1333-P: A Mutation Causing Glucose-6-Phosphate Dehydrogenase Deficiency Increases the Risk of Diabetes Complications in Men with African Ancestry
Authors: BREEYEAR JOSEPH H. , HELLWEGE JACKLYN , HOUSE JOHN S. , MITCHELL SABRINA L. , CHAREST BRIAN , BASNET TIL B. , REAVEN PETER , MEIGS JAMES B. , RHEE MARY K. , SUN YANG , WILSON OTIS , HUNG ADRIANA M. , IYENGAR SUDHA K. , ROTROFF DANIEL M. , BUSE JOHN B. , LEONG AARON , MERCADER JOSEP M. , BRANTLEY MILAM , PEACHEY NEAL S. , MOTSINGER-REIF ALISON , WILSON PETER W. , SUN YAN , GIRI AYUSH , PHILLIPS LAWRENCE S. , EDWARDS TODD L. 
Published: June 2024

Prolonged hyperglycemia leads to diabetes complications, especially in individuals with African ancestry (AFR) - a health disparity. Glucose-6-phosphate dehydrogenase deficiency (G6PDd) disproportionately affects men with AFR ancestry (prevalence 9.5% vs. 2.2% in the US population) and shortens red cell lifespan, reducing HbA1c with no effect on glucose levels. We investigated whether men with AFR ancestry and G6PDd were at increased risk of diabetes complications. We performed a multi-ethnic genome-wide association study meta-analysis of diabetic retinopathy (DR) using the VA Million Veteran Program (MVP) dataset (nmax = 192,406) and studied clinical impact with the MVP and ACCORD trial datasets. Nine significant loci were associated with DR, including a causal variant for G6PDd [rs1050828-T, OR 1.48 (95% CI 1.45 - 1.51), p = 1.99x10-90)]. Plasma glucose was much higher in those with vs. without G6PDd in the year preceding diabetes diagnosis (168 vs. 137 mg/dL, respectively) and insulin prescription (253 vs. 233), both p &lt;0.001. In a Cox proportional hazards analysis, ACCORD participants with vs. without G6PDd had a higher likelihood of DR [HR 1.78 (1.55 - 2.04), p &lt;0.001] and neuropathy (HR 1.37 (1.23 - 1.54), p &lt;0.005]. A mediation analysis of G6PDd on DR showed that risk was fully attributable to higher glucose levels. In MVP participants, compared to those without G6PDd who were in the top two tertiles of HbA1c regressed onto plasma glucose, the risk of DR was increased with G6PDd (OR 1.40), but lower than the risk of DR in those without G6PDd who were in the lowest tertile of A1c vs. glucose (OR 1.61) - consistent with risk due to inadequate treatment rather than oxidative stress alone. Conclusions: Management based on both glucose and HbA1c, rather than HbA1c alone, might be needed to reduce diabetes complications in both individuals with African ancestry who have G6PDd, and other individuals with low HbA1c levels relative to their glucose levels.

Disclosure
J.H. Breeyear: None. J. Hellwege: None. J.S. House: None. S.L. Mitchell: None. B. Charest: None. T.B. Basnet: None. P. Reaven: Research Support; Dexcom, Inc. J.B. Meigs: None. M.K. Rhee: Research Support; Kowa Pharmaceuticals America, Inc. Y. Sun: None. O. Wilson: None. A.M. Hung: None. S.K. Iyengar: None. D.M. Rotroff: Consultant; Novo Nordisk. Research Support; Bayer Inc. J.B. Buse: Other Relationship; Novo Nordisk. Consultant; Corcept Therapeutics. Research Support; Corcept Therapeutics, Dexcom, Inc., Insulet Corporation. Consultant; Alkahest, Anji Pharmaceuticals, Aqua Medical, Altimmune Inc., AstraZeneca, Boehringer-Ingelheim, CeQur, Eli Lilly and Company, embecta, GentiBio, Glyscend Inc., Mellitus Health, Metsera, Pendulum Therapeutics, Praetego, LLC, Stability Health, Terns Pharmaceuticals, Insulet Corporation, Vertex Pharmaceuticals Incorporated, vTv Therapeutics. Other Relationship; Medtronic. Stock/Shareholder; Glyscend Inc., Mellitus Health, Pendulum Therapeutics, Praetego, LLC, Stability Health. A. Leong: Other Relationship; Merck & Co., Inc. J.M. Mercader: None. M. Brantley: None. N.S. Peachey: None. A. Motsinger-Reif: None. P.W. Wilson: None. Y. Sun: None. A. Giri: None. L.S. Phillips: Other Relationship; Diasyst, Inc. Research Support; Kowa Pharmaceuticals America, Inc., Janssen Pharmaceuticals, Inc., AbbVie Inc., Novo Nordisk, GlaxoSmithKline plc, Abbott, Sanofi-Aventis U.S., Pfizer Inc. T.L. Edwards: None.

Funding
NEI (F31EY033663, T32EY021453-10, R01EY025295, R01EY032159, P30-EY026877), NICHD (K12HD043483), NIAMS (K12AR084232-24), NIDDK (R01DK127083, K01DK120631, R21AI156161), NHGRI (U01HG011723, UL1TR002378)