Adaptive selection at G6PD and disparities in diabetes complications
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-ancestr...
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| Veröffentlicht in: | Nature medicine 2024-09, Vol.30 (9), p.2480-2488 |
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| creator | Breeyear, Joseph H. Hellwege, Jacklyn N. Schroeder, Philip H. House, John S. Poisner, Hannah M. Mitchell, Sabrina L. Charest, Brian Khakharia, Anjali Basnet, Til B. Halladay, Christopher W. Reaven, Peter D. Meigs, James B. Rhee, Mary K. Sun, Yang Lynch, Mary G. Bick, Alexander G. Wilson, Otis D. Hung, Adriana M. Nealon, Cari L. Iyengar, Sudha K. Rotroff, Daniel M. Buse, John B. Leong, Aaron Mercader, Josep M. Sobrin, Lucia Brantley, Milam A. Peachey, Neal S. Motsinger-Reif, Alison A. Wilson, Peter W. Sun, Yan V. Giri, Ayush Phillips, Lawrence S. Edwards, Todd L. |
| description | 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.
A combined-ancestry GWAS of diabetic retinopathy, comprising 68,169 cases and 129,188 controls, revealed nine previously unreported loci associated with the condition, including an evolutionarily adaptive genetic variant alongside a potential functional mechanism that influences racial disparities in diabetes complications among individuals of non-Hispanic African ancestry. |
| doi_str_mv | 10.1038/s41591-024-03089-1 |
| format | Article |
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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.
A combined-ancestry GWAS of diabetic retinopathy, comprising 68,169 cases and 129,188 controls, revealed nine previously unreported loci associated with the condition, including an evolutionarily adaptive genetic variant alongside a potential functional mechanism that influences racial disparities in diabetes complications among individuals of non-Hispanic African ancestry.</description><identifier>ISSN: 1078-8956</identifier><identifier>ISSN: 1546-170X</identifier><identifier>EISSN: 1546-170X</identifier><identifier>DOI: 10.1038/s41591-024-03089-1</identifier><identifier>PMID: 38918629</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>631/208 ; 692/163/2743/137/138 ; Alleles ; Biomedical and Life Sciences ; Biomedicine ; Black People - genetics ; Blood Glucose - metabolism ; Cancer Research ; Cardiovascular diseases ; Cardiovascular system ; Diabetes ; Diabetes Complications - epidemiology ; Diabetes Complications - genetics ; Diabetes mellitus ; Diabetic neuropathy ; Diabetic retinopathy ; Diabetic Retinopathy - epidemiology ; Diabetic Retinopathy - genetics ; Female ; Gene frequency ; Genetic diversity ; Genetic variance ; Genome-wide association studies ; Genome-Wide Association Study ; Genotypes ; Glucose ; Glucose 6 phosphate dehydrogenase ; Glucosephosphate dehydrogenase ; Glucosephosphate Dehydrogenase - genetics ; Glucosephosphate Dehydrogenase Deficiency - complications ; Glucosephosphate Dehydrogenase Deficiency - epidemiology ; Glucosephosphate Dehydrogenase Deficiency - genetics ; Glycated Hemoglobin - metabolism ; Health risks ; Hemoglobin ; Humans ; Infectious Diseases ; Life span ; Malaria ; Male ; Metabolic Diseases ; Middle Aged ; Molecular Medicine ; Neuropathy ; Neurosciences ; Polymorphism, Single Nucleotide ; Population genetics ; Populations ; Race factors ; Retinopathy ; Vector-borne diseases</subject><ispartof>Nature medicine, 2024-09, Vol.30 (9), p.2480-2488</ispartof><rights>The Author(s), under exclusive licence to Springer Nature America, Inc. 2024. 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The Author(s), under exclusive licence to Springer Nature America, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c256t-37a5897d9562d775b84d3a3505e94dec810d0bf657f5a6a610cec8e6ba9987d63</cites><orcidid>0000-0001-8494-3660 ; 0000-0001-7479-0920 ; 0000-0002-2838-1824 ; 0000-0002-6542-8046 ; 0000-0002-6179-0515 ; 0000-0003-4318-6119 ; 0000-0002-7786-4670 ; 0000-0003-1652-3642 ; 0000-0002-8447-7871 ; 0000-0002-9723-3876 ; 0000-0001-7488-250X ; 0000-0002-4419-7226 ; 0000-0001-5824-9595 ; 0000-0001-8923-6690</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41591-024-03089-1$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41591-024-03089-1$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,777,781,27905,27906,41469,42538,51300</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38918629$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Breeyear, Joseph H.