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Genome-wide association study of urinary albumin excretion rate in patients with type 1 diabetes

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Abstract

Aims/hypothesis

An abnormal urinary albumin excretion rate (AER) is often the first clinically detectable manifestation of diabetic nephropathy. Our aim was to estimate the heritability and to detect genetic variation associated with elevated AER in patients with type 1 diabetes.

Methods

The discovery phase genome-wide association study (GWAS) included 1,925 patients with type 1 diabetes and with data on 24 h AER. AER was analysed as a continuous trait and the analysis was stratified by the use of antihypertensive medication. Signals with a p value <10−4 were followed up in 3,750 additional patients with type 1 diabetes from seven studies.

Results

The narrow-sense heritability, captured with our genotyping platform, was estimated to explain 27.3% of the total AER variability, and 37.6% after adjustment for covariates. In the discovery stage, five single nucleotide polymorphisms in the GLRA3 gene were strongly associated with albuminuria (p < 5 × 10−8). In the replication group, a nominally significant association (p = 0.035) was observed between albuminuria and rs1564939 in GLRA3, but this was in the opposite direction. Sequencing of the surrounding genetic region in 48 Finnish and 48 UK individuals supported the possibility that population-specific rare variants contribute to the synthetic association observed at the common variants in GLRA3. The strongest replication (p = 0.026) was obtained for rs2410601 between the PSD3 and SH2D4A genes. Pathway analysis highlighted natural killer cell mediated immunity processes.

Conclusions/interpretation

This study suggests novel pathways and molecular mechanisms for the pathogenesis of albuminuria in type 1 diabetes.

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Abbreviations

AER:

Albumin excretion rate

ACR:

Albumin-to-creatinine ratio

AHT:

Antihypertensive

CEU:

Centre d’Etude du Polymorphisme (Utah residents with northern and western European ancestry)

ESRD:

End-stage renal disease

FinnDiane:

Finnish Diabetic Nephropathy study

GLRA3 :

Glycine receptor subunit α-3

GWAS:

Genome-wide association study

LD:

Linkage disequilibrium

MAF:

Minor allele frequency

NFS-ORPS:

UK Nephropathy Family Study and Oxford Regional Prospective Study

nU-AER:

Overnight urine AER

QQ-plot:

Quantile–quantile plot

SDR:

Scania Diabetes Registry

SNP:

Single nucleotide polymorphism

SUMMIT:

SUrrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools

UK-ROI:

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

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Acknowledgements

We would like to acknowledge M. Parkkonen, A. Sandelin, A.-R. Salonen, T. Soppela and J. Tuomikangas (Folkhälsan Research Center, Helsinki, Finland and Division of Nephrology, Helsinki University Central Hospital, Helsinki, Finland) for their skilful laboratory assistance. We also thank all the patients who participated in the study and gratefully acknowledge all the physicians and nurses at each centre involved in the recruitment of participants (ESM [Table 8]).

Funding

The FinnDiane study was supported by grants from the Folkhälsan Research Foundation, the Wilhelm and Else Stockmann Foundation, Liv och Hälsa Foundation, Helsinki University Central Hospital Research Funds (EVO), the Sigrid Juselius Foundation, the Finnish Cultural Foundation, the Signe and Ane Gyllenberg Foundation, Finska Läkaresällskapet, Academy of Finland (no. 134379), Novo Nordisk Foundation and Tekes. The research was supported by the European Union Seventh Framework Program (FP7/2007–2013) for the Innovative Medicine Initiative under grant agreement no. IMI/115006 (the SUMMIT consortium), the Northern Ireland Research and Development Office and the Northern Ireland Kidney Research Fund.

Duality of interest

P-HG has received lecture honorariums from AbbVie, Boehringer Ingelheim, Cebix, Eli Lilly, Genzyme, Novartis, Novo Nordisk, MSD and Medscape, and research grants from Eli Lilly and Roche. P-HG is also an advisory board member of Boehringer Ingelheim, Eli Lilly and Novartis. The other authors declare that they have no duality of interest associated with this manuscript.

