Endocrinol Metab.  2015 Jun;30(2):147-158. 10.3803/EnM.2015.30.2.147.

Genetic Studies on Diabetic Microvascular Complications: Focusing on Genome-Wide Association Studies

• Kwak SH
• Park KS

• KMID: 2282004
• DOI: http://doi.org/10.3803/EnM.2015.30.2.147

Abstract

Diabetes is a common metabolic disorder with a worldwide prevalence of 8.3% and is the leading cause of visual loss, end-stage renal disease and amputation. Recently, genome-wide association studies (GWASs) have identified genetic risk factors for diabetic microvascular complications of retinopathy, nephropathy, and neuropathy. We summarized the recent findings of GWASs on diabetic microvascular complications and highlighted the challenges and our opinion on future directives. Five GWASs were conducted on diabetic retinopathy, nine on nephropathy, and one on neuropathic pain. The majority of recent GWASs were underpowered and heterogeneous in terms of study design, inclusion criteria and phenotype definition. Therefore, few reached the genome-wide significance threshold and the findings were inconsistent across the studies. Recent GWASs provided novel information on genetic risk factors and the possible pathophysiology of diabetic microvascular complications. However, further collaborative efforts to standardize phenotype definition and increase sample size are necessary for successful genetic studies on diabetic microvascular complications.

Keyword

Diabetes; Microvascular complication; Retinopathy; Nephropathy; Neuropathy; Genome-wide association study; Genetics

MeSH Terms

Amputation
Diabetic Retinopathy
Genetics
Genome-Wide Association Study*
Kidney Failure, Chronic
Neuralgia
Phenotype
Prevalence
Risk Factors
Sample Size

Reference

1. Korean Diabetes Association. Diabetes Fact Sheet in Korea 2013 [Internet]. Seoul: Korean Diabetes Association;c2011. cited 2015 May 16. Available from: http://www.diabetes.or.kr/temp/diabetes_factsheet_2013111.pdf.

2. Jin DC, Han JS. Renal replacement therapy in Korea, 2012. Kidney Res Clin Pract. 2014; 33:9–18.

3. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998; 352:837–853. PMID: 9742976.

4. ACCORD Study Group. ACCORD Eye Study Group. Chew EY, Ambrosius WT, Davis MD, Danis RP, Gangaputra S, Greven CM, Hubbard L, Esser BA, Lovato JF, Perdue LH, Goff DC Jr, Cushman WC, Ginsberg HN, Elam MB, Genuth S, Gerstein HC, Schubart U, Fine LJ. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med. 2010; 363:233–244. PMID: 20587587.

5. Ismail-Beigi F, Craven T, Banerji MA, Basile J, Calles J, Cohen RM, Cuddihy R, Cushman WC, Genuth S, Grimm RH Jr, Hamilton BP, Hoogwerf B, Karl D, Katz L, Krikorian A, O'Connor P, Pop-Busui R, Schubart U, Simmons D, Taylor H, Thomas A, Weiss D, Hramiak I. ACCORD trial group. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet. 2010; 376:419–430. PMID: 20594588.

6. Looker HC, Nelson RG, Chew E, Klein R, Klein BE, Knowler WC, Hanson RL. Genome-wide linkage analyses to identify Loci for diabetic retinopathy. Diabetes. 2007; 56:1160–1166. PMID: 17395753.

7. Hietala K, Forsblom C, Summanen P, Groop PH. FinnDiane Study Group. Heritability of proliferative diabetic retinopathy. Diabetes. 2008; 57:2176–2180. PMID: 18443200.

8. Young BA, Maynard C, Boyko EJ. Racial differences in diabetic nephropathy, cardiovascular disease, and mortality in a national population of veterans. Diabetes Care. 2003; 26:2392–2399. PMID: 12882868.

9. Awata T, Inoue K, Kurihara S, Ohkubo T, Watanabe M, Inukai K, Inoue I, Katayama S. A common polymorphism in the 5'-untranslated region of the VEGF gene is associated with diabetic retinopathy in type 2 diabetes. Diabetes. 2002; 51:1635–1639. PMID: 11978667.

