New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes

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Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN. Furthermore, strong familial aggregation supports genetic susceptibility to DN. However, the genes and the molecular mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ∼2.4 million single nucleotide polymorphisms (SNPs) imputed in 6,691 individuals. After additional genotyping of 41 top ranked SNPs representing 24 independent signals in 5,873 individuals, combined meta-analysis revealed association of two SNPs with ESRD: rs7583877 in the AFF3 gene (P = 1.2×10⁻⁸) and an intergenic SNP on chromosome 15q26 between the genes RGMA and MCTP2, rs12437854 (P = 2.0×10⁻⁹). Functional data suggest that AFF3 influences renal tubule fibrosis via the transforming growth factor-beta (TGF-β1) pathway. The strongest association with DN as a primary phenotype was seen for an intronic SNP in the ERBB4 gene (rs7588550, P = 2.1×10⁻⁷), a gene with type 2 diabetes DN differential expression and in the same intron as a variant with cis-eQTL expression of ERBB4. All these detected associations represent new signals in the pathogenesis of DN.

Vyšlo v časopise: New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes. PLoS Genet 8(9): e32767. doi:10.1371/journal.pgen.1002921
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002921

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Zdroje

1. U S Renal Data System (1-12-0011) USRDS 2011 Annual Data Report. Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2011.

2. RitzE, ZengXX, RychlikI (2011) Clinical manifestation and natural history of diabetic nephropathy. Contrib Nephrol 170: 19–27.

3. KrolewskiAS, WarramJH, ChristliebAR, BusickEJ, KahnCR (1985) The changing natural history of nephropathy in type I diabetes. Am J Med 78: 785–794.

4. de BoerIH, RueTC, HallYN, HeagertyPJ, WeissNS, et al. (2011) Temporal trends in the prevalence of diabetic kidney disease in the United States. JAMA 305: 2532–2539.

5. RosolowskyET, SkupienJ, SmilesAM, NiewczasM, RoshanB, et al. (2011) Risk for ESRD in type 1 diabetes remains high despite renoprotection. J Am Soc Nephrol 22: 545–553.

6. HarjutsaloV, KatohS, SartiC, TajimaN, TuomilehtoJ (2004) Population-based assessment of familial clustering of diabetic nephropathy in type 1 diabetes. Diabetes 53: 2449–2454.

7. von BerghAR, BeverlooHB, RomboutP, van WeringER, van WeelMH, et al. (2002) LAF4, an AF4-related gene, is fused to MLL in infant acute lymphoblastic leukemia. Genes Chromosomes Cancer 35: 92–96.

8. MaC, StaudtLM (1996) LAF-4 encodes a lymphoid nuclear protein with transactivation potential that is homologous to AF-4, the gene fused to MLL in t(4;11) leukemias. Blood 87: 734–745.

9. MelkoM, DouguetD, BensaidM, ZongaroS, VerheggenC, et al. (2011) Functional characterization of the AFF (AF4/FMR2) family of RNA-binding proteins: insights into the molecular pathology of FRAXE intellectual disability. Hum Mol Genet 20: 1873–1885.

10. von BerghAR, BeverlooHB, RomboutP, van WeringER, van WeelMH, et al. (2002) LAF4, an AF4-related gene, is fused to MLL in infant acute lymphoblastic leukemia. Genes Chromosomes Cancer 35: 92–96.

11. BartonA, EyreS, KeX, HinksA, BowesJ, et al. (2009) Identification of AF4/FMR2 family, member 3 (AFF3) as a novel rheumatoid arthritis susceptibility locus and confirmation of two further pan-autoimmune susceptibility genes. Hum Mol Genet 18: 2518–2522.

12. PlantD, FlynnE, MbarekH, DieudeP, CornelisF, et al. (2010) Investigation of potential non-HLA rheumatoid arthritis susceptibility loci in a European cohort increases the evidence for nine markers. Ann Rheum Dis 69: 1548–1553.

