ArticleNature medicine2024
Adaptive selection at G6PD and disparities in diabetes complications.
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Article in Nature medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers, 1 of them a synthesis that pooled it.
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21citing papers in PubMed, 1 pooled it
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Who cites it
21 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Pan-UK Biobank genome-wide association analyses enhance discovery and resolution of ancestry-enriched effects.Nature genetics · 2025Pooled it
- Disentangling Sex Differences in Sulfonylurea Drug Response With Genome-Wide Association Studies in Individuals With Type 2 Diabetes.Clinical pharmacology and therapeutics · 2026Article
- The shape of fitness functions and the distribution of mutational effect sizes jointly limit adaptation by regulatory mutations.Nature ecology & evolution · 2026Article
- Evidence for G6PD variant classification from multiplexed functional assays.Genome biology · 2026Article
- Higher diabetes genetic load in proliferative diabetic retinopathy in South India: The South Indian GeNetics of DiAbeTic Retinopathy (SIGNATR) study.Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie · 2026Article
- Insights into the genetic aetiology of diabetes in Africa.EBioMedicine · 2026Review
- Clinical trial landscape of diabetic retinopathy: global advancements and future directions.International journal of surgery (London, England) · 2026Article
- Article
- Linking the plasma proteome to genetics in individuals from continental Africa provides insights into type 2 diabetes pathogenesis.Nature genetics · 2026Article
- Genome sequencing of 35,024 predominantly African ancestry persons addresses gaps in genomics and healthcare.medRxiv : the preprint server for health sciences · 2025Article
- Undiagnosed G6PD Deficiency in Black and Asian Individuals Is Prevalent and Contributes to Health Inequalities in Type 2 Diabetes Diagnosis and Complications.Diabetes care · 2025Article
- Diabetic retinal disease.Nature reviews. Disease primers · 2025Review
- Phenotypic and Genetic Diversity in Diabetes Across Populations.The Journal of clinical endocrinology and metabolism · 2025Review
- Bench to all Bedsides in Genomics and Precision Medicine.Journal of the American Heart Association · 2025Article
- Expanding scope of genetic studies in the era of biobanks.Human molecular genetics · 2025Article
- Insights into the molecular underpinning of type 2 diabetes complications.Human molecular genetics · 2025Review
- Enhancing NADPH to restore redox homeostasis and lysosomal function in G6PD-deficient microglia.Heliyon · 2025Article
- A clinical algorithm to identify people with the glucose-6-phosphate dehydrogenase p.Val68Met variant at risk for diabetes undertreatment.Genetics in medicine open · 2025Article
- Development of electronic health record based algorithms to identify individuals with diabetic retinopathy.Journal of the American Medical Informatics Association : JAMIA · 2024Article
- Unveiling the Predictive Model for Macrovascular Complications in Type 2 Diabetes Mellitus: microRNAs Expression, Lipid Profile, and Oxidative Stress Markers.International journal of molecular sciences · 2024Article
Corrections and comments
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Authors and funding
34 authors.
Joseph H BreeyearBiostatistics and Computational Biology Branch, Division of Intramural Research, National Institute of Environmental Health Sciences, Durham, NC, USA.ORCID http://orcid.org/0000-0002-6179-0515
Jacklyn N HellwegeVA Tennessee Valley Healthcare System (626), Nashville, TN, USA.ORCID http://orcid.org/0000-0001-7479-0920
Philip H SchroederProgram in Metabolism, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
John S HouseBiostatistics and Computational Biology Branch, Division of Intramural Research, National Institute of Environmental Health Sciences, Durham, NC, USA.ORCID http://orcid.org/0000-0002-8447-7871
Hannah M PoisnerVanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA.ORCID http://orcid.org/0000-0003-1652-3642
Sabrina L MitchellVA Tennessee Valley Healthcare System (626), Nashville, TN, USA.
Brian CharestMassachusetts Veterans Epidemiology Research and Information Center, Boston, MA, USA.
Anjali KhakhariaAtlanta VA Medical Center, Decatur, GA, USA.
Til B BasnetDivision of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Christopher W HalladayProvidence VA Medical Center, Providence, RI, USA.
Peter D ReavenPhoenix VA Health Care System, Phoenix, AZ, USA.ORCID http://orcid.org/0000-0001-8923-6690
James B MeigsProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Mary K RheeAtlanta VA Medical Center, Decatur, GA, USA.