10. Abhary S, Burdon KP, Laurie KJ, Thorpe S, Landers J, Goold L, Lake S, Petrovsky N, Craig JE. Aldose reductase gene polymorphisms and diabetic retinopathy susceptibility. Diabetes Care. 2010; 33:1834–1836. PMID: 20424224.

11. Tong Z, Yang Z, Patel S, Chen H, Gibbs D, Yang X, Hau VS, Kaminoh Y, Harmon J, Pearson E, Buehler J, Chen Y, Yu B, Tinkham NH, Zabriskie NA, Zeng J, Luo L, Sun JK, Prakash M, Hamam RN, Tonna S, Constantine R, Ronquillo CC, Sadda S, Avery RL, Brand JM, London N, Anduze AL, King GL, Bernstein PS, Watkins S. Genetics of Diabetes and Diabetic Complication Study Group. Jorde LB, Li DY, Aiello LP, Pollak MR, Zhang K. Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications. Proc Natl Acad Sci U S A. 2008; 105:6998–7003. PMID: 18458324.

12. Wang F, Fang Q, Yu N, Zhao D, Zhang Y, Wang J, Wang Q, Zhou X, Cao X, Fan X. Association between genetic polymorphism of the angiotensin-converting enzyme and diabetic nephropathy: a meta-analysis comprising 26,580 subjects. J Renin Angiotensin Aldosterone Syst. 2012; 13:161–174. PMID: 21810896.

13. Ma RC, Tam CH, Wang Y, Luk AO, Hu C, Yang X, Lam V, Chan AW, Ho JS, Chow CC, Tong PC, Jia W, Ng MC, So WY, Chan JC. Genetic variants of the protein kinase C-beta 1 gene and development of end-stage renal disease in patients with type 2 diabetes. JAMA. 2010; 304:881–889. PMID: 20736472.

14. Sobrin L, Green T, Sim X, Jensen RA, Tai ES, Tay WT, Wang JJ, Mitchell P, Sandholm N, Liu Y, Hietala K, Iyengar SK. Family Investigation of Nephropathy and Diabetes-Eye Research Group. Brooks M, Buraczynska M, Van Zuydam N, Smith AV, Gudnason V, Doney AS, Morris AD, Leese GP, Palmer CN. Wellcome Trust Case Control Consortium 2. Swaroop A, Taylor HA Jr, Wilson JG, Penman A, Chen CJ, Groop PH, Saw SM, Aung T, Klein BE, Rotter JI, Siscovick DS, Cotch MF, Klein R, Daly MJ, Wong TY. Candidate gene association study for diabetic retinopathy in persons with type 2 diabetes: the Candidate gene Association Resource (CARe). Invest Ophthalmol Vis Sci. 2011; 52:7593–7602. PMID: 21873659.