13. BarrettJC, ClaytonDG, ConcannonP, AkolkarB, CooperJD, et al. (2009) Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 41: 703–707.

14. WallaceC, RotivalM, CooperJD, RiceCM, YangJH, et al. (2012) Statistical colocalization of monocyte gene expression and genetic risk variants for type 1 diabetes. Hum Mol Genet

15. GassmannM, CasagrandaF, OrioliD, SimonH, LaiC, et al. (1995) Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature 378: 390–394.

16. TidcombeH, Jackson-FisherA, MathersK, SternDF, GassmannM, et al. (2003) Neural and mammary gland defects in ErbB4 knockout mice genetically rescued from embryonic lethality. Proc Natl Acad Sci U S A 100: 8281–8286.

17. PrickettTD, AgrawalNS, WeiX, YatesKE, LinJC, et al. (2009) Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4. Nat Genet 41: 1127–1132.

18. VeikkolainenV, NaillatF, RailoA, ChiL, ManninenA, et al. (2012) ErbB4 modulates tubular cell polarity and lumen diameter during kidney development. J Am Soc Nephrol 23: 112–122.

19. ZengF, ZhangMZ, SinghAB, ZentR, HarrisRC (2007) ErbB4 isoforms selectively regulate growth factor induced Madin-Darby canine kidney cell tubulogenesis. Mol Biol Cell 18: 4446–4456.

20. BerthierCC, ZhangH, SchinM, HengerA, NelsonRG, et al. (2009) Enhanced expression of Janus kinase-signal transducer and activator of transcription pathway members in human diabetic nephropathy. Diabetes 58: 469–477.

21. ZuberAM, CentenoG, PradervandS, NikolaevaS, MaquelinL, et al. (2009) Molecular clock is involved in predictive circadian adjustment of renal function. Proc Natl Acad Sci U S A 106: 16523–16528.

22. MarfellaCG, HenningerN, LeBlancSE, KrishnanN, GarlickDS, et al. (2008) A mutation in the mouse Chd2 chromatin remodeling enzyme results in a complex renal phenotype. Kidney Blood Press Res 31: 421–432.

23. MalhotraA, KobesS, KnowlerWC, BaierLJ, BogardusC, et al. (2011) A genome-wide association study of BMI in American Indians. Obesity (Silver Spring) 19: 2102–2106.

24. KimY, KleppelMM, ButkowskiR, MauerSM, WieslanderJ, et al. (1991) Differential expression of basement membrane collagen chains in diabetic nephropathy. Am J Pathol 138: 413–420.

25. YagameM, KimY, ZhuD, SuzukiD, EguchiK, et al. (1995) Differential distribution of type IV collagen chains in patients with diabetic nephropathy in non-insulin-dependent diabetes mellitus. Nephron 70: 42–48.

26. BritanovaO, LukyanovS, GrussP, TarabykinV (2002) The mouse Laf4 gene: exon/intron organization, cDNA sequence, alternative splicing, and expression during central nervous system development. Genomics 80: 31–37.

27. BrennanEP, MorineMJ, WalshDW, RoxburghSA, LindenmeyerMT, et al. (2012) Next-generation sequencing identifies TGF-beta1-associated gene expression profiles in renal epithelial cells reiterated in human diabetic nephropathy. Biochim Biophys Acta 1822: 589–599.

28. KalluriR, WeinbergRA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119: 1420–1428.

29. KrupaA, JenkinsR, LuoDD, LewisA, PhillipsA, et al. (2010) Loss of MicroRNA-192 promotes fibrogenesis in diabetic nephropathy. J Am Soc Nephrol 21: 438–447.

30. MorrisseyJ, GuoG, MoridairaK, FitzgeraldM, McCrackenR, et al. (2002) Transforming growth factor-beta induces renal epithelial jagged-1 expression in fibrotic disease. J Am Soc Nephrol 13: 1499–1508.

