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Diabetologia

, Volume 61, Issue 7, pp 1623–1632 | Cite as

SLC30A8 polymorphism and BMI complement HLA-A*24 as risk factors for poor graft function in islet allograft recipients

  • Else M. Balke
  • Simke Demeester
  • DaHae Lee
  • Pieter Gillard
  • Robert Hilbrands
  • Ursule Van de Velde
  • Bart J. Van der Auwera
  • Zhidong Ling
  • Bart O. Roep
  • Daniël G. Pipeleers
  • Bart Keymeulen
  • Frans K. Gorus
Article

Abstract

Aims/hypothesis

HLA-A*24 carriership hampers achievement of insulin independence in islet allograft recipients. However, less than half of those who fail to achieve insulin independence carry the allele. We investigated whether genetic polymorphism at the recipients’ zinc transporter 8-encoding SLC30A8 gene (rs13266634) could complement their HLA-A*24 status in predicting functional graft outcome.

Methods

We retrospectively analysed data of a hospital-based patient cohort followed for 18 months post transplantation. Forty C-peptide-negative type 1 diabetic individuals who received >2 million beta cells (>4000 islet equivalents) per kg body weight in one or two intraportal implantations under similar immunosuppression were genotyped for SLC30A8. Outcome measurements included achievement and maintenance of graft function. Metabolic benefit was defined as <25% CV of fasting glycaemia in the presence of >331 pmol/l C-peptide, in addition to achievement of insulin independence and maintenance of C-peptide positivity.

Results

In multivariate analysis, HLA-A*24 positivity, presence of SLC30A8 CT or TT genotypes and BMI more than or equal to the group median (23.9 kg/m2) were independently associated with failure to achieve insulin independence (p = 0.015–0.046). The risk increased with the number of factors present (p < 0.001). High BMI interacted with SLC30A8 T allele carriership to independently predict difficulty in achieving graft function with metabolic benefit (p = 0.015). Maintenance of C-peptide positivity was mainly associated with older age at the time of implantation. Only HLA-A*24 carriership independently predicted failure to maintain acceptable graft function once achieved (p = 0.012).

Conclusions/interpretation

HLA-A*24, the SLC30A8 T allele and high BMI are associated with poor graft outcome and should be considered in the interpretation of future transplantation trials.

Trial registration

ClinicalTrials.gov NCT00798785 and NCT00623610

Keywords

Body mass index Genetics of type 1 diabetes HLA class I Human islet transplantation Zinc transporter 8 

Abbreviations

BW

Body weight

CVfg

CV of fasting glycaemia

IEQ

Islet equivalents

ZnT8

Zinc transporter 8

Notes

Acknowledgements

The authors thank M. Robyn, B. Swennen, K. Rouffe and N. Pardon (Leuven University Hospitals, Leuven, Belgium); S. Vandenhoeck, S. Thomas and V. Van Damme (Brussels University Hospitals, Brussels, Belgium); and R. Braspenning (Antwerp University Hospital, Antwerp, Belgium) for completing all clamp tests.

Contribution statement

EMB, SD, BK and FKG designed the study and acquired, researched and interpreted the data. EMB and SD performed the statistical analyses. DL, PG, RH, UVdV, BJVdA, ZL, BOR and DGP contributed to the data acquisition, analysis and interpretation. EMB and FKG drafted the manuscript and SD, DL, PG, RH, UVdV, BJVdA, ZL, BOR, DGP and BK revised it critically. All authors approved the final version of the manuscript. FKG and BK are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Funding

This study was supported by the JDRF (grant 4/2005/1327) and the Willy Gepts Fund of Brussels University Hospitals. PG is funded by the Clinical Research Foundation of Leuven University Hospitals, Catholic University of Leuven.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Supplementary material

125_2018_4609_MOESM1_ESM.pdf (858 kb)
ESM (PDF 858 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Else M. Balke
    • 1
  • Simke Demeester
    • 1
  • DaHae Lee
    • 1
    • 2
  • Pieter Gillard
    • 1
    • 2
  • Robert Hilbrands
    • 1
  • Ursule Van de Velde
    • 1
  • Bart J. Van der Auwera
    • 1
  • Zhidong Ling
    • 1
  • Bart O. Roep
    • 3
    • 4
  • Daniël G. Pipeleers
    • 1
  • Bart Keymeulen
    • 1
  • Frans K. Gorus
    • 1
  1. 1.Diabetes Research CenterVrije Universiteit BrusselBrusselsBelgium
  2. 2.Department of EndocrinologyUniversity Hospitals LeuvenLeuvenBelgium
  3. 3.Department of Immunohaematology and Blood TransfusionLeiden University Medical CenterLeidenthe Netherlands
  4. 4.Department of Diabetes Immunology, Diabetes and Metabolism Research InstituteBeckman Research Institute at the City of HopeDuarteUSA

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