15. International HapMap Consortium. Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL, Gibbs RA, Belmont JW, Boudreau A, Hardenbol P, Leal SM, Pasternak S, Wheeler DA, Willis TD, Yu F, Yang H, Zeng C, Gao Y, Hu H, Hu W, Li C, Lin W, Liu S, Pan H, Tang X, Wang J, Wang W, Yu J, Zhang B, Zhang Q, Zhao H, Zhao H, Zhou J, Gabriel SB, Barry R, Blumenstiel B, Camargo A, Defelice M, Faggart M, Goyette M, Gupta S, Moore J, Nguyen H, Onofrio RC, Parkin M, Roy J, Stahl E, Winchester E, Ziaugra L, Altshuler D, Shen Y, Yao Z, Huang W, Chu X, He Y, Jin L, Liu Y, Shen Y, Sun W, Wang H, Wang Y, Wang Y, Xiong X, Xu L, Waye MM, Tsui SK, Xue H, Wong JT, Galver LM, Fan JB, Gunderson K, Murray SS, Oliphant AR, Chee MS, Montpetit A, Chagnon F, Ferretti V, Leboeuf M, Olivier JF, Phillips MS, Roumy S, Sallee C, Verner A, Hudson TJ, Kwok PY, Cai D, Koboldt DC, Miller RD, Pawlikowska L, Taillon-Miller P, Xiao M, Tsui LC, Mak W, Song YQ, Tam PK, Nakamura Y, Kawaguchi T, Kitamoto T, Morizono T, Nagashima A, Ohnishi Y, Sekine A, Tanaka T, Tsunoda T, Deloukas P, Bird CP, Delgado M, Dermitzakis ET, Gwilliam R, Hunt S, Morrison J, Powell D, Stranger BE, Whittaker P, Bentley DR, Daly MJ, de Bakker PI, Barrett J, Chretien YR, Maller J, McCarroll S, Patterson N, Pe'er I, Price A, Purcell S, Richter DJ, Sabeti P, Saxena R, Schaffner SF, Sham PC, Varilly P, Altshuler D, Stein LD, Krishnan L, Smith AV, Tello-Ruiz MK, Thorisson GA, Chakravarti A, Chen PE, Cutler DJ, Kashuk CS, Lin S, Abecasis GR, Guan W, Li Y, Munro HM, Qin ZS, Thomas DJ, McVean G, Auton A, Bottolo L, Cardin N, Eyheramendy S, Freeman C, Marchini J, Myers S, Spencer C, Stephens M, Donnelly P, Cardon LR, Clarke G, Evans DM, Morris AP, Weir BS, Tsunoda T, Mullikin JC, Sherry ST, Feolo M, Skol A, Zhang H, Zeng C, Zhao H, Matsuda I, Fukushima Y, Macer DR, Suda E, Rotimi CN, Adebamowo CA, Ajayi I, Aniagwu T, Marshall PA, Nkwodimmah C, Royal CD, Leppert MF, Dixon M, Peiffer A, Qiu R, Kent A, Kato K, Niikawa N, Adewole IF, Knoppers BM, Foster MW, Clayton EW, Watkin J, Gibbs RA, Belmont JW, Muzny D, Nazareth L, Sodergren E, Weinstock GM, Wheeler DA, Yakub I, Gabriel SB, Onofrio RC, Richter DJ, Ziaugra L, Birren BW, Daly MJ, Altshuler D, Wilson RK, Fulton LL, Rogers J, Burton J, Carter NP, Clee CM, Griffiths M, Jones MC, McLay K, Plumb RW, Ross MT, Sims SK, Willey DL, Chen Z, Han H, Kang L, Godbout M, Wallenburg JC, L'Archeveque P, Bellemare G, Saeki K, Wang H, An D, Fu H, Li Q, Wang Z, Wang R, Holden AL, Brooks LD, McEwen JE, Guyer MS, Wang VO, Peterson JL, Shi M, Spiegel J, Sung LM, Zacharia LF, Collins FS, Kennedy K, Jamieson R, Stewart J. A second generation human haplotype map of over 3.1 million SNPs. Nature. 2007; 449:851–861. PMID: 17943122.

16. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, Cho JH, Guttmacher AE, Kong A, Kruglyak L, Mardis E, Rotimi CN, Slatkin M, Valle D, Whittemore AS, Boehnke M, Clark AG, Eichler EE, Gibson G, Haines JL, Mackay TF, McCarroll SA, Visscher PM. Finding the missing heritability of complex diseases. Nature. 2009; 461:747–753. PMID: 19812666.

17. Sladek R, Rocheleau G, Rung J, Dina C, Shen L, Serre D, Boutin P, Vincent D, Belisle A, Hadjadj S, Balkau B, Heude B, Charpentier G, Hudson TJ, Montpetit A, Pshezhetsky AV, Prentki M, Posner BI, Balding DJ, Meyre D, Polychronakos C, Froguel P. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature. 2007; 445:881–885. PMID: 17293876.

18. DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium. Asian Genetic Epidemiology Network Type 2 Diabetes (AGEN-T2D) Consortium. South Asian Type 2 Diabetes (SAT2D) Consortium. Mexican American Type 2 Diabetes (MAT2D) Consortium. Type 2 Diabetes Genetic Exploration by Nex-generation sequencing in muylti-Ethnic Samples (T2D-GENES) Consortium. Mahajan A, Go MJ, Zhang W, Below JE, Gaulton KJ, Ferreira T, Horikoshi M, Johnson AD, Ng MC, Prokopenko I, Saleheen D, Wang X, Zeggini E, Abecasis GR, Adair LS, Almgren P, Atalay M, Aung T, Baldassarre D, Balkau B, Bao Y, Barnett AH, Barroso I, Basit A, Been LF, Beilby J, Bell GI, Benediktsson R, Bergman RN, Boehm BO, Boerwinkle E, Bonnycastle LL, Burtt N, Cai Q, Campbell H, Carey J, Cauchi S, Caulfield M, Chan JC, Chang LC, Chang TJ, Chang YC, Charpentier G, Chen CH, Chen H, Chen YT, Chia KS, Chidambaram M, Chines PS, Cho NH, Cho YM, Chuang LM, Collins FS, Cornelis MC, Couper DJ, Crenshaw AT, van Dam RM, Danesh J, Das D, de Faire U, Dedoussis G, Deloukas P, Dimas AS, Dina C, Doney AS, Donnelly PJ, Dorkhan M, van Duijn C, Dupuis J, Edkins S, Elliott P, Emilsson V, Erbel R, Eriksson JG, Escobedo J, Esko T, Eury E, Florez JC, Fontanillas P, Forouhi NG, Forsen T, Fox C, Fraser RM, Frayling TM, Froguel P, Frossard P, Gao Y, Gertow K, Gieger C, Gigante B, Grallert H, Grant GB, Grrop LC, Groves CJ, Grundberg E, Guiducci C, Hamsten A, Han BG, Hara K, Hassanali N, Hattersley AT, Hayward C, Hedman AK, Herder C, Hofman A, Holmen OL, Hovingh K, Hreidarsson AB, Hu C, Hu FB, Hui J, Humphries SE, Hunt SE, Hunter DJ, Hveem K, Hydrie ZI, Ikegami H, Illig T, Ingelsson E, Islam M, Isomaa B, Jackson AU, Jafar T, James A, Jia W, Jockel KH, Jonsson A, Jowett JB, Kadowaki T, Kang HM, Kanoni S, Kao WH, Kathiresan S, Kato N, Katulanda P, Keinanen-Kiukaanniemi KM, Kelly AM, Khan H, Khaw KT, Khor CC, Kim HL, Kim S, Kim YJ, Kinnunen L, Klopp N, Kong A, Korpi-Hyovalti E, Kowlessur S, Kraft P, Kravic J, Kristensen MM, Krithika S, Kumar A, Kumate J, Kuusisto J, Kwak SH, Laakso M, Lagou V, Lakka TA, Langenberg C, Langford C, Lawrence R, Leander K, Lee JM, Lee NR, Li M, Li X, Li Y, Liang J, Liju S, Lim WY, Lind L, Lindgren CM, Lindholm E, Liu CT, Liu JJ, Lobbens S, Long J, Loos RJ, Lu W, Luan J, Lyssenko V, Ma RC, Maeda S, Magi R, Mannisto S, Matthews DR, Meigs JB, Melander O, Metspalu A, Meyer J, Mirza G, Mihailov E, Moebus S, Mohan V, Mohlke KL, Morris AD, Muhleisen TW, Muller-Nurasyid M, Musk B, Nakamura J, Nakashima E, Navarro P, Ng PK, Nica AC, Nilsson PM, Njolstad I, Nothen MM, Ohnaka K, Ong TH, Owen KR, Palmer CN, Pankow JS, Park KS, Parkin M, Pechlivanis S, Pedersen NL, Peltonen L, Perry JR, Peters A, Pinidiyapathirage JM, Platou CG, Potter S, Price JF, Qi L, Radha V, Rallidis L, Rasheed A, Rathman W, Rauramaa R, Raychaudhuri S, Rayner NW, Rees SD, Rehnberg E, Ripatti S, Robertson N, Roden M, Rossin EJ, Rudan I, Rybin D, Saaristo TE, Salomaa V, Saltevo J, Samuel M, Sanghera DK, Saramies J, Scott J, Scott LJ, Scott RA, Segre AV, Sehmi J, Sennblad B, Shah N, Shah S, Shera AS, Shu XO, Shuldiner AR, Sigurdsson G, Sijbrands E, Silveira A, Sim X, Sivapalaratnam S, Small KS, So WY, Stancakova A, Stefansson K, Steinbach G, Steinthorsdottir V, Stirrups K, Strawbridge RJ, Stringham HM, Sun Q, Suo C, Syvanen AC, Takayanagi R, Takeuchi F, Tay WT, Teslovich TM, Thorand B, Thorleifsson G, Thorsteinsdottir U, Tikkanen E, Trakalo J, Tremoli E, Trip MD, Tsai FJ, Tuomi T, Tuomilehto J, Uitterlinden AG, Valladares-Salgado A, Vedantam S, Veglia F, Voight BF, Wang C, Wareham NJ, Wennauer R, Wickremasinghe AR, Wilsgaard T, Wilson JF, Wiltshire S, Winckler W, Wong TY, Wood AR, Wu JY, Wu Y, Yamamoto K, Yamauchi T, Yang M, Yengo L, Yokota M, Young R, Zabaneh D, Zhang F, Zhang R, Zheng W, Zimmet PZ, Altshuler D, Bowden DW, Cho YS, Cox NJ, Cruz M, Hanis CL, Kooner J, Lee JY, Seielstad M, Teo YY, Boehnke M, Parra EJ, Chambers JC, Tai ES, McCarthy MI, Morris AP. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility. Nat Genet. 2014; 46:234–244. PMID: 24509480.

