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Cited by 1,797Genetic Associations and EpidemiologyDiabetes and associated disordersGenetic Mapping and Diversity in Plants and Animals

Genetics of diabetes mellitus and diabetes complications

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Cole, Joanne B., Florez, Jose C.·2020·Nature Reviews Nephrology
DOI 10.1038/s41581-020-0278-5PMC PMC9639302
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Abstract

Diabetes is one of the fastest growing diseases worldwide, projected to affect 693 million adults by 2045. Devastating macrovascular complications (cardiovascular disease) and microvascular complications (such as diabetic kidney disease, diabetic retinopathy and neuropathy) lead to increased mortality, blindness, kidney failure and an overall decreased quality of life in individuals with diabetes. Clinical risk factors and glycaemic control alone cannot predict the development of vascular complications; numerous genetic studies have demonstrated a clear genetic component to both diabetes and its complications. Early research aimed at identifying genetic determinants of diabetes complications relied on familial linkage analysis suited to strong-effect loci, candidate gene studies prone to false positives, and underpowered genome-wide association studies limited by sample size. The explosion of new genomic datasets, both in terms of biobanks and aggregation of worldwide cohorts, has more than doubled the number of genetic discoveries for both diabetes and diabetes complications. We focus herein on genetic discoveries for diabetes and diabetes complications, empowered primarily through genome-wide association studies, and emphasize the gaps in research for taking genomic discovery to the next level.

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  • Genetic and phenotypic differences due to foetal and childhood nutrition and growth also influence worldwide variations in diabetes, especially when accompanied by rapid weight gain, as in the high diabetes prevalence in south Asia.

    “Genetic and phenotypic differences due to foetal and childhood nutrition and growth also influence worldwide variations, especially when accompanied with rapid weight gain—for example the high diabetes prevalence in south Asia.56,57”

    From Worldwide trends in diabetes prevalence and treatment from 1990 to 2022: a pooled analysis of 1108 population-representative studies with 141 million participants (2024) · cites this paper as [56]

    The Introduction describes genetic and environmental components of diabetes, and the Diabetes section discusses genetic studies across populations (page unavailable). Neither passage addresses foetal or childhood nutrition and growth, rapid weight gain, or their proposed role in South Asia’s diabetes prevalence; targeted searches for those terms found no supporting passage in our copy. (LLM, conf=0.73)

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  1. [2]Morrish NJ Mortality and causes of death in the WHO multinational study of vascular disease in diabetes. Diabetologia 44, S14, doi: 10.1007/PL00002934 (2001). 11587045 · DOI · Paper page
  2. [3]da Rocha Fernandes J IDF Diabetes Atlas estimates of 2014 global health expenditures on diabetes. Diabetes Res. Clin. Pract 117, 48– 54, doi: 10.1016/j.diabres.2016.04.016 (2016). 27329022 · DOI
  3. [5]Liyanage T Worldwide access to treatment for end-stage kidney disease: A systematic review. Lancet 385, 1975– 1982, doi: 10.1016/S0140-6736(14)61601-9 (2015). 25777665 · DOI
  4. [6]Brownlee M Biochemistry and molecular cell biology of diabetic complications. Nature 414, 813– 820, doi: 10.1038/414813a (2001). 11742414 · DOI · Paper page
  5. [9]Ahlqvist E Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables. Lancet Diabetes Endocrinol 6, 361– 369, doi: 10.1016/S2213-8587(18)30051-2 (2018). 29503172 · DOI · Paper page
  6. [10]Nathan DM The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N. Engl. J. Med 329, 977– 986, doi: 10.1056/nejm199309303291401 (1993). 8366922 · DOI · Paper page
  7. [13]Prospective UK Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ (Clinical research ed.) 317, 703– 713 (1998). PMC28659 9732337
