Skip to main content
Erschienen in: Diabetologia 7/2018

20.04.2018 | Article

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

verfasst von: 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

Erschienen in: Diabetologia | Ausgabe 7/2018

Einloggen, um Zugang zu erhalten

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
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
Zurück zum Zitat Demeester S, Balke EM, Van der Auwera BJ et al (2016) HLA-A*24 carrier status and autoantibody surges posttransplantation associate with poor functional outcome in recipients of an islet allograft. Diabetes Care 39:1060–1064CrossRefPubMed Demeester S, Balke EM, Van der Auwera BJ et al (2016) HLA-A*24 carrier status and autoantibody surges posttransplantation associate with poor functional outcome in recipients of an islet allograft. Diabetes Care 39:1060–1064CrossRefPubMed
2.
Zurück zum Zitat Wenzlau JM, Juhl K, Yu L et al (2007) The cation efflux transporter ZnT8 (SLC30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci U S A 104:17040–17045CrossRefPubMedPubMedCentral Wenzlau JM, Juhl K, Yu L et al (2007) The cation efflux transporter ZnT8 (SLC30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci U S A 104:17040–17045CrossRefPubMedPubMedCentral
3.
Zurück zum Zitat Dang M, Rockell J, Wagner R et al (2011) Human type 1 diabetes is associated with T cell autoimmunity to zinc transporter 8. J Immunol 186:6056–6063CrossRefPubMedPubMedCentral Dang M, Rockell J, Wagner R et al (2011) Human type 1 diabetes is associated with T cell autoimmunity to zinc transporter 8. J Immunol 186:6056–6063CrossRefPubMedPubMedCentral
4.
Zurück zum Zitat Énée É, Kratzer R, Arnoux JB et al (2012) ZnT8 is a major CD8+ T cell-recognized autoantigen in pediatric type 1 diabetes. Diabetes 61:1779–1784CrossRefPubMedPubMedCentral Énée É, Kratzer R, Arnoux JB et al (2012) ZnT8 is a major CD8+ T cell-recognized autoantigen in pediatric type 1 diabetes. Diabetes 61:1779–1784CrossRefPubMedPubMedCentral
5.
Zurück zum Zitat Chimienti F, Devergnas S, Favier A, Seve M (2004) Identification and cloning of a beta-cell-specific zinc transporter, ZnT-8, localized into insulin secretory granules. Diabetes 53:2330–2337CrossRefPubMed Chimienti F, Devergnas S, Favier A, Seve M (2004) Identification and cloning of a beta-cell-specific zinc transporter, ZnT-8, localized into insulin secretory granules. Diabetes 53:2330–2337CrossRefPubMed
6.
Zurück zum Zitat Palmiter RD, Huang L (2004) Efflux and compartmentalization of zinc by members of the SLC30 family of solute carriers. Pflugers Arch 447:744–751CrossRefPubMed Palmiter RD, Huang L (2004) Efflux and compartmentalization of zinc by members of the SLC30 family of solute carriers. Pflugers Arch 447:744–751CrossRefPubMed
7.
Zurück zum Zitat Solomou A, Meur G, Bellomo E et al (2015) The zinc transporter SLC30A8/ZnT8 is required in a subpopulation of pancreatic alpha-cells for hypoglycemia-induced glucagon secretion. J Biol Chem 290:21432–21442CrossRefPubMedPubMedCentral Solomou A, Meur G, Bellomo E et al (2015) The zinc transporter SLC30A8/ZnT8 is required in a subpopulation of pancreatic alpha-cells for hypoglycemia-induced glucagon secretion. J Biol Chem 290:21432–21442CrossRefPubMedPubMedCentral
8.
Zurück zum Zitat Smidt K, Pedersen SB, Brock B et al (2007) Zinc-transporter genes in human visceral and subcutaneous adipocytes: lean versus obese. Mol Cell Endocrinol 264:68–73CrossRefPubMed Smidt K, Pedersen SB, Brock B et al (2007) Zinc-transporter genes in human visceral and subcutaneous adipocytes: lean versus obese. Mol Cell Endocrinol 264:68–73CrossRefPubMed