</creatorcontrib><creatorcontrib>Hellwege, Jacklyn N.</creatorcontrib><creatorcontrib>Schroeder, Philip H.</creatorcontrib><creatorcontrib>House, John S.</creatorcontrib><creatorcontrib>Poisner, Hannah M.</creatorcontrib><creatorcontrib>Mitchell, Sabrina L.</creatorcontrib><creatorcontrib>Charest, Brian</creatorcontrib><creatorcontrib>Khakharia, Anjali</creatorcontrib><creatorcontrib>Basnet, Til B.</creatorcontrib><creatorcontrib>Halladay, Christopher W.</creatorcontrib><creatorcontrib>Reaven, Peter D.</creatorcontrib><creatorcontrib>Meigs, James B.</creatorcontrib><creatorcontrib>Rhee, Mary K.</creatorcontrib><creatorcontrib>Sun, Yang</creatorcontrib><creatorcontrib>Lynch, Mary G.</creatorcontrib><creatorcontrib>Bick, Alexander G.</creatorcontrib><creatorcontrib>Wilson, Otis D.</creatorcontrib><creatorcontrib>Hung, Adriana M.</creatorcontrib><creatorcontrib>Nealon, Cari L.</creatorcontrib><creatorcontrib>Iyengar, Sudha K.</creatorcontrib><creatorcontrib>Rotroff, Daniel M.</creatorcontrib><creatorcontrib>Buse, John B.</creatorcontrib><creatorcontrib>Leong, Aaron</creatorcontrib><creatorcontrib>Mercader, Josep M.</creatorcontrib><creatorcontrib>Sobrin, Lucia</creatorcontrib><creatorcontrib>Brantley, Milam A.</creatorcontrib><creatorcontrib>Peachey, Neal S.</creatorcontrib><creatorcontrib>Motsinger-Reif, Alison A.</creatorcontrib><creatorcontrib>Wilson, Peter W.</creatorcontrib><creatorcontrib>Sun, Yan V.</creatorcontrib><creatorcontrib>Giri, Ayush</creatorcontrib><creatorcontrib>Phillips, Lawrence S.</creatorcontrib><creatorcontrib>Edwards, Todd L.</creatorcontrib><creatorcontrib>VA Million Veteran Program</creatorcontrib><title>Adaptive selection at G6PD and disparities in diabetes complications</title><title>Nature medicine</title><addtitle>Nat Med</addtitle><addtitle>Nat Med</addtitle><description>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.
A combined-ancestry GWAS of diabetic retinopathy, comprising 68,169 cases and 129,188 controls, revealed nine previously unreported loci associated with the condition, including an evolutionarily adaptive genetic variant alongside a potential functional mechanism that influences racial disparities in diabetes complications among individuals of non-Hispanic African ancestry.</description><subject>631/208</subject><subject>692/163/2743/137/138</subject><subject>Alleles</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Black People - genetics</subject><subject>Blood Glucose - metabolism</subject><subject>Cancer Research</subject><subject>Cardiovascular diseases</subject><subject>Cardiovascular system</subject><subject>Diabetes</subject><subject>Diabetes Complications - epidemiology</subject><subject>Diabetes Complications - genetics</subject><subject>Diabetes mellitus</subject><subject>Diabetic neuropathy</subject><subject>Diabetic 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span</subject><subject>Malaria</subject><subject>Male</subject><subject>Metabolic Diseases</subject><subject>Middle Aged</subject><subject>Molecular Medicine</subject><subject>Neuropathy</subject><subject>Neurosciences</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Population genetics</subject><subject>Populations</subject><subject>Race factors</subject><subject>Retinopathy</subject><subject>Vector-borne 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(Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Nature medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Breeyear, Joseph H.</au><au>Hellwege, Jacklyn N.</au><au>Schroeder, Philip H.</au><au>House, John S.</au><au>Poisner, Hannah M.</au><au>Mitchell, Sabrina L.