Yang SunDepartment of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA, USA.
Mary G LynchAtlanta VA Medical Center, Decatur, GA, USA.
Alexander G BickDivision of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.ORCID http://orcid.org/0000-0001-5824-9595
Otis D WilsonVA Tennessee Valley Healthcare System (626), Nashville, TN, USA.
Adriana M HungVA Tennessee Valley Healthcare System (626), Nashville, TN, USA.
Cari L NealonEye Clinic, VA Northeast Ohio Healthcare System, Cleveland, OH, USA.
Sudha K IyengarResearch Service, VA Northeast Ohio Healthcare System, Cleveland, OH, USA.ORCID http://orcid.org/0000-0001-7488-250X
Daniel M RotroffDepartment of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
John B BuseDivision of Endocrinology & Metabolism, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0002-9723-3876
Aaron LeongProgram in Metabolism, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Josep M MercaderProgram in Metabolism, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0001-8494-3660
Lucia SobrinDepartment of Ophthalmology, Mass Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
Milam A BrantleyVA Tennessee Valley Healthcare System (626), Nashville, TN, USA.
Neal S PeacheyResearch Service, VA Northeast Ohio Healthcare System, Cleveland, OH, USA.ORCID http://orcid.org/0000-0002-4419-7226
Alison A Motsinger-ReifBiostatistics and Computational Biology Branch, Division of Intramural Research, National Institute of Environmental Health Sciences, Durham, NC, USA.
Peter W WilsonAtlanta VA Medical Center, Decatur, GA, USA.
Yan V SunAtlanta VA Medical Center, Decatur, GA, USA.ORCID http://orcid.org/0000-0002-2838-1824
VA Million Veteran Program
Ayush GiriVA Tennessee Valley Healthcare System (626), Nashville, TN, USA. ayush.giri@vumc.org.ORCID http://orcid.org/0000-0002-7786-4670
Lawrence S PhillipsAtlanta VA Medical Center, Decatur, GA, USA.ORCID http://orcid.org/0000-0002-6542-8046
Todd L EdwardsDivision of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. todd.l.edwards@vumc.org.ORCID http://orcid.org/0000-0003-4318-6119
Funding
Implementing a Maternal health and PRegnancy Outcomes Vision for Everyone (IMPROVE)UL1TR002378 · NCATS · EMORY UNIVERSITY · PI Andres J Garcia, Elizabeth O. Ofili · 2017 to 2026
$92.1MNorth Carolina Translational and Clinical Sciences Institute (NC TraCS)UM1TR004406 · NCATS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI NICHOLAS J SHAHEEN · 2023 to 2026
$37.5MTISSUE CULTURE AND HYBRIDOMA MODULEP30EY011373 · NEI · CASE WESTERN RESERVE UNIVERSITY · PI Irina A Pikuleva · 1997 to 2026
$17.7MBuilding Interdisciplinary Research Careers in Women's HealthK12HD043483 · NICHD · VANDERBILT UNIVERSITY MEDICAL CENTER · PI HARTMANN, KATHERINE E, MAJOR, AMY S · 2002 to 2023
$10.3MStanford Vision Research CoreP30EY026877 · NEI · STANFORD UNIVERSITY · PI Jeffrey L Goldberg · 2017 to 2026
$8.0MRESOURCE/SERVICE CORE C - MOLECULAR INFORMATICS MODULEP30EY025585 · NEI · CLEVELAND CLINIC LERNER COM-CWRU · PI BELA ANAND-APTE · 2016 to 2026
$7.7MDevelopment of Polygenic Risk Scores for Diabetes and Complications across the Life-Span in Populations of Multiple AncestriesU01HG011723 · NHGRI · BROAD INSTITUTE, INC. · PI Alisa Knodle Manning, Josep Maria Mercader · 2021 to 2026
$5.7MNRSA Training CoreTL1TR002244 · NCATS · VANDERBILT UNIVERSITY MEDICAL CENTER · PI Julie A. Bastarache · 2017 to 2026
$4.6MTOPMed Omics of Type 2 Diabetes and Quantitative TraitsUM1DK078616 · NIDDK · MASSACHUSETTS GENERAL HOSPITAL · PI MANNING, ALISA KNODLE · 2021 to 2025
$3.8MThe Genetic Epidemiology of Rotator Cuff Tears: the cuffGEN Study - SupplementR01AR074989 · NIAMS · UT SOUTHWESTERN MEDICAL CENTER · PI JAIN, NITIN B · 2020 to 2025
$3.6MThe role of primary cilia in glaucoma pathogenesisR01EY025295 · NEI · STANFORD UNIVERSITY · PI Yang Sun · 2016 to 2026
$3.5MUnderstanding causal mechanisms in preeclampsia through genetic instrumental variablesR01HL161516 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI Ayush Giri · 2022 to 2026