31. WalshDW, RoxburghSA, McGettiganP, BerthierCC, HigginsDG, et al. (2008) Co-regulation of Gremlin and Notch signalling in diabetic nephropathy. Biochim Biophys Acta 1782: 10–21.

32. BieleszB, SirinY, SiH, NiranjanT, GruenwaldA, et al. (2010) Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans. J Clin Invest 120: 4040–4054.

33. DresslerGR (2008) Another niche for Notch. Kidney Int 73: 1207–1209.

34. MurphyM, GodsonC, CannonS, KatoS, MackenzieHS, et al. (1999) Suppression subtractive hybridization identifies high glucose levels as a stimulus for expression of connective tissue growth factor and other genes in human mesangial cells. J Biol Chem 274: 5830–5834.

35. KramerHJ, NguyenQD, CurhanG, HsuCY (2003) Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus. JAMA 289: 3273–3277.

36. PerkinsBA, NelsonRG, OstranderBE, BlouchKL, KrolewskiAS, et al. (2005) Detection of renal function decline in patients with diabetes and normal or elevated GFR by serial measurements of serum cystatin C concentration: results of a 4-year follow-up study. J Am Soc Nephrol 16: 1404–1412.

37. ForsblomC, HarjutsaloV, ThornLM, WadenJ, TolonenN, et al. (2011) Competing-risk analysis of ESRD and death among patients with type 1 diabetes and macroalbuminuria. J Am Soc Nephrol 22: 537–544.

38. DupuisJ, LangenbergC, ProkopenkoI, SaxenaR, SoranzoN, et al. (2010) New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 42: 105–116.

39. EhretGB, MunroePB, RiceKM, BochudM, JohnsonAD, et al. (2011) Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 478: 103–109.

40. HeidIM, JacksonAU, RandallJC, WinklerTW, QiL, et al. (2010) Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat Genet 42: 949–960.

41. WillerCJ, SannaS, JacksonAU, ScuteriA, BonnycastleLL, et al. (2008) Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 40: 161–169.

42. DupuisJ, LangenbergC, ProkopenkoI, SaxenaR, SoranzoN, et al. (2010) New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 42: 105–116.

43. HeidIM, JacksonAU, RandallJC, WinklerTW, QiL, et al. (2010) Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat Genet 42: 949–960.

44. KottgenA, GlazerNL, DehghanA, HwangSJ, KatzR, et al. (2009) Multiple loci associated with indices of renal function and chronic kidney disease. Nat Genet 41: 712–717.

45. ChambersJC, ZhangW, LordGM, van derHP, LawlorDA, et al. (2010) Genetic loci influencing kidney function and chronic kidney disease. Nat Genet 42: 373–375.

46. BurrenOS, AdlemEC, AchuthanP, ChristensenM, CoulsonRM, et al. (2011) T1DBase: update 2011, organization and presentation of large-scale data sets for type 1 diabetes research. Nucleic Acids Res 39: D997–1001.

47. KottgenA, PattaroC, BogerCA, FuchsbergerC, OldenM, et al. (2010) New loci associated with kidney function and chronic kidney disease. Nat Genet 42: 376–384.

48. SegreAV, GroopL, MoothaVK, DalyMJ, AltshulerD (2010) Common inherited variation in mitochondrial genes is not enriched for associations with type 2 diabetes or related glycemic traits. PLoS Genet 6 doi:10.1371/journal.pgen.1001058.

49. ChambersJC, ZhangW, LordGM, van derHP, LawlorDA, et al. (2010) Genetic loci influencing kidney function and chronic kidney disease. Nat Genet 42: 373–375.

50. FeehallyJ, FarrallM, BolandA, GaleDP, GutI, et al. (2010) HLA has strongest association with IgA nephropathy in genome-wide analysis. J Am Soc Nephrol 21: 1791–1797.

51. RampoldiL, ScolariF, AmorosoA, GhiggeriG, DevuystO (2011) The rediscovery of uromodulin (Tamm-Horsfall protein): from tubulointerstitial nephropathy to chronic kidney disease. Kidney Int 80: 338–347.