19. Hivert MF, Vassy JL, Meigs JB. Susceptibility to type 2 diabetes mellitus: from genes to prevention. Nat Rev Endocrinol. 2014; 10:198–205. PMID: 24535206.

20. Early Treatment Diabetic Retinopathy Study Research Group. Grading diabetic retinopathy from stereoscopic color fundus photographs: an extension of the modified Airlie House classification. ETDRS report number 10. Ophthalmology. 1991; 98(5 Suppl):786–806. PMID: 2062513.

21. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol. 1984; 102:520–526. PMID: 6367724.

22. Fu YP, Hallman DM, Gonzalez VH, Klein BE, Klein R, Hayes MG, Cox NJ, Bell GI, Hanis CL. Identification of diabetic retinopathy genes through a genome-wide association study among Mexican-Americans from Starr County, Texas. J Ophthalmol. 2010; 2010:pii: 861291.

23. Huang YC, Lin JM, Lin HJ, Chen CC, Chen SY, Tsai CH, Tsai FJ. Genome-wide association study of diabetic retinopathy in a Taiwanese population. Ophthalmology. 2011; 118:642–648. PMID: 21310492.

24. Grassi MA, Tikhomirov A, Ramalingam S, Below JE, Cox NJ, Nicolae DL. Genome-wide meta-analysis for severe diabetic retinopathy. Hum Mol Genet. 2011; 20:2472–2481. PMID: 21441570.

25. Sheu WH, Kuo JZ, Lee IT, Hung YJ, Lee WJ, Tsai HY, Wang JS, Goodarzi MO, Klein R, Klein BE, Ipp E, Lin SY, Guo X, Hsieh CH, Taylor KD, Fu CP, Rotter JI, Chen YD. Genome-wide association study in a Chinese population with diabetic retinopathy. Hum Mol Genet. 2013; 22:3165–3173. PMID: 23562823.

26. Awata T, Yamashita H, Kurihara S, Morita-Ohkubo T, Miyashita Y, Katayama S, Mori K, Yoneya S, Kohda M, Okazaki Y, Maruyama T, Shimada A, Yasuda K, Nishida N, Tokunaga K, Koike A. Correction: a genome-wide association study for diabetic retinopathy in a Japanese population: potential association with a long intergenic non-coding RNA. PLoS One. 2015; 10:e0126789. PMID: 25910184.

