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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.

TitleImpact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis.
Publication TypeJournal Article
Year of Publication2017
AuthorsWheeler E, Leong A, Liu C-T, et al.
Secondary AuthorsMeigs JB
Corporate AuthorsEPIC-CVD Consortium, EPIC-InterAct Consortium, LifeLines Cohort Study
JournalPLoS Med
Volume14
Issue9
Paginatione1002383
Date Published2017 Sep
ISSN1549-1676
KeywordsDiabetes Mellitus, Type 2, Genetic Variation, Genome-Wide Association Study, Glycated Hemoglobin A, Humans, Phenotype, Risk
Abstract

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.

DOI10.1371/journal.pmed.1002383
Alternate JournalPLoS Med
PubMed ID28898252
PubMed Central IDPMC5595282
Grant ListU01 HG007417 / HG / NHGRI NIH HHS / United States
MR/K002414/1 / / Medical Research Council / United Kingdom
R01 DK106236 / DK / NIDDK NIH HHS / United States
R01 DK089174 / DK / NIDDK NIH HHS / United States
MC_UU_12019/1 / / Medical Research Council / United Kingdom
UL1 TR000124 / TR / NCATS NIH HHS / United States
S10 OD018522 / OD / NIH HHS / United States
MC_UU_12015/1 / / Medical Research Council / United Kingdom
R01 HL105756 / HL / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
MC_UU_12015/2 / / Medical Research Council / United Kingdom
K24 DK106414 / DK / NIDDK NIH HHS / United States
K24 DK080140 / DK / NIDDK NIH HHS / United States
P30 DK020541 / DK / NIDDK NIH HHS / United States
UM1 CA182913 / CA / NCI NIH HHS / United States
U01 DK078616 / DK / NIDDK NIH HHS / United States
U01 DK062370 / DK / NIDDK NIH HHS / United States
MR/K013351/1 / / Medical Research Council / United Kingdom
P30 DK020572 / DK / NIDDK NIH HHS / United States
RG/14/5/30893 / / British Heart Foundation / United Kingdom
UL1 TR001881 / TR / NCATS NIH HHS / United States
G0601261 / / Medical Research Council / United Kingdom
U54 GM115428 / GM / NIGMS NIH HHS / United States
RG/10/12/28456 / / British Heart Foundation / United Kingdom