  8. [17]Mahaffey Kenneth W Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups. Circulation 140, 739– 750, doi: 10.1161/CIRCULATIONAHA.119.042007 (2019). 31291786 PMC6727954 · DOI · Paper page
  9. [19]Santer R Molecular Analysis of the SGLT2 Gene in Patients with Renal Glucosuria. J. Am. Soc. Nephrol 14, 2873– 2882, doi: 10.1097/01.Asn.0000092790.89332.D2 (2003). 14569097 · DOI
  10. [20]Deckert T & Poulsen J Diabetic nephropathy: fault or destiny? Diabetologia 21, 178– 183 (1981). 7297791
  11. [21]Quinn M, Angelico MC, Warram JH & Krolewski AS Familial factors determine the development of diabetic nephropathy in patients with IDDM. Diabetologia 39, 940– 945, doi: 10.1007/BF00403913 (1996). 8858216 · DOI
  12. [22]Seaquist ER, Goetz FC, Rich S & Barbosa J Familial clustering of diabetic kidney disease. N. Engl. J. Med 320, 1161– 1165 (1989). 2710189
  13. [23]Earle K, Walker J, Hill C & Viberti G Familial clustering of cardiovascular disease in patients with insulin-dependent diabetes and nephropathy. N. Engl. J. Med 326, 673– 677 (1992). 1736105
  14. [24]Tuomilehto J Incidence of cardiovascular disease in type 1 (insulin-dependent) diabetic subjects with and without diabetic nephropathy in Finland. Diabetologia 41, 784– 790, doi: 10.1007/s001250050988 (1998). 9686919 · DOI
  15. [26]Fajans SS & Bell GI MODY: history, genetics, pathophysiology, and clinical decision making. Diabetes Care 34, 1878– 1884 (2011). 21788644 PMC3142024
  16. [27]Mahajan A Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps. Nat. Genet 50, 1505– 1513, doi: 10.1038/s41588-018-0241-6 (2018). 30297969 PMC6287706 · DOI · Paper page
  17. [28]Udler MS Type 2 diabetes: multiple genes, multiple diseases. Curr. Diab. Rep 19, 55, doi: 10.1007/s11892-019-1169-7 (2019). 31292748 PMC6620259 · DOI
  18. [29]Robertson CC & Rich SS Genetics of type 1 diabetes. Curr. Opin. Genet. Dev 50, 7– 16, doi: 10.1016/j.gde.2018.01.006 (2018). 29453110 · DOI
  19. [31]Barrett JC Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat. Genet 41, 703 (2009). 19430480 PMC2889014
  20. [32]Cooper NJ Type 1 diabetes genome-wide association analysis with imputation identifies five new risk regions. bioRxiv, 120022, doi: 10.1101/120022 (2017). · DOI
  21. [33]Onengut-Gumuscu S Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers. Nat. Genet 47, 381, doi: 10.1038/ng.3245 (2015). 25751624 PMC4380767 · DOI
  22. [34]Ge Y Targeted deep sequencing in multiple-affected sibships of European ancestry identifies rare deleterious variants in PTPN22 that confer risk for type 1 diabetes. Diabetes 65, 794– 802, doi: 10.2337/db15-0322 (2016). 26631741 PMC4764149 · DOI
  23. [35]Ingelsson E & McCarthy Mark I Human genetics of obesity and type 2 diabetes mellitus. Circ. Genom. Precis. Med 11, e002090, doi: 10.1161/CIRCGEN.118.002090 (2018). 29899044 PMC6405228 · DOI
  24. [36]Prasad RB & Groop L Genetics of type 2 diabetes—Pitfalls and possibilities. Genes 6, 87– 123 (2015). 25774817 PMC4377835
  25. [37]Florez JC The genetics of type 2 diabetes and related traits Switzerland: Springer International Publishing (2016).
  26. [38]Chen J Genome-wide association study of type 2 diabetes in Africa. Diabetologia 62, 1204– 1211, doi: 10.1007/s00125-019-4880-7 (2019). 31049640 PMC6560001 · DOI
  27. [39]Ng MCY Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes. PLoS Genet 10, e1004517, doi: 10.1371/journal.pgen.1004517 (2014). 25102180 PMC4125087 · DOI
  28. [40]Imamura M Genome-wide association studies in the Japanese population identify seven novel loci for type 2 diabetes. Nat. Commun 7, 10531, doi: 10.1038/ncomms10531 https://www.nature.com/articles/ncomms10531#supplementary-information (2016). 26818947 PMC4738362 · DOI
  29. [41]Qi Q Genetics of Type 2 Diabetes in U.S. Hispanic/Latino Individuals: Results From the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Diabetes 66, 1419– 1425, doi: 10.2337/db16-1150 (2017). 28254843 PMC5399610 · DOI
  30. [42]Cho YS Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in East Asians. Nat. Genet 44, 67 (2012). PMC3582398 22158537
  31. [43]Kooner JS Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci. Nat. Genet 43, 984, doi: 10.1038/ng.921 https://www.nature.com/articles/ng.921#supplementary-information (2011). 21874001 PMC3773920 · DOI