27. Perkovic V, Heerspink HL, Chalmers J, Woodward M, Jun M, Li Q, MacMahon S, Cooper ME, Hamet P, Marre M, Mogensen CE, Poulter N, Mancia G, Cass A, Patel A, Zoungas S. ADVANCE Collaborative Group. Intensive glucose control improves kidney outcomes in patients with type 2 diabetes. Kidney Int. 2013; 83:517–523. PMID: 23302714.

28. The Diabetes Control and Complications Trial Research Group. 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. 1993; 329:977–986. PMID: 8366922.

29. Shimazaki A, Kawamura Y, Kanazawa A, Sekine A, Saito S, Tsunoda T, Koya D, Babazono T, Tanaka Y, Matsuda M, Kawai K, Iiizumi T, Imanishi M, Shinosaki T, Yanagimoto T, Ikeda M, Omachi S, Kashiwagi A, Kaku K, Iwamoto Y, Kawamori R, Kikkawa R, Nakajima M, Nakamura Y, Maeda S. Genetic variations in the gene encoding ELMO1 are associated with susceptibility to diabetic nephropathy. Diabetes. 2005; 54:1171–1178. PMID: 15793258.

30. Hanson RL, Craig DW, Millis MP, Yeatts KA, Kobes S, Pearson JV, Lee AM, Knowler WC, Nelson RG, Wolford JK. Identification of PVT1 as a candidate gene for end-stage renal disease in type 2 diabetes using a pooling-based genome-wide single nucleotide polymorphism association study. Diabetes. 2007; 56:975–983. PMID: 17395743.

31. Pezzolesi MG, Poznik GD, Mychaleckyj JC, Paterson AD, Barati MT, Klein JB, Ng DP, Placha G, Canani LH, Bochenski J, Waggott D, Merchant ML, Krolewski B, Mirea L, Wanic K, Katavetin P, Kure M, Wolkow P, Dunn JS, Smiles A, Walker WH, Boright AP, Bull SB. DCCT/EDIC Research Group. Doria A, Rogus JJ, Rich SS, Warram JH, Krolewski AS. Genome-wide association scan for diabetic nephropathy susceptibility genes in type 1 diabetes. Diabetes. 2009; 58:1403–1410. PMID: 19252134.

32. Craig DW, Millis MP, DiStefano JK. Genome-wide SNP genotyping study using pooled DNA to identify candidate markers mediating susceptibility to end-stage renal disease attributed to type 1 diabetes. Diabet Med. 2009; 26:1090–1098. PMID: 19929986.

33. McDonough CW, Palmer ND, Hicks PJ, Roh BH, An SS, Cooke JN, Hester JM, Wing MR, Bostrom MA, Rudock ME, Lewis JP, Talbert ME, Blevins RA, Lu L, Ng MC, Sale MM, Divers J, Langefeld CD, Freedman BI, Bowden DW. A genome-wide association study for diabetic nephropathy genes in African Americans. Kidney Int. 2011; 79:563–572. PMID: 21150874.

34. Sandholm N, Salem RM, McKnight AJ, Brennan EP, Forsblom C, Isakova T, McKay GJ, Williams WW, Sadlier DM, Makinen VP, Swan EJ, Palmer C, Boright AP, Ahlqvist E, Deshmukh HA, Keller BJ, Huang H, Ahola AJ, Fagerholm E, Gordin D, Harjutsalo V, He B, Heikkila O, Hietala K, Kyto J, Lahermo P, Lehto M, Lithovius R, Osterholm AM, Parkkonen M, Pitkaniemi J, Rosengard-Barlund M, Saraheimo M, Sarti C, Soderlund J, Soro-Paavonen A, Syreeni A, Thorn LM, Tikkanen H, Tolonen N, Tryggvason K, Tuomilehto J, Waden J, Gill GV, Prior S, Guiducci C, Mirel DB, Taylor A, Hosseini SM. DCCT/EDIC Research Group. Parving HH, Rossing P, Tarnow L, Ladenvall C, Alhenc-Gelas F, Lefebvre P, Rigalleau V, Roussel R, Tregouet DA, Maestroni A, Maestroni S, Falhammar H, Gu T, Mollsten A, Cimponeriu D, Ioana M, Mota M, Mota E, Serafinceanu C, Stavarachi M, Hanson RL, Nelson RG, Kretzler M, Colhoun HM, Panduru NM, Gu HF, Brismar K, Zerbini G, Hadjadj S, Marre M, Groop L, Lajer M, Bull SB, Waggott D, Paterson AD, Savage DA, Bain SC, Martin F, Hirschhorn JN, Godson C, Florez JC, Groop PH, Maxwell AP. New susceptibility loci associated with kidney disease in type 1 diabetes. PLoS Genet. 2012; 8:e1002921. PMID: 23028342.