9.
Zurück zum Zitat Wenzlau JM, Liu Y, Yu L et al (2008) A common nonsynonymous single nucleotide polymorphism in the SLC30A8 gene determines ZnT8 autoantibody specificity in type 1 diabetes. Diabetes 57:2693–2697CrossRefPubMedPubMedCentral Wenzlau JM, Liu Y, Yu L et al (2008) A common nonsynonymous single nucleotide polymorphism in the SLC30A8 gene determines ZnT8 autoantibody specificity in type 1 diabetes. Diabetes 57:2693–2697CrossRefPubMedPubMedCentral
10.
11.
Zurück zum Zitat Kang ES, Kim MS, Kim YS et al (2008) A polymorphism in the zinc transporter gene SLC30A8 confers resistance against posttransplantation diabetes mellitus in renal allograft recipients. Diabetes 57:1043–2047CrossRefPubMed Kang ES, Kim MS, Kim YS et al (2008) A polymorphism in the zinc transporter gene SLC30A8 confers resistance against posttransplantation diabetes mellitus in renal allograft recipients. Diabetes 57:1043–2047CrossRefPubMed
12.
Zurück zum Zitat Sladek R, Rocheleau G, Rung J et al (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445:881–885CrossRefPubMed Sladek R, Rocheleau G, Rung J et al (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445:881–885CrossRefPubMed
13.
15.
Zurück zum Zitat Hosseini-Esfahani F, Mirmiran P, Koochakpoor G et al (2017) Some dietary factors can modulate the effect of the zinc transporters 8 polymorphism on the risk of metabolic syndrome. Sci Rep 7:1649CrossRefPubMedPubMedCentral Hosseini-Esfahani F, Mirmiran P, Koochakpoor G et al (2017) Some dietary factors can modulate the effect of the zinc transporters 8 polymorphism on the risk of metabolic syndrome. Sci Rep 7:1649CrossRefPubMedPubMedCentral
16.
Zurück zum Zitat Hardy AB, Wijesekara N, Genkin I et al (2012) Effects of high-fat diet feeding on Znt8-null mice: differences between beta cell and global knockout of Znt8. Am J Physiol Endocrinol Metab 302:E1084–E1096CrossRefPubMedPubMedCentral Hardy AB, Wijesekara N, Genkin I et al (2012) Effects of high-fat diet feeding on Znt8-null mice: differences between beta cell and global knockout of Znt8. Am J Physiol Endocrinol Metab 302:E1084–E1096CrossRefPubMedPubMedCentral
17.
Zurück zum Zitat Ferrara CT, Geyer SM, Liu YF et al (2017) Excess BMI in childhood: a modifiable risk factor for type 1 diabetes development? Diabetes Care 40:698–701CrossRefPubMedPubMedCentral Ferrara CT, Geyer SM, Liu YF et al (2017) Excess BMI in childhood: a modifiable risk factor for type 1 diabetes development? Diabetes Care 40:698–701CrossRefPubMedPubMedCentral
18.
Zurück zum Zitat Lauria A, Barker A, Schloot N et al (2015) BMI is an important driver of beta cell loss in type 1 diabetes upon diagnosis in 10- to 18-year-old children. Eur J Endocrinol 172:107–113CrossRefPubMed Lauria A, Barker A, Schloot N et al (2015) BMI is an important driver of beta cell loss in type 1 diabetes upon diagnosis in 10- to 18-year-old children. Eur J Endocrinol 172:107–113CrossRefPubMed
19.
Zurück zum Zitat Gillard P, Hilbrands R, Van de Velde U et al (2013) Minimal functional beta-cell mass in intraportal implants that reduces glycemic variability in type 1 diabetic recipients. Diabetes Care 36:3483–3488CrossRefPubMedPubMedCentral Gillard P, Hilbrands R, Van de Velde U et al (2013) Minimal functional beta-cell mass in intraportal implants that reduces glycemic variability in type 1 diabetic recipients. Diabetes Care 36:3483–3488CrossRefPubMedPubMedCentral
20.
