Diabetologia

, Volume 57, Issue 8, pp 1611–1622 | Cite as

Novel genetic susceptibility loci for diabetic end-stage renal disease identified through robust naive Bayes classification

  • Francesco Sambo
  • Alberto Malovini
  • Niina Sandholm
  • Monica Stavarachi
  • Carol Forsblom
  • Ville-Petteri Mäkinen
  • Valma Harjutsalo
  • Raija Lithovius
  • Daniel Gordin
  • Maija Parkkonen
  • Markku Saraheimo
  • Lena M. Thorn
  • Nina Tolonen
  • Johan Wadén
  • Bing He
  • Anne-May Österholm
  • Jaako Tuomilehto
  • Maria Lajer
  • Rany M. Salem
  • Amy Jayne McKnight
  • The GENIE Consortium
  • Lise Tarnow
  • Nicolae M. Panduru
  • Nicola Barbarini
  • Barbara Di Camillo
  • Gianna M. Toffolo
  • Karl Tryggvason
  • Riccardo Bellazzi
  • Claudio Cobelli
  • The FinnDiane Study Group
  • Per-Henrik Groop
Article

Abstract

Aims/hypothesis

Diabetic nephropathy is a major diabetic complication, and diabetes is the leading cause of end-stage renal disease (ESRD). Family studies suggest a hereditary component for diabetic nephropathy. However, only a few genes have been associated with diabetic nephropathy or ESRD in diabetic patients. Our aim was to detect novel genetic variants associated with diabetic nephropathy and ESRD.

Methods

We exploited a novel algorithm, ‘Bag of Naive Bayes’, whose marker selection strategy is complementary to that of conventional genome-wide association models based on univariate association tests. The analysis was performed on a genome-wide association study of 3,464 patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study and subsequently replicated with 4,263 type 1 diabetes patients from the Steno Diabetes Centre, the All Ireland-Warren 3-Genetics of Kidneys in Diabetes UK collection (UK–Republic of Ireland) and the Genetics of Kidneys in Diabetes US Study (GoKinD US).

Results

Five genetic loci (WNT4/ZBTB40-rs12137135, RGMA/MCTP2-rs17709344, MAPRE1P2-rs1670754, SEMA6D/SLC24A5-rs12917114 and SIK1-rs2838302) were associated with ESRD in the FinnDiane study. An association between ESRD and rs17709344, tagging the previously identified rs12437854 and located between the RGMA and MCTP2 genes, was replicated in independent case–control cohorts. rs12917114 near SEMA6D was associated with ESRD in the replication cohorts under the genotypic model (p < 0.05), and rs12137135 upstream of WNT4 was associated with ESRD in Steno.

Conclusions/interpretation

This study supports the previously identified findings on the RGMA/MCTP2 region and suggests novel susceptibility loci for ESRD. This highlights the importance of applying complementary statistical methods to detect novel genetic variants in diabetic nephropathy and, in general, in complex diseases.

Keywords

Bag of Naive Bayes Diabetic nephropathy End-stage renal disease Susceptibility loci 

Abbreviations

ACR

Albumin/creatinine ratio

BAI

Body adiposity index

BoNB

Bag of Naive Bayes

DBP

Diastolic blood pressure

eGFR

Estimated GFR

ESRD

End-stage renal disease

FDR

False discovery rate

FinnDiane

Finnish Diabetic Nephropathy Study

GENIE

Genetics of Nephropathy–an International Effort

GoKinD US

Genetics of Kidneys in Diabetes US Study

GWAS

Genome-wide association study

MCC

Matthews correlation coefficient

NBC

Naive Bayes classifier

SBP

Systolic blood pressure

SNP

Single nucleotide polymorphism

UK-ROI

All Ireland-Warren 3-Genetics of Kidneys in Diabetes UK collection (UK and Republic of Ireland)