35. Sandholm N, McKnight AJ, Salem RM, Brennan EP, Forsblom C, Harjutsalo V, Makinen VP, McKay GJ, Sadlier DM, Williams WW, Martin F, Panduru NM, Tarnow L, Tuomilehto J, Tryggvason K, Zerbini G, Comeau ME, Langefeld CD, Consortium F, Godson C, Hirschhorn JN, Maxwell AP, Florez JC, Groop PH. FinnDiane Study Group and the GENIE Consortium. Chromosome 2q31.1 associates with ESRD in women with type 1 diabetes. J Am Soc Nephrol. 2013; 24:1537–1543. PMID: 24029427.

36. Sandholm N, Forsblom C, Makinen VP, McKnight AJ, Osterholm AM, He B, Harjutsalo V, Lithovius R, Gordin D, Parkkonen M, Saraheimo M, Thorn LM, Tolonen N, Waden J, Tuomilehto J, Lajer M, Ahlqvist E, Mollsten A, Marcovecchio ML, Cooper J, Dunger D, Paterson AD, Zerbini G, Groop L, Consortium S, Tarnow L, Maxwell AP, Tryggvason K, Groop PH. SUMMIT Consortium, FinnDiane Study Group. Genome-wide association study of urinary albumin excretion rate in patients with type 1 diabetes. Diabetologia. 2014; 57:1143–1153. PMID: 24595857.

37. Germain M, Pezzolesi MG, Sandholm N, McKnight AJ, Susztak K, Lajer M, Forsblom C, Marre M, Parving HH, Rossing P, Toppila I, Skupien J, Roussel R, Ko YA, Ledo N, Folkersen L, Civelek M, Maxwell AP, Tregouet DA, Groop PH, Tarnow L, Hadjadj S. SORBS1 gene, a new candidate for diabetic nephropathy: results from a multi-stage genome-wide association study in patients with type 1 diabetes. Diabetologia. 2015; 58:543–548. PMID: 25476525.

38. Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P, Lauria G, Malik RA, Spallone V, Vinik A, Bernardi L, Valensi P. Toronto Diabetic Neuropathy Expert Group. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010; 33:2285–2293. PMID: 20876709.

39. Dyck PJ, Albers JW, Andersen H, Arezzo JC, Biessels GJ, Bril V, Feldman EL, Litchy WJ, O'Brien PC, Russell JW. Toronto Expert Panel on Diabetic Neuropathy. Diabetic polyneuropathies: update on research definition, diagnostic criteria and estimation of severity. Diabetes Metab Res Rev. 2011; 27:620–628. PMID: 21695763.

40. Meng W, Deshmukh HA, van Zuydam NR, Liu Y, Donnelly LA, Zhou K. Wellcome Trust Case Control Consortium 2 (WTCCC2). Surrogate Markers for Micro- and Macro-Vascular Hard Endpoints for Innovative Diabetes Tools (SUMMIT) Study Group. Morris AD, Colhoun HM, Palmer CN, Smith BH. A genome-wide association study suggests an association of Chr8p213 (GFRA2) with diabetic neuropathic pain. Eur J Pain. 2015; 19:392–399. PMID: 24974787.