  32. [45]Williams AL Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico. Nature 506, 97– 101, doi: 10.1038/nature12828 (2014). 24390345 PMC4127086 · DOI
  33. [47]Spracklen CN Identification of type 2 diabetes loci in 433,540 East Asian individuals. bioRxiv, 685172, doi: 10.1101/685172 (2019). PMC7292783 32499647 · DOI
  34. [48]Mahajan A Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes. Nat. Genet 50, 559– 571, doi: 10.1038/s41588-018-0084-1 (2018). 29632382 PMC5898373 · DOI · Paper page
  35. [49]Mahajan A 303-OR: ADA Presidents’ Select Abstract: Transethnic Association Study of Type 2 Diabetes in More than a Million Individuals. Diabetes 68, 303-OR, doi: 10.2337/db19-303-OR (2019). · DOI
  36. [51]Andersen MK Genetics of Type 2 Diabetes: the Power of Isolated Populations. Curr. Diab. Rep 16, 65, doi: 10.1007/s11892-016-0757-z (2016). 27189761 · DOI
  37. [52]Langenberg C & Lotta LA Genomic insights into the causes of type 2 diabetes. Lancet 391, 2463– 2474, doi: 10.1016/S0140-6736(18)31132-2 (2018). 29916387 · DOI
  38. [53]Flannick J Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls. Nature 570, 71– 76, doi: 10.1038/s41586-019-1231-2 (2019). 31118516 PMC6699738 · DOI · Paper page
  39. [54]Dwivedi OP Loss of ZnT8 function protects against diabetes by enhanced insulin secretion. Nat. Genet 51, 1596– 1606, doi: 10.1038/s41588-019-0513-9 (2019). 31676859 PMC6858874 · DOI
  40. [56]Martínez-Castelao A, Navarro-González J, Górriz J & de Alvaro F The concept and the epidemiology of diabetic nephropathy have changed in recent years. J. Clin. Med 4, 1207– 1216 (2015). 26239554 PMC4484995
  41. [57]Anders HJ, Huber TB, Isermann B & Schiffer M CKD in diabetes: diabetic kidney disease versus nondiabetic kidney disease. Nat. Rev. Nephrol, 1 (2018). 29654297
  42. [58]Pettitt DJ, Saad MF, Bennett PH, Nelson RG & Knowler WC Familial predisposition to renal disease in two generations of Pima Indians with Type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 33, 438– 443, doi: 10.1007/BF00404096 (1990). 2401399 · DOI
  43. [59]Harjutsalo V, Katoh S, Sarti C, Tajima N & Tuomilehto J Population-Based Assessment of Familial Clustering of Diabetic Nephropathy in Type 1 Diabetes. Diabetes 53, 2449 (2004). 15331558
  44. [60]Borch-Johnsen K Is diabetic nephropathy an inherited complication? Kidney Int 41, 719– 722 (1992). 1513092
  45. [61]Sandholm N The Genetic Landscape of Renal Complications in Type 1 Diabetes. J. Am. Soc. Nephrol, doi: 10.1681/asn.2016020231 (2016). PMC5280020 27647854 · DOI
  46. [62]Sandholm N Genome-wide association study of urinary albumin excretion rate in patients with type 1 diabetes. Diabetologia 57, 1143– 1153, doi: 10.1007/s00125-014-3202-3 (2014). 24595857 · DOI
  47. [63]van Zuydam NR A genome-wide association study of diabetic kidney disease in subjects with type 2 diabetes. Diabetes 67, 1414– 1427 (2018). 29703844 PMC6014557
  48. [64]Imperatore G Sib-pair linkage analysis for susceptibility genes for microvascular complications among Pima Indians with type 2 diabetes. Pima Diabetes Genes Group. Diabetes 47, 821– 830, doi: 10.2337/diabetes.47.5.821 (1998). 9588456 · DOI
  49. [65]Iyengar SK Genome-wide scans for diabetic nephropathy and albuminuria in multiethnic populations. Diabetes 56, 1577– 1585 (2007). 17363742
  50. [66]Schelling JR Genome-Wide Scan for Estimated Glomerular Filtration Rate in Multi-Ethnic Diabetic Populations. Diabetes 57, 235– 243, doi: 10.2337/db07-0313 (2008). 18003762 · DOI
  51. [67]Vardarli I Gene for susceptibility to diabetic nephropathy in type 2 diabetes maps to 18q22.3–23. Kidney Int 62, 2176– 2183, doi: 10.1046/j.1523-1755.2002.00663.x (2002). 12427143 · DOI
  52. [68]Janssen B Carnosine as a protective factor in diabetic nephropathy: association with a leucine repeat of the carnosinase gene CNDP1. Diabetes 54, 2320– 2327 (2005). 16046297
  53. [69]Mooyaart AL Genetic associations in diabetic nephropathy: a meta-analysis. Diabtologia 54, 544– 553, doi: 10.1007/s00125-010-1996-1 (2011). PMC3034040 21127830 · DOI
  54. [70]Tong Z Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications. PNAS 105, 6998– 7003 (2008). 18458324 PMC2383970
  55. [71]Reutens AT Epidemiology of diabetic kidney disease. Medical Clinics 97, 1– 18 (2013). 23290726
