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
Publication Date
September 12, 2017
Journal
PLOS Medicine
Authors
Eleanor Wheeler, Aaron Leong, Ching-Ti Liu, Marie-France Hivert, et al
Volume
14
Issue
9
Pages
e1002383
DOI
https://dx.plos.org/10.1371/journal.pmed.1002383
Publisher URL
http://journals.plos.org/plosmedicine/article?id=10.1371%2Fjournal.pmed.1002383
Scopus
85029711090
Mendeley
http://www.mendeley.com/research/impact-common-genetic-determinants-hemoglobin-a1c-type-2-diabetes-risk-diagnosis-ancestrally-diverse
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Shyong", "last_name"=>"Tai", "scopus_author_id"=>"7005660980"}, {"first_name"=>"Elizabeth", "last_name"=>"Selvin", "scopus_author_id"=>"6602453920"}, {"first_name"=>"Jerome I.", "last_name"=>"Rotter", "scopus_author_id"=>"56284453500"}, {"first_name"=>"Claudia", "last_name"=>"Langenberg", "scopus_author_id"=>"9938997700"}, {"first_name"=>"Inês", "last_name"=>"Barroso", "scopus_author_id"=>"57193022162"}, {"first_name"=>"James B.", "last_name"=>"Meigs", "scopus_author_id"=>"7006125159"}], "year"=>2017, "source"=>"PLoS Medicine", "identifiers"=>{"pui"=>"618522866", "pmid"=>"28898252", "doi"=>"10.1371/journal.pmed.1002383", "issn"=>"15491676", "scopus"=>"2-s2.0-85029711090", "sgr"=>"85029711090", "isbn"=>"1111111111"}, "id"=>"b6e3e64d-af25-3677-a8c9-3dfb99270fce", "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.", "link"=>"http://www.mendeley.com/research/impact-common-genetic-determinants-hemoglobin-a1c-type-2-diabetes-risk-diagnosis-ancestrally-diverse", "reader_count"=>103, "reader_count_by_academic_status"=>{"Unspecified"=>8, "Professor > Associate Professor"=>5, "Librarian"=>4, "Student > Doctoral Student"=>5, "Researcher"=>34, "Student > Ph. D. Student"=>9, "Student > Postgraduate"=>5, "Other"=>9, "Student > Master"=>9, "Student > Bachelor"=>4, "Lecturer"=>1, "Lecturer > Senior Lecturer"=>2, "Professor"=>8}, "reader_count_by_user_role"=>{"Unspecified"=>8, "Professor > Associate Professor"=>5, "Librarian"=>4, "Student > Doctoral Student"=>5, "Researcher"=>34, "Student > Ph. D. Student"=>9, "Student > Postgraduate"=>5, "Other"=>9, "Student > Master"=>9, "Student > Bachelor"=>4, "Lecturer"=>1, "Lecturer > Senior Lecturer"=>2, "Professor"=>8}, "reader_count_by_subject_area"=>{"Unspecified"=>23, "Environmental Science"=>1, "Biochemistry, Genetics and Molecular Biology"=>14, "Nursing and Health Professions"=>3, "Mathematics"=>2, "Medicine and Dentistry"=>33, "Agricultural and Biological Sciences"=>17, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Psychology"=>1, "Social Sciences"=>2, "Economics, Econometrics and Finance"=>1, "Energy"=>1, "Immunology and Microbiology"=>1, "Linguistics"=>1, "Neuroscience"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>33}, "Social Sciences"=>{"Social Sciences"=>2}, "Psychology"=>{"Psychology"=>1}, "Mathematics"=>{"Mathematics"=>2}, "Unspecified"=>{"Unspecified"=>23}, "Environmental Science"=>{"Environmental Science"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}, "Neuroscience"=>{"Neuroscience"=>2}, "Energy"=>{"Energy"=>1}, "Economics, Econometrics and Finance"=>{"Economics, Econometrics and Finance"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>17}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>3}, "Linguistics"=>{"Linguistics"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>14}}, "group_count"=>8}
CrossRef 8129 Mar 19:10 UTC

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Scopus 7509 Mar 16:08 UTC

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