$3.2MACL HHS U18DP006711BLRD VA I01 BX004557BLRD VA I01 BX005831BLRD VA IK6 BX005233CSRD VA I01 CX001481CSRD VA I01 CX001737CSRD VA I01 CX001897Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID) R21AI156161NCATS NIH HHS TL1 TR002244NCATS NIH HHS UL1 TR002378NCATS NIH HHS UM1 TR004406NCCDPHP CDC HHS U18 DP006711NEI NIH HHS F31 EY033663NEI NIH HHS P30 EY011373NEI NIH HHS P30 EY025585NEI NIH HHS P30 EY026877NEI NIH HHS R01 EY025295NEI NIH HHS R01 EY032159NEI NIH HHS R01 EY036685NEI NIH HHS T32 EY021453NHGRI NIH HHS U01 HG011723NHLBI NIH HHS R01 HL110380NHLBI NIH HHS R01 HL161516NIAID NIH HHS R21 AI156161NIAMS NIH HHS K12 AR084232NIAMS NIH HHS R01 AR074989NICHD NIH HHS K12 HD043483NIDDK NIH HHS K01 DK120631NIDDK NIH HHS R01 DK127083NIDDK NIH HHS UM1 DK078616U.S. Department of Health & Human Services | CDC | National Center for Chronic Disease Prevention and Health Promotion (CDC's National Center for Chronic Disease Prevention and Health Promotion) U18DP006711U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) K12HD043483U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS) TL1TR002244U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS) UL1TR002378U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS) UM1TR00406U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI) F31EY033663U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI) P30EY011373U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI) P30EY025885U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI) P30EY026877U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI) R01EY025295U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI) R01EY032159U.S. Department of Health & Human Services | NIH | National Eye Institute (NEI) T32 EY021453-10U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) R01HL161516U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI) U01HG011723U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) R01AR074989U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases) K01DK120631U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases) R01DK127083
Abstract
Diabetes complications occur at higher rates in individuals of African ancestry. Glucose-6-phosphate dehydrogenase deficiency (G6PDdef), common in some African populations, confers malaria resistance, and reduces hemoglobin A1c (HbA1c) levels by shortening erythrocyte lifespan. In a combined-ancestry genome-wide association study of diabetic retinopathy, we identified nine loci including a G6PDdef causal variant, rs1050828 -T (Val98Met), which was also associated with increased risk of other diabetes complications. The effect of rs1050828 -T on retinopathy was fully mediated by glucose levels. In the years preceding diabetes diagnosis and insulin prescription, glucose levels were significantly higher and HbA1c significantly lower in those with versus without G6PDdef. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, participants with G6PDdef had significantly higher hazards of incident retinopathy and neuropathy. At the same HbA1c levels, G6PDdef participants in both ACCORD and the Million Veteran Program had significantly increased risk of retinopathy. We estimate that 12% and 9% of diabetic retinopathy and neuropathy cases, respectively, in participants of African ancestry are due to this exposure. Across continentally defined ancestral populations, the differences in frequency of rs1050828 -T and other G6PDdef alleles contribute to disparities in diabetes complications. Diabetes management guided by glucose or potentially genotype-adjusted HbA1c levels could lead to more timely diagnoses and appropriate intensification of therapy, decreasing the risk of diabetes complications in patients with G6PDdef alleles.
Indexed as
Diabetes ComplicationsDiabetic RetinopathyGenome-Wide Association StudyGlucosephosphate DehydrogenaseGlucosephosphate Dehydrogenase DeficiencyBlack PeopleBlood GlucoseFemaleGlycated HemoglobinHumansMaleMiddle AgedPolymorphism, Single NucleotideBlood GlucoseG6PD protein, humanGlucosephosphate DehydrogenaseGlycated Hemoglobin
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