</au><au>Charest, Brian</au><au>Khakharia, Anjali</au><au>Basnet, Til B.</au><au>Halladay, Christopher W.</au><au>Reaven, Peter D.</au><au>Meigs, James B.</au><au>Rhee, Mary K.</au><au>Sun, Yang</au><au>Lynch, Mary G.</au><au>Bick, Alexander G.</au><au>Wilson, Otis D.</au><au>Hung, Adriana M.</au><au>Nealon, Cari L.</au><au>Iyengar, Sudha K.</au><au>Rotroff, Daniel M.</au><au>Buse, John B.</au><au>Leong, Aaron</au><au>Mercader, Josep M.</au><au>Sobrin, Lucia</au><au>Brantley, Milam A.</au><au>Peachey, Neal S.</au><au>Motsinger-Reif, Alison A.</au><au>Wilson, Peter W.</au><au>Sun, Yan V.</au><au>Giri, Ayush</au><au>Phillips, Lawrence S.</au><au>Edwards, Todd L.</au><aucorp>VA Million Veteran Program</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Adaptive selection at G6PD and disparities in diabetes complications</atitle><jtitle>Nature medicine</jtitle><stitle>Nat Med</stitle><addtitle>Nat Med</addtitle><date>2024-09</date><risdate>2024</risdate><volume>30</volume><issue>9</issue><spage>2480</spage><epage>2488</epage><pages>2480-2488</pages><issn>1078-8956</issn><issn>1546-170X</issn><eissn>1546-170X</eissn><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.
A combined-ancestry GWAS of diabetic retinopathy, comprising 68,169 cases and 129,188 controls, revealed nine previously unreported loci associated with the condition, including an evolutionarily adaptive genetic variant alongside a potential functional mechanism that influences racial disparities in diabetes complications among individuals of non-Hispanic African ancestry.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>38918629</pmid><doi>10.1038/s41591-024-03089-1</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0001-8494-3660</orcidid><orcidid>https://orcid.org/0000-0001-7479-0920</orcidid><orcidid>https://orcid.org/0000-0002-2838-1824</orcidid><orcidid>https://orcid.org/0000-0002-6542-8046</orcidid><orcidid>https://orcid.org/0000-0002-6179-0515</orcidid><orcidid>https://orcid.org/0000-0003-4318-6119</orcidid><orcidid>https://orcid.org/0000-0002-7786-4670</orcidid><orcidid>https://orcid.org/0000-0003-1652-3642</orcidid><orcidid>https://orcid.org/0000-0002-8447-7871</orcidid><orcidid>https://orcid.org/0000-0002-9723-3876</orcidid><orcidid>https://orcid.org/0000-0001-7488-250X</orcidid><orcidid>https://orcid.org/0000-0002-4419-7226</orcidid><orcidid>https://orcid.org/0000-0001-5824-9595</orcidid><orcidid>https://orcid.org/0000-0001-8923-6690</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1078-8956 |
| ispartof | Nature medicine, 2024-09, Vol.30 (9), p.2480-2488 |
| issn | 1078-8956 1546-170X 1546-170X |
| language | eng |
| recordid | cdi_proquest_miscellaneous_3072291904 |
| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature Journals Online |
| subjects | 631/208 692/163/2743/137/138 Alleles Biomedical and Life Sciences Biomedicine Black People - genetics Blood Glucose - metabolism Cancer Research Cardiovascular diseases Cardiovascular system Diabetes Diabetes Complications - epidemiology Diabetes Complications - genetics Diabetes mellitus Diabetic neuropathy Diabetic retinopathy Diabetic Retinopathy - epidemiology Diabetic Retinopathy - genetics Female Gene frequency Genetic diversity Genetic variance Genome-wide association studies Genome-Wide Association Study Genotypes Glucose Glucose 6 phosphate dehydrogenase Glucosephosphate dehydrogenase Glucosephosphate Dehydrogenase - genetics Glucosephosphate Dehydrogenase Deficiency - complications Glucosephosphate Dehydrogenase Deficiency - epidemiology Glucosephosphate Dehydrogenase Deficiency - genetics Glycated Hemoglobin - metabolism Health risks Hemoglobin Humans Infectious Diseases Life span Malaria Male Metabolic Diseases Middle Aged Molecular Medicine Neuropathy Neurosciences Polymorphism, Single Nucleotide Population genetics Populations Race factors Retinopathy Vector-borne diseases |
| title | Adaptive selection at G6PD and disparities in diabetes complications |
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