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Adaptive selection at G6PD and disparities in diabetes complications

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.

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Fig. 1: Manhattan plots of diabetic retinopathy genome-wide association studies by genetic ancestry.
Fig. 2: Box plots summarizing differences in HbA1c, plasma glucose and predicted HbA1c by G6PDdef status.
Fig. 3: Fitted log-odds of diabetic retinopathy by G6PDdef allele status.
Fig. 4: PheWAS plots summarizing the association of the G6PDdef risk allele with PheCodes in men with and without diabetes with NH-AFR ancestry.

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Data availability

The individual-level data from BioVU, MVP and MGBB are not able to be shared. Individual-level data from the UK Biobank are freely available to approved researchers. Individual-level phenotype data are also available to UK Biobank approved researchers for the health record datasets from which our trait of interest was derived. Instructions for access to UK Biobank data are available at https://www.ukbiobank.ac.uk/enable-your-research. The published article includes all significant results generated during this study. Summary statistics for genome-wide significant variants are available in the Supplementary Tables. Statistically significant reports for S-PrediXcan results for all tissues and PheWAS analyses are also available in the Supplementary Tables.

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Acknowledgements

This research is based on data from the Million Veteran Program, the Office of Research and Development and the Veterans Health Administration. This research was funded in part by the Extramural Research Programs of the NIH and in part by the Intramural Research Program of the National Institute of Environmental Health Sciences. This publication does not represent the views of the Department of Veterans Affairs or the US Government. Mass General Brigham Biobank provided samples, genomic data and health information data. Efforts were supported by the NEI (grant nos. F31 EY033663 (J.H.B.), T32 EY021453-10 (J.H.B.), R01 EY025295 (Y.S.), R01 EY032159 (Y.S.), P30 EY026877 (Y.S.), P30 EY025885 (N.S.P.), P30 EY011373 (S.K.I.)), the NICHD (grant no. K12 HD043483 (J.N.H.)), the NIAMS (grant nos. R01 AR074989 (A.G.), K12 AR084232-24 (T.L.E.)), the NIDDK (grant nos. R01 DK127083 (M.K.R.), R01 DK127083 (L.S.P.), K01 DK120631 (A.G.)), the NHLBI (grant nos. R01 HL110380 (J.B.B.), R01 HL161516 (A.G.)), the NIAID (grant no. R21 AI156161 (L.S.P.)), the NHGRI (grant nos. U01 HG011723 (J.M.M.), U01 HG011723 (A.L.)), the NCATS (grant nos. TL1 TR002244 (J.H.B.), UM1 TR00406 (J.B.B.), UL1 TR002378 (L.S.P.)), the NCCDPHP (grant no. U18 DP006711 (L.S.P.)), the VA Office of Research & Development (grant nos. CSP 2002 (M.K.R.), CSP 2008 (L.S.P.), I01 CX001899 (L.S.P.), I01 CX001737 (L.S.P.), I01 BX005831 (L.S.P.), IK6 BX005233 (N.S.P.), I01 BX004557 (N.S.P.), I01 CX001481 (Y.S.)), the Doris Duke Foundation (grant no. 2020096 (A.L.)), the American Diabetes Association (grant nos. 1-19-ICTS-068 (J.M.M.), 11-22-ICTSPM-16 (J.M.M.), 7-22-ICTSPM-23 (A.L.)), a Cystic Fibrosis Foundation Award (grant no. PHILLI12A0 (L.S.P.)), an Unrestricted Grant from Research to Prevent Blindness (Stanford University, Y.S.) and the Intramural Research Program of the National Institute of Environmental Health Sciences (J.H.B., J.S.H. and A.A.M.-R.).

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J.H.B., P.W.W., Y.V.S., A.G., L.S.P. and T.L.E. conceptualized the study. J.H.B., S.L.M., T.B.B., A.M.H., C.L.N., D.M.R., J.B.B., A.L., J.M.M., Y.V.S., A.G., L.S.P. and T.L.E. were responsible for the methodology. J.H.B., J.N.H., P.H.S., J.S.H. and H.M.P. performed the investigations. J.H.B., L.S.P. and T.L.E. wrote the original draft of the manuscript. J.H.B., J.N.H., J.S.H., S.L.M., T.B.B., P.D.R., J.B.M., M.K.R., Y.S., M.G.L., A.G.B., A.M.H., S.K.I., D.M.R., J.B.B., J.M.M., L.S., M.A.B., N.S.P., A.A.M.-R., P.W.W., Y.V.S., A.G., L.S.P. and T.L.E. reviewed and edited the manuscript. J.H.B., J.S.H. and A.G. performed visualizations. A.M.H., J.M.M., L.S., A.A.M.-R., Y.V.S., A.G., L.S.P. and T.L.E. were responsible for resources. B.C., A.K., C.W.H. and O.D.W. curated the data. P.W.W., Y.V.S., A.G., L.S.P. and T.L.E. supervised the study. P.W.W., Y.V.S., A.G., L.S.P. and T.L.E. were responsible for funding acquisition.

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Correspondence to Ayush Giri or Todd L. Edwards.

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L.S.P. declares that there is no duality of interest associated with this manuscript. With regard to potential conflicts of interest, L.S.P. has or had research support from Merck, Pfizer, Eli Lilly, Novo Nordisk, Sanofi, PhaseBio, Roche, Abbvie, Vascular Pharmaceuticals, Janssen, Glaxo SmithKline and the Cystic Fibrosis Foundation. L.S.P. is also a cofounder, Officer and Board member and stockholder for a company, Diasyst, Inc., which markets software aimed to help improve diabetes management. J.H.B., J.N.H., P.H.S., J.S.H., H.M.P., S.L.M., B.C., A.K., T.B.B., C.W.H., P.D.R., J.B.M., M.K.R., Y.S., M.G.L., A.G.B., O.D.W., A.M.H., C.L.N., S.K.I., D.M.R., J.B.B., A.L., J.M.M., L.S., M.A.B., N.S.P., A.A.M.-R., P.W.W., Y.V.S., A.G. and T.L.E. declare no conflict of interests.

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Extended data

Extended Data Fig. 1 Line graph summarizing the fitted log-odds of diabetic retinopathy and corresponding 95% confidence band by mean HbA1c post diabetes diagnosis, stratified by G6PDdef risk allele status in men of NH-AFR ancestry with diabetes.

(a) Line graph summarizing the fitted log-odds of diabetic retinopathy and corresponding 95% confidence band by mean HbA1c post diabetes diagnosis, stratified by G6PDdef risk allele status in men of NH-AFR ancestry with diabetes. The y-axis shows mean fitted log-odds of diabetic retinopathy, the x-axis shows HbA1c (%), the colored lines represent G6PDdef risk allele status, between the dotted lines represents 99% of the data. (b) The individual points used to calculate the fitted log-odds of diabetic retinopathy and corresponding 95% confidence band by mean HbA1c post diabetes diagnosis, stratified by G6PDdef risk allele status in men of NH-AFR ancestry with diabetes.

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Breeyear, J.H., Hellwege, J.N., Schroeder, P.H. et al. Adaptive selection at G6PD and disparities in diabetes complications. Nat Med (2024). https://doi.org/10.1038/s41591-024-03089-1

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