  56. [72]Pezzolesi MG Genome-Wide Association Scan for Diabetic Nephropathy Susceptibility Genes in Type 1 Diabetes. Diabetes 58, 1403 (2009). 19252134 PMC2682673
  57. [73]Martini S From Single Nucleotide Polymorphism to Transcriptional Mechanism: A Model for FRMD3 in Diabetic Nephropathy. Diabetes 62, 2605– 2612, doi: 10.2337/db12-1416 (2013). 23434934 PMC3712052 · DOI
  58. [74]Sandholm N New susceptibility loci associated with kidney disease in type 1 diabetes. PLoS Genet 8, e1002921 (2012). 23028342 PMC3447939
  59. [75]Sandholm N Chromosome 2q31. 1 associates with ESRD in women with type 1 diabetes. J. Am. Soc. Nephrol 24, 1537– 1543 (2013). 24029427 PMC3785274
  60. [76]Salem RM Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen. J. Am. Soc. Nephrol., ASN 2019030218, doi: 10.1681/asn.2019030218 (2019). PMC6779358 31537649 · DOI
  61. [77]Longo I COL4A3/COL4A4 mutations: From familial hematuria to autosomal-dominant or recessive Alport syndrome. Kidney Int 61, 1947– 1956, doi: 10.1046/j.1523-1755.2002.00379.x (2002). 12028435 · DOI
  62. [78]Taira M A variant within the FTO confers susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes. PLoS One 13, e0208654, doi: 10.1371/journal.pone.0208654 (2018). 30566433 PMC6300288 · DOI
  63. [79]Sandholm N & Groop PH Genetic basis of diabetic kidney disease and other diabetic complications. Curr. Opin. Genet. Dev 50, 17– 24, doi: 10.1016/j.gde.2018.01.002 (2018). 29453109 · DOI
  64. [80]Ahlqvist E, Van Zuydam NR, Groop LC & McCarthy MI The genetics of diabetic complications. Nat. Rev. Nephrol 11, 277 (2015). 25825086
  65. [81]Sandholm N Confirmation of GLRA3 as a susceptibility locus for albuminuria in Finnish patients with type 1 diabetes. Sci. Rep 8, 12408, doi: 10.1038/s41598-018-29211-1 (2018). 30120300 PMC6098108 · DOI
  66. [82]Iyengar SK Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND). PLoS Genet 11, e1005352, doi: 10.1371/journal.pgen.1005352 (2015). 26305897 PMC4549309 · DOI
  67. [83]Guan M Genome-wide association study identifies novel loci for type 2 diabetes-attributed end-stage kidney disease in African Americans. Hum. Genomics 13, 21, doi: 10.1186/s40246-019-0205-7 (2019). 31092297 PMC6521376 · DOI
  68. [84]Köttgen A Multiple loci associated with indices of renal function and chronic kidney disease. Nat. Genet 41, 712, doi: 10.1038/ng.377 https://www.nature.com/articles/ng.377#supplementary-information (2009). 19430482 PMC3039280 · DOI
  69. [85]Böger CA CUBN is a gene locus for albuminuria. J. Am. Soc. Nephrol 22, 555– 570, doi: 10.1681/asn.2010060598 (2011). 21355061 PMC3060449 · DOI
  70. [86]Pattaro C Genome-Wide Association and Functional Follow-Up Reveals New Loci for Kidney Function. PLoS Genet 8, e1002584, doi: 10.1371/journal.pgen.1002584 (2012). 22479191 PMC3315455 · DOI
  71. [87]Gorski M Genome-wide association study of kidney function decline in individuals of European descent. Kidney Int 87, 1017– 1029, doi: 10.1038/ki.2014.361 (2015). 25493955 PMC4425568 · DOI
  72. [88]Teumer A Genome-wide Association Studies Identify Genetic Loci Associated With Albuminuria in Diabetes. Diabetes 65, 803– 817, doi: 10.2337/db15-1313 (2016). 26631737 PMC4764151 · DOI
  73. [89]Pattaro C Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function. Nat. Commun 7, 10023, doi: 10.1038/ncomms10023 http://www.nature.com/articles/ncomms10023#supplementary-information (2016). 26831199 PMC4735748 · DOI
  74. [90]Li M SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function. J. Am. Soc. Nephrol 28, 981– 994, doi: 10.1681/asn.2016020131 (2017). 27920155 PMC5328154 · DOI
  75. [91]Gorski M 1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function. Sci. Rep 7, 45040, doi: 10.1038/srep45040 https://www.nature.com/articles/srep45040#supplementary-information (2017). 28452372 PMC5408227 · DOI
  76. [92]Haas ME Genetic Association of Albuminuria with Cardiometabolic Disease and Blood Pressure. Am. J. Hum. Genet 103, 461– 473, doi: 10.1016/j.ajhg.2018.08.004 (2018). 30220432 PMC6174360 · DOI
  77. [93]Ahluwalia TS A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes: results from an exome-wide association study of albuminuria. Diabetologia 62, 292– 305, doi: 10.1007/s00125-018-4783-z (2019). 30547231 PMC6323095 · DOI
  78. [94]Teumer A Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria. Nat. Commun 10, 4130, doi: 10.1038/s41467-019-11576-0 (2019). 31511532 PMC6739370 · DOI