52. KaoWH, KlagMJ, MeoniLA, ReichD, Berthier-SchaadY, et al. (2008) MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat Genet 40: 1185–1192.

53. RossetS, TzurS, BeharDM, WasserWG, SkoreckiK (2011) The population genetics of chronic kidney disease: insights from the MYH9-APOL1 locus. Nat Rev Nephrol 7: 313–326.

54. StanescuHC, Arcos-BurgosM, MedlarA, BockenhauerD, KottgenA, et al. (2011) Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy. N Engl J Med 364: 616–626.

55. KottgenA, GlazerNL, DehghanA, HwangSJ, KatzR, et al. (2009) Multiple loci associated with indices of renal function and chronic kidney disease. Nat Genet 41: 712–717.

56. KottgenA, PattaroC, BogerCA, FuchsbergerC, OldenM, et al. (2010) New loci associated with kidney function and chronic kidney disease. Nat Genet 42: 376–384.

57. RampoldiL, ScolariF, AmorosoA, GhiggeriG, DevuystO (2011) The rediscovery of uromodulin (Tamm-Horsfall protein): from tubulointerstitial nephropathy to chronic kidney disease. Kidney Int 80: 338–347.

58. KaoWH, KlagMJ, MeoniLA, ReichD, Berthier-SchaadY, et al. (2008) MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat Genet 40: 1185–1192.

59. RossetS, TzurS, BeharDM, WasserWG, SkoreckiK (2011) The population genetics of chronic kidney disease: insights from the MYH9-APOL1 locus. Nat Rev Nephrol 7: 313–326.

60. StanescuHC, Arcos-BurgosM, MedlarA, BockenhauerD, KottgenA, et al. (2011) Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy. N Engl J Med 364: 616–626.

61. McKnightAJ, PattersonCC, PettigrewKA, SavageDA, KilnerJ, et al. (2010) A GREM1 gene variant associates with diabetic nephropathy. J Am Soc Nephrol 21: 773–781.

62. SyreeniA, El OstaA, ForsblomC, SandholmN, ParkkonenM, et al. (2011) Genetic examination of SETD7 and SUV39H1/H2 methyltransferases and the risk of diabetes complications in patients with type 1 diabetes. Diabetes 60: 3073–3080.

63. PezzolesiMG, PoznikGD, MychaleckyjJC, PatersonAD, BaratiMT, et al. (2009) Genome-wide association scan for diabetic nephropathy susceptibility genes in type 1 diabetes. Diabetes 58: 1403–1410.

64. PezzolesiMG, PoznikGD, MychaleckyjJC, PatersonAD, BaratiMT, et al. (2009) Genome-wide association scan for diabetic nephropathy susceptibility genes in type 1 diabetes. Diabetes 58: 1403–1410.

65. PurcellS, NealeB, Todd-BrownK, ThomasL, FerreiraMA, et al. (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81: 559–575.

66. PriceAL, PattersonNJ, PlengeRM, WeinblattME, ShadickNA, et al. (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38: 904–909.

67. PurcellS, NealeB, Todd-BrownK, ThomasL, FerreiraMA, et al. (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81: 559–575.

68. WillerCJ, LiY, AbecasisGR (2010) METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26: 2190–2191.

69. PruimRJ, WelchRP, SannaS, TeslovichTM, ChinesPS, et al. (2010) LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26: 2336–2337.

70. CohenCD, KretzlerM (2002) Gene expression analysis in microdissected renal tissue. Current challenges and strategies. Nephron 92: 522–528.

71. IrizarryRA, BolstadBM, CollinF, CopeLM, HobbsB, et al. (2003) Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res 31: e15.

72. JohnsonWE, LiC, RabinovicA (2007) Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics 8: 118–127.

73. DaiM, WangP, BoydAD, KostovG, AtheyB, et al. (2005) Evolving gene/transcript definitions significantly alter the interpretation of GeneChip data. Nucleic Acids Res 33: e175.