Supplementary material

125_2014_3256_MOESM1_ESM.pdf (103 kb)
ESM Table 1(PDF 102 kb)
125_2014_3256_MOESM2_ESM.pdf (109 kb)
ESM Table 2(PDF 108 kb)
125_2014_3256_MOESM3_ESM.pdf (105 kb)
ESM Table 3(PDF 104 kb)
125_2014_3256_MOESM4_ESM.xls (36 kb)
ESM Table 4(XLS 35 kb)
125_2014_3256_MOESM5_ESM.pdf (87 kb)
ESM Table 5(PDF 87 kb)
125_2014_3256_MOESM6_ESM.pdf (75 kb)
ESM Table 6(PDF 74 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Francesco Sambo
    • 1
  • Alberto Malovini
    • 2
    • 3
  • Niina Sandholm
    • 4
    • 5
    • 6
  • Monica Stavarachi
    • 4
    • 7
  • Carol Forsblom
    • 4
    • 5
  • Ville-Petteri Mäkinen
    • 8
    • 9
  • Valma Harjutsalo
    • 4
    • 5
    • 10
  • Raija Lithovius
    • 4
    • 5
  • Daniel Gordin
    • 4
    • 5
  • Maija Parkkonen
    • 4
    • 5
  • Markku Saraheimo
    • 4
    • 5
  • Lena M. Thorn
    • 4
    • 5
  • Nina Tolonen
    • 4
    • 5
  • Johan Wadén
    • 4
    • 5
  • Bing He
    • 11
  • Anne-May Österholm
    • 11
  • Jaako Tuomilehto
    • 10
    • 12
    • 13
  • Maria Lajer
    • 14
  • Rany M. Salem
    • 15
    • 16
    • 17
  • Amy Jayne McKnight
    • 18
  • The GENIE Consortium
    • 19
  • Lise Tarnow
    • 20
    • 21
  • Nicolae M. Panduru
    • 4
    • 22
  • Nicola Barbarini
    • 2
  • Barbara Di Camillo
    • 1
  • Gianna M. Toffolo
    • 1
  • Karl Tryggvason
    • 10
  • Riccardo Bellazzi
    • 2
  • Claudio Cobelli
    • 1
  • The FinnDiane Study Group
    • 19
  • Per-Henrik Groop
    • 4
    • 5
    • 23
  1. 1.Department of Information EngineeringUniversity of PadovaPadovaItaly
  2. 2.Department of Industrial and Information EngineeringUniversity of PaviaPaviaItaly
  3. 3.IRCCS Fondazione Salvatore MaugeriPaviaItaly
  4. 4.Folkhälsan Institute of GeneticsFolkhälsan Research CentreHelsinkiFinland
  5. 5.Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Biomedicum HelsinkiUniversity of HelsinkiHelsinkiFinland
  6. 6.Department of Biomedical Engineering and Computational ScienceAalto University, School of ScienceHelsinkiFinland
  7. 7.Department of GeneticsUniversity of BucharestBucharestRomania
  8. 8.Department of Integrative Biology and PhysiologyUniversity of CaliforniaLos AngelesUSA
  9. 9.South Australian Health and Medical Research InstituteAdelaideAustralia
  10. 10.Diabetes Prevention UnitNational Institute for Health and WelfareHelsinkiFinland
  11. 11.Division of Matrix Biology, Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSweden
  12. 12.Centre for Vascular PreventionDanube-University KremsKremsAustria
  13. 13.Diabetes Research GroupKing Abdulaziz UniversityJeddahSaudi Arabia
  14. 14.Clinical Research DepartmentSteno Diabetes CentreGentofteDenmark
  15. 15.Department of GeneticsHarvard Medical SchoolBostonUSA
  16. 16.Program in Medical and Population GeneticsBroad InstituteCambridgeUSA
  17. 17.Department of EndocrinologyChildren’s Hospital BostonBostonUSA
  18. 18.Nephrology Research, Centre for Public HealthQueen’s University of BelfastBelfastUK
  19. 19.c/o P-H Groop, Division of Nephrology, Department of MedicineHelsinki University Central HospitalHelsinkiFinland
  20. 20.Faculty of Health SciencesUniversity of AarhusAarhusDenmark
  21. 21.Research UnitNordsjaellands HospitalHilleroedDenmark
  22. 22.Department of Pathophysiology, 2nd Clinical DepartmentCarol Davila University of Medicine and PharmacyBucharestRomania
  23. 23.Baker IDI Heart & Diabetes InstituteMelbourneAustralia

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