  79. [95]Yau JWY Global Prevalence and Major Risk Factors of Diabetic Retinopathy. Diabetes Care 35, 556– 564, doi: 10.2337/dc11-1909 (2012). 22301125 PMC3322721 · DOI · Paper page
  80. [96]Sivaprasad S, Gupta B, Crosby-Nwaobi R & Evans J Prevalence of Diabetic Retinopathy in Various Ethnic Groups: A Worldwide Perspective. Surv. Ophthalmol 57, 347– 370, doi: 10.1016/j.survophthal.2012.01.004 (2012). 22542913 · DOI
  81. [98]Bunce C & Wormald R Causes of blind certifications in England and Wales: April 1999–March 2000. Eye 22, 905 (2008). 17332762
  82. [99]Klein R, Klein BE & Moss SE Visual impairment in diabetes. Ophthalmology 91, 1– 9 (1984). 6709312
  83. [100]Leslie R & Pyke D Diabetic retinopathy in identical twins. Diabetes 31, 19– 21 (1982). 6759208
  84. [101]The Diabetes Control and Complications Trial Research Group. Clustering of Long-Term Complications in Families With Diabetes in the Diabetes Control and Complications Trial. Diabetes 46, 1829– 1839, doi: 10.2337/diab.46.11.1829 (1997). 9356033 · DOI
  85. [102]Looker HC Genome-wide linkage analyses to identify loci for diabetic retinopathy. Diabetes 56, 1160– 1166 (2007). 17395753
  86. [103]Arar NH Heritability of the severity of diabetic retinopathy: The FIND-Eye Study. Invest. Ophthalmol. Vis. Sci 49, 3839– 3845, doi: 10.1167/iovs.07-1633 (2008). 18765632 PMC2583147 · DOI
  87. [104]Hietala K, Forsblom C, Summanen P & Groop PH Heritability of Proliferative Diabetic Retinopathy. Diabetes 57, 2176– 2180, doi: 10.2337/db07-1495 (2008). 18443200 PMC2494680 · DOI
  88. [105]Hallman DM Familial aggregation of severity of diabetic retinopathy in Mexican Americans from Starr County, Texas. Diabetes Care 28, 1163– 1168 (2005). 15855583
  89. [106]Hampton BM, Schwartz SG, Brantley MA Jr. & Flynn HW Jr. Update on genetics and diabetic retinopathy. Clin. Ophthalmol 9, 2175– 2193, doi: 10.2147/OPTH.S94508 (2015). 26648684 PMC4664538 · DOI
  90. [107]Cho H & Sobrin L Genetics of diabetic retinopathy. Curr. Diab. Rep 14, 515, doi: 10.1007/s11892-014-0515-z (2014). 24952107 PMC4125976 · DOI
  91. [108]Burdon KP Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene. Diabetologia 58, 2288– 2297, doi: 10.1007/s00125-015-3697-2 (2015). 26188370 · DOI
  92. [109]Meng W A genome-wide association study suggests new evidence for an association of the NADPH Oxidase 4 (NOX4) gene with severe diabetic retinopathy in type 2 diabetes. Acta Ophthalmol 96, e811– e819, doi: 10.1111/aos.13769 (2018). 30178632 PMC6263819 · DOI
  93. [110]Li J, Wang JJ & Zhang SX NADPH Oxidase4-derived H2O2 Promotes Aberrant Retinal Neovascularization via Activation of VEGF Receptor 2 Pathway in Oxygen-induced Retinopathy. Invest. Ophthalmol. Vis. Sci 55, 2955– 2955 (2014). PMC4381975 25866826
  94. [111]Wang H, Yang Z, Jiang Y & Hartnett ME Endothelial NADPH oxidase 4 mediates vascular endothelial growth factor receptor 2-induced intravitreal neovascularization in a rat model of retinopathy of prematurity. Mol. Vis 20, 231– 241 (2014). 24623966 PMC3945806
  95. [112]Pollack S Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control. Diabetes 68, 441– 456, doi: 10.2337/db18-0567 (2019). 30487263 PMC6341299 · DOI
  96. [113]Shtir C Exome-based case–control association study using extreme phenotype design reveals novel candidates with protective effect in diabetic retinopathy. Hum. Genet 135, 193– 200, doi: 10.1007/s00439-015-1624-8 (2016). 26693933 · DOI
  97. [114]Ung C Whole exome sequencing identification of novel candidate genes in patients with proliferative diabetic retinopathy. Vision Res 139, 168– 176, doi: 10.1016/j.visres.2017.03.007 (2017). 28431867 PMC5912887 · DOI
  98. [115]Johannsen L Evaluation of Patients With Symptoms Suggestive of Chronic Polyneuropathy. J. Clin. Neuromuscul. Dis 3, 47– 52 (2001). 19078654
  99. [116]Pop-Busui R Diabetic Neuropathy: A Position Statement by the American Diabetes Association. Diabetes Care 40, 136– 154, doi: 10.2337/dc16-2042 (2017). 27999003 PMC6977405 · DOI · Paper page
  100. [117]Singh N, Armstrong DG & Lipsky BA Preventing Foot Ulcers in Patients With Diabetes. JAMA 293, 217– 228, doi: 10.1001/jama.293.2.217 (2005). 15644549 · DOI