Zurück zum Zitat Campbell PM, Salam A, Ryan EA et al (2007) Pretransplant HLA antibodies are associated with reduced graft survival after clinical islet transplantation. Am J Transplant 7:1242–1248CrossRefPubMed Campbell PM, Salam A, Ryan EA et al (2007) Pretransplant HLA antibodies are associated with reduced graft survival after clinical islet transplantation. Am J Transplant 7:1242–1248CrossRefPubMed
21.
Zurück zum Zitat Brooks AM, Carter V, Liew A et al (2015) De novo donor specific HLA antibodies are associated with rapid loss of graft function following islet transplantation in type 1 diabetes. Am J Transplant 15:3239–3246CrossRefPubMed Brooks AM, Carter V, Liew A et al (2015) De novo donor specific HLA antibodies are associated with rapid loss of graft function following islet transplantation in type 1 diabetes. Am J Transplant 15:3239–3246CrossRefPubMed
22.
Zurück zum Zitat Keymeulen B, Gillard P, Mathieu C et al (2006) Correlation between beta cell mass and glycemic control in type 1 diabetic recipients of islet cell graft. Proc Natl Acad Sci U S A 103:17444–17449CrossRefPubMedPubMedCentral Keymeulen B, Gillard P, Mathieu C et al (2006) Correlation between beta cell mass and glycemic control in type 1 diabetic recipients of islet cell graft. Proc Natl Acad Sci U S A 103:17444–17449CrossRefPubMedPubMedCentral
23.
Zurück zum Zitat De Pauw PE, Vermeulen I, Ubani OC et al (2008) Simultaneous measurement of plasma concentrations of proinsulin and C-peptide and their ratio with a trefoil-type time-resolved fluorescence immunoassay. Clin Chem 54:1990–1998CrossRefPubMed De Pauw PE, Vermeulen I, Ubani OC et al (2008) Simultaneous measurement of plasma concentrations of proinsulin and C-peptide and their ratio with a trefoil-type time-resolved fluorescence immunoassay. Clin Chem 54:1990–1998CrossRefPubMed
24.
Zurück zum Zitat Van Dalem A, Demeester S, Balti EV et al (2016) Prediction of impending diabetes through automated dual-label measurement of proinsulin:C-peptide ratio. PLoS One 11:E0166702CrossRefPubMedPubMedCentral Van Dalem A, Demeester S, Balti EV et al (2016) Prediction of impending diabetes through automated dual-label measurement of proinsulin:C-peptide ratio. PLoS One 11:E0166702CrossRefPubMedPubMedCentral
25.
Zurück zum Zitat Demeester S, Keymeulen B, Kaufman L et al (2015) Preexisting insulin autoantibodies predict efficacy of otelixizumab in preserving residual beta cell function in recent-onset type 1 diabetes. Diabetes Care 38:644–651PubMedPubMedCentral Demeester S, Keymeulen B, Kaufman L et al (2015) Preexisting insulin autoantibodies predict efficacy of otelixizumab in preserving residual beta cell function in recent-onset type 1 diabetes. Diabetes Care 38:644–651PubMedPubMedCentral
26.
Zurück zum Zitat Decochez K, Tits J, Coolens JL et al (2000) High frequency of persisting or increasing islet-specific autoantibody levels after diagnosis of type 1 diabetes presenting before 40 years of age. The Belgian Diabetes Registry. Diabetes Care 23:838–844CrossRefPubMed Decochez K, Tits J, Coolens JL et al (2000) High frequency of persisting or increasing islet-specific autoantibody levels after diagnosis of type 1 diabetes presenting before 40 years of age. The Belgian Diabetes Registry. Diabetes Care 23:838–844CrossRefPubMed
27.
Zurück zum Zitat Mbunwe E, Van der Auwera BJ, Vermeulen I et al (2013) HLA-A*24 is an independent predictor of 5-year progression to diabetes in autoantibody-positive first-degree relatives of type 1 diabetic patients. Diabetes 62:1345–1350CrossRefPubMedPubMedCentral Mbunwe E, Van der Auwera BJ, