BackgroundGlycated 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 & findingsUsing 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.ConclusionsAs 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, ...

A systematic review of non‐genetic predictors and genetic factors of glycated haemoglobin in type 1 diabetes one year after diagnosis

“…The two genes (SORCS1 and GSC) detected by GWAS were not replicated in 1486 T2D patients as part of the Norwegian population‐based cohort (HUNT2) . Several meta‐analysis or GWAS identified more than 60 SNPs associated with HbA1c level in non‐diabetic individuals in different cohorts from European, African, East Asian, and South Asian ancestry but have never been investigated in T1D patients. These loci were classified in three functional groups: glycaemic, erythrocytic, or unclassified function.…”

Mendelian Randomization Study of Obesity and Cerebrovascular Disease

“…Briefly, 317,195 individuals of European ancestry were included to generate summary level GWAS data for SBP corrected for the effects of antihypertensive treatment. European ancestry–specific genome‐wide meta‐analysis summary statistics for association with HbA1c and FG were available through the latest effort of the Meta‐Analyses of Glucose and Insulin‐Related Traits Consortium (MAGIC) . Genotyping and bioinformatic genetic analysis of each of these GWAS followed standardized procedures that are harmonized and comparable across the studies.…”

“…Genotyping and bioinformatic genetic analysis of each of these GWAS followed standardized procedures that are harmonized and comparable across the studies. Detailed genotype and phenotype assessment procedures have been previously published . Additional demographic and phenotypic information on the included studies is available in the Table.…”

2. Classification and Diagnosis of Diabetes:Standards of Medical Care in Diabetes—2018

“…Another genetic variant, X-linked glucose-6-phosphate dehydrogenase G202A, carried by 11% of African Americans, was associated with a decrease in A1C of about 0.8% in hemizygous men and 0.7% in homozygous women compared with those without the variant (12).…”