  101. [118]Most RS & Sinnock P The Epidemiology of Lower Extremity Amputations in Diabetic Individuals. Diabetes Care 6, 87– 91, doi: 10.2337/diacare.6.1.87 (1983). 6839926 · DOI
  102. [119]Young MJ, Boulton AJM, Macleod AF, Williams DRR & Sonksen PH A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia 36, 150– 154, doi: 10.1007/BF00400697 (1993). 8458529 · DOI · Paper page
  103. [120]Maser RE Epidemiological Correlates of Diabetic Neuropathy: Report From Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes 38, 1456– 1461, doi: 10.2337/diab.38.11.1456 (1989). 2620781 · DOI
  104. [122]Tesfaye S Vascular Risk Factors and Diabetic Neuropathy. N. Engl. J. Med 352, 341– 350, doi: 10.1056/NEJMoa032782 (2005). 15673800 · DOI · Paper page
  105. [123]Monti MC Familial Risk Factors for Microvascular Complications and Differential Male-Female Risk in a Large Cohort of American Families with Type 1 Diabetes. J. Clin. Endocrinol. Metab 92, 4650– 4655, doi: 10.1210/jc.2007-1185 (2007). 17878250 · DOI
  106. [124]Meng W A Genome-wide Association Study Provides Evidence of Sex-specific Involvement of Chr1p35.1 (ZSCAN20-TLR12P) and Chr8p23.1 (HMGB1P46) With Diabetic Neuropathic Pain. EBioMedicine 2, 1386– 1393, doi: 10.1016/j.ebiom.2015.08.001 (2015). 26629533 PMC4634194 · DOI
  107. [125]Meng W A genome-wide association study suggests an association of Chr8p21.3 (GFRA2) with diabetic neuropathic pain. Eur. J. Pain 19, 392– 399, doi: 10.1002/ejp.560 (2015). 24974787 PMC4737240 · DOI
  108. [126]Meng W A genome-wide association study suggests that MAPK14 is associated with diabetic foot ulcers. Br. J. Dermatol 177, 1664– 1670, doi: 10.1111/bjd.15787 (2017). 28672053 PMC5829525 · DOI
  109. [127]Politi C Recent advances in exploring the genetic susceptibility to diabetic neuropathy. Diabetes Res. Clin. Pract 120, 198– 208, doi: 10.1016/j.diabres.2016.08.006 (2016). 27596057 · DOI
  110. [128]Witzel II Identifying Common Genetic Risk Factors of Diabetic Neuropathies. Front. Endocrinol 6, doi: 10.3389/fendo.2015.00088 (2015). PMC4447004 26074879 · DOI
  111. [129]Tang Y A Genetic Locus on Chromosome 2q24 Predicting Peripheral Neuropathy Risk in Type 2 Diabetes: Results From the ACCORD and BARI 2D Studies. Diabetes 68, 1649– 1662, doi: 10.2337/db19-0109 (2019). 31127053 PMC6692816 · DOI
  112. [130]Blesneac I Rare NaV1.7 variants associated with painful diabetic peripheral neuropathy. Pain 159, 469– 480, doi: 10.1097/j.pain.0000000000001116 (2018). 29176367 PMC5828379 · DOI
  113. [132]Haffner SM, Lehto S, Rönnemaa T, Pyörälä K & Laakso M Mortality from Coronary Heart Disease in Subjects with Type 2 Diabetes and in Nondiabetic Subjects with and without Prior Myocardial Infarction. N. Engl. J. Med 339, 229– 234, doi: 10.1056/nejm199807233390404 (1998). 9673301 · DOI · Paper page
  114. [133]Soedamah-Muthu SS High Risk of Cardiovascular Disease in Patients With Type 1 Diabetes in the UK. Diabetes Care 29, 798– 804, doi: 10.2337/diacare.29.04.06.dc05-1433 (2006). 16567818 · DOI
  115. [134]Turnbull FM Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia 52, 2288– 2298, doi: 10.1007/s00125-009-1470-0 (2009). 19655124 · DOI · Paper page
  116. [135]Parry HM Both high and low HbA1c predict incident heart failure in type 2 diabetes mellitus. Circ. Heart Fail 8, 236– 242, doi: 10.1161/circheartfailure.113.000920 (2015). 25561089 PMC4366571 · DOI
  117. [137]De Ferranti SD Type 1 diabetes mellitus and cardiovascular disease: a scientific statement from the American Heart Association and American Diabetes Association. Circulation 130, 1110– 1130 (2014). 25114208
  118. [138]Klein BEK Cardiovascular Disease, Mortality, and Retinal Microvascular Characteristics in Type 1 Diabetes: Wisconsin Epidemiologic Study of Diabetic Retinopathy. Arch. Intern. Med 164, 1917– 1924, doi: 10.1001/archinte.164.17.1917 (2004). 15451768 · DOI
  119. [139]Zdravkovic S Heritability of death from coronary heart disease: a 36‐year follow‐ up of 20 966 Swedish twins. J. Intern. Med 252, 247– 254 (2002). 12270005
  120. [141]Simonson MA, Wills AG, Keller MC & McQueen MB Recent methods for polygenic analysis of genome-wide data implicate an important effect of common variants on cardiovascular disease risk. BMC Med. Genet 12, 146, doi: 10.1186/1471-2350-12-146 (2011). 22029572 PMC3213201 · DOI
  121. [142]Wagenknecht Lynne E Familial Aggregation of Coronary Artery Calcium in Families with Type 2 Diabetes. Circulation 103, 1353– 1353, doi: 10.1161/circ.103.suppl_1.9998-11 (2001). 11289053 · DOI
  122. [143]Lange LA Heritability and Expression of C-Reactive Protein in Type 2 Diabetes in the Diabetes Heart Study. Ann. Hum. Genet 70, 717– 725, doi: 10.1111/j.1469-1809.2006.00280.x (2006). 17044846 · DOI
  123. [144]Lange LA Heritability of Carotid Artery Intima-Medial Thickness in Type 2 Diabetes. Stroke 33, 1876– 1881, doi: 10.1161/01.STR.0000019909.71547.AA (2002). 12105369 · DOI
  124. [145]Erdmann J, Kessler T, Munoz Venegas L & Schunkert H A decade of genome-wide association studies for coronary artery disease: the challenges ahead. Cardiovasc. Res 114, 1241– 1257, doi: 10.1093/cvr/cvy084 (2018). 29617720 · DOI
  125. [146]Qi L Genetic susceptibility to coronary heart disease in type 2 diabetes. J. Am. Coll. Cardiol 58, 2675– 2682, doi: 10.1016/j.jacc.2011.08.054 (2011). 22152955 PMC3240896 · DOI
  126. [147]Parry HM Genetic variants predicting left ventricular hypertrophy in a diabetic population: a Go-DARTS study including meta-analysis. Cardiovasc. Diabetol 12, 109, doi: 10.1186/1475-2840-12-109 (2013). 23879873 PMC3729417 · DOI
  127. [148]Cox AJ Genetic risk score associations with cardiovascular disease and mortality in the Diabetes Heart Study. Diabetes Care 37, 1157– 1164, doi: 10.2337/dc13-1514 (2014). 24574349 PMC4178326 · DOI
  128. [149]Doria A Interaction Between Poor Glycemic Control and 9p21 Locus on Risk of Coronary Artery Disease in Type 2 Diabetes. JAMA 300, 2389– 2397, doi: 10.1001/jama.2008.649 (2008). 19033589 PMC2762126 · DOI
  129. [150]Zhang LW Interaction of type 2 diabetes mellitus with Chromosome 9p21 rs10757274 polymorphism on the risk of myocardial infarction: a case–control study in Chinese population. BMC Cardiovasc. Disord 14, 170, doi: 10.1186/1471-2261-14-170 (2014). 25430018 PMC4255939 · DOI
  130. [151]Qi L Association Between a Genetic Variant Related to Glutamic Acid Metabolism and Coronary Heart Disease in Individuals With Type 2 Diabetes. JAMA 310, 821– 828, doi: 10.1001/jama.2013.276305 (2013). 23982368 PMC3858847 · DOI
  131. [152]Prudente S Genetic Variant at the GLUL Locus Predicts All-Cause Mortality in Patients With Type 2 Diabetes. Diabetes 64, 2658– 2663, doi: 10.2337/db14-1653 (2015). 25677913 PMC4477355 · DOI
  132. [153]The Look AHEAD Research Group. Prospective Association of GLUL rs10911021 With Cardiovascular Morbidity and Mortality Among Individuals With Type 2 Diabetes: The Look AHEAD Study. Diabetes 65, 297– 302, doi: 10.2337/db15-0890 (2016). 26395743 PMC4686954 · DOI
  133. [154]Shah HS Genetic Predictors of Cardiovascular Mortality During Intensive Glycemic Control in Type 2 Diabetes: Findings From the ACCORD Clinical Trial. Diabetes Care 39, 1915– 1924, doi: 10.2337/dc16-0285 (2016). 27527847 PMC5079609 · DOI
  134. [155]Shah HS Modulation of GLP-1 Levels by a Genetic Variant That Regulates the Cardiovascular Effects of Intensive Glycemic Control in ACCORD. Diabetes Care 41, 348– 355, doi: 10.2337/dc17-1638 (2018). 29183908 PMC5780047 · DOI
  135. [159]Gerstein HC Effects of intensive glucose lowering in type 2 diabetes. N. Engl. J. Med 358, 2545– 2559, doi: 10.1056/NEJMoa0802743 (2008). 18539917 PMC4551392 · DOI · Paper page
  136. [160]Investigators OT Basal insulin and cardiovascular and other outcomes in dysglycemia. N. Engl. J. Med 367, 319– 328 (2012). 22686416
  137. [162]Ray KK Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet 373, 1765– 1772, doi: 10.1016/s0140-6736(09)60697-8 (2009). 19465231 · DOI · Paper page
  138. [164]Boussageon R Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials. BMJ 343, d4169, doi: 10.1136/bmj.d4169 (2011). 21791495 PMC3144314 · DOI · Paper page
  139. [165]Holman RR, Paul SK, Bethel MA, Matthews DR & Neil HAW 10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes. N. Engl. J. Med 359, 1577– 1589, doi: 10.1056/NEJMoa0806470 (2008). 18784090 · DOI · Paper page
  140. [166]Gerstein HC Effects of intensive glycaemic control on ischaemic heart disease: analysis of data from the randomised, controlled ACCORD trial. Lancet 384, 1936– 1941, doi: 10.1016/s0140-6736(14)60611-5 (2014). 25088437 PMC4397008 · DOI
  141. [169]Merino J Genetically Driven Hyperglycemia Increases Risk of Coronary Artery Disease Separately From Type 2 Diabetes. Diabetes Care 40, 687– 693, doi: 10.2337/dc16-2625 (2017). 28298470 PMC5399655 · DOI
  142. [170]Rani PK Albuminuria and diabetic retinopathy in type 2 diabetes mellitus Sankara Nethralaya Diabetic Retinopathy Epidemiology and Molecular Genetic Study (SN-DREAMS, report 12). Diabetol. Metab. Syndr 3, 9 (2011). 21612596 PMC3125333
  143. [171]Groop PH The Presence and Severity of Chronic Kidney Disease Predicts All-Cause Mortality in Type 1 Diabetes. Diabetes 58, 1651– 1658, doi: 10.2337/db08-1543 (2009). 19401416 PMC2699848 · DOI · Paper page
  144. [172]Chavers BM, Mauer SM, Ramsay RC & Steffes MW Relationship between retinal and glomerular lesions in IDDM patients. Diabetes 43, 441– 446, doi: 10.2337/diab.43.3.441 (1994). 8314018 · DOI
  145. [173]Klein R The Relationship of Diabetic Retinopathy to Preclinical Diabetic Glomerulopathy Lesions in Type 1 Diabetic Patients. Diabetes 54, 527– 533, doi: 10.2337/diabetes.54.2.527 (2005). 15677511 · DOI
  146. [175]Hill MN Risk of foot complications in long-term diabetic patients with and without ESRD: a preliminary study. ANNA J 23, 381– 389 (1996). 8900683
  147. [176]Eggers PW, Gohdes D & Pugh J Nontraumatic lower extremity amputations in the Medicare end-stage renal disease population. Kidney Int 56, 1524– 1533, doi: 10.1046/j.1523-1755.1999.00668.x (1999). 10504504 · DOI
  148. [177]Drury PL Estimated glomerular filtration rate and albuminuria are independent predictors of cardiovascular events and death in type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetologia 54, 32– 43, doi: 10.1007/s00125-010-1854-1 (2011). 20668832 · DOI · Paper page
  149. [178]Nichols GA, Déruaz-Luyet A, Hauske SJ & Brodovicz KG The association between estimated glomerular filtration rate, albuminuria, and risk of cardiovascular hospitalizations and all-cause mortality among patients with type 2 diabetes. J. Diabetes Complications 32, 291– 297, doi: 10.1016/j.jdiacomp.2017.12.003 (2018). 29352693 · DOI
  150. [179]Fuller JH, Stevens LK, Wang SL & and the WHO Multinational Study Group. Risk factors for cardiovascular mortality and morbidity: The WHO multinational study of vascular disease in diabetes. Diabetologia 44, S54, doi: 10.1007/PL00002940 (2001). 11587051 · DOI
  151. [180]Cheung N Is diabetic retinopathy an independent risk factor for ischemic stroke? Stroke 38, 398– 401 (2007). 17194880
  152. [182]Mukhopadhyay N, Noble JA, Govil M, Marazita ML & Greenberg DA Identifying genetic risk loci for diabetic complications and showing evidence for heterogeneity of type 1 diabetes based on complications risk. PLoS One 13, e0192696, doi: 10.1371/journal.pone.0192696 (2018). 29444168 PMC5812614 · DOI
  153. [183]Scott RA An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans. Diabetes 66, 2888– 2902, doi: 10.2337/db16-1253 (2017). 28566273 PMC5652602 · DOI
  154. [184]McCarthy S A reference panel of 64,976 haplotypes for genotype imputation. Nat. Genet 48, 1279 (2016). 27548312 PMC5388176

Cited by

Sorted by citations

Authors
Cole, J. B., & Florez, J. C.
Affiliations
Broad Institute (US)
ORCID
Cole, Joanne B.
Venue
Nature Reviews Nephrology
Publisher
Springer Science and Business Media LLC
Published
2020-05-12
Volume
16
Issue
7
Pages
377-390
ISSN
  • 1745-8323 (ISSN-L)
  • 1759-5061
  • 1759-507X
DOI
10.1038/s41581-020-0278-5
PMC
PMC9639302
OpenAlex
W3024085885
Cited by
1,797
References
28
Citations by year
2026: 191 · 2025: 413 · 2024: 476 · 2023: 355 · 2022: 237 · 2021: 116 · 2020: 9
FWCI
25.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Reviews Nephrology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (K24DK110550, R01DK105154)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
Keywords
diabetes mellitus, diabetes complications, genetic factors, macrovascular complications, cardiovascular disease, microvascular complications, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, genome-wide association study, genetic susceptibility loci, biobanks, candidate gene association
MeSH terms
Cardiovascular Diseases, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Diabetic Neuropathies, Diabetic Retinopathy, Humans, Diabetes Complications

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