Contribution statement

NS and AJM contributed to the conception and design of the study, analysed and interpreted the data and drafted the article. CF and V-PM contributed to the conception and design of the study and interpretation of the results and critically revised the article. CF also contributed to the acquisition of data. A-MÖ, BH, EA and JC contributed to the analysis and acquisition of the data and critically revised the article. VH, RL, DG, MP, MS, LMT, NT, JW, JT, ML, AM, MLM, DD, ADP, GZ, LG and LT contributed to the acquisition of the phenotype and/or genotype data and reviewed the manuscript critically. APM and KT contributed to the conception and study design and to the data acquisition and revised the article critically.

P-HG designed and supervised the study and reviewed the article critically, and is responsible for the integrity of the work as a whole. All authors approved the final version of the article to be published.

Author information

Authors and Affiliations

  1. Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland

    Niina Sandholm, Carol Forsblom, Ville-Petteri Mäkinen, Valma Harjutsalo, Raija Lithovius, Daniel Gordin, Maija Parkkonen, Markku Saraheimo, Lena M. Thorn, Nina Tolonen, Johan Wadén & Per-Henrik Groop

  2. Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Biomedicum Helsinki, Haartmaninkatu 8, P.O. Box 63, 00014, University of Helsinki, Helsinki, Finland

    Niina Sandholm, Carol Forsblom, Ville-Petteri Mäkinen, Valma Harjutsalo, Raija Lithovius, Daniel Gordin, Maija Parkkonen, Markku Saraheimo, Lena M. Thorn, Nina Tolonen, Johan Wadén & Per-Henrik Groop

  3. Department of Biomedical Engineering and Computational Science, Aalto University School of Science, Helsinki, Finland

    Niina Sandholm

  4. Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, USA

    Ville-Petteri Mäkinen

  5. Nephrology Research, Centre for Public Health, Queen’s University of Belfast, Belfast, UK

    Amy Jayne McKnight & Alexander P. Maxwell

  6. Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

    Anne-May Österholm, Bing He & Karl Tryggvason

  7. Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland

    Valma Harjutsalo & Jaakko Tuomilehto

  8. Centre for Vascular Prevention, Danube-University Krems, Krems, Austria

    Jaakko Tuomilehto

  9. Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia

    Jaakko Tuomilehto

  10. Clinical Research Department, Steno Diabetes Center, Gentofte, Denmark

    Maria Lajer & Lise Tarnow

  11. Department of Clinical Sciences, Diabetes and Endocrinology, Skåne University Hospital, Lund University, Malmö, Sweden

    Emma Ahlqvist & Leif Groop

  12. Department of Clinical Sciences, Paediatrics, Umeå University, Umeå, Sweden

    Anna Möllsten

  13. Department of Paediatrics, Institute of Metabolic Science, University of Cambridge, Cambridge, UK

    M. Loredana Marcovecchio & David Dunger

  14. Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK

    Jason Cooper

  15. Genetics and Genome Biology Program, Hospital for Sick Children Research Institute, Toronto, ON, Canada

    Andrew D. Paterson

  16. Complications of Diabetes Unit, Division of Metabolic and Cardiovascular Sciences, San Raffaele Scientific Institute, Milan, Italy

    Gianpaolo Zerbini

  17. Health, Aarhus University, Aarhus, Denmark

    Lise Tarnow

  18. Research Unit, Nordsjaellands Hospital, Hilleroed, Denmark

    Lise Tarnow

  19. Regional Nephrology Unit, Belfast City Hospital, Belfast, UK

    Alexander P. Maxwell

  20. Baker IDI Heart & Diabetes Institute, Melbourne, VIC, Australia

    Per-Henrik Groop

Authors
  1. Niina Sandholm
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  2. Carol Forsblom
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  6. Bing He
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  19. M. Loredana Marcovecchio
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  21. David Dunger
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  23. Gianpaolo Zerbini
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  26. Alexander P. Maxwell
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  27. Karl Tryggvason
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  28. Per-Henrik Groop
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on behalf of The SUMMIT Consortium

on behalf of the FinnDiane Study Group

Corresponding author

Correspondence to Per-Henrik Groop.

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Sandholm, N., Forsblom, C., Mäkinen, VP. et al. Genome-wide association study of urinary albumin excretion rate in patients with type 1 diabetes. Diabetologia 57, 1143–1153 (2014). https://doi.org/10.1007/s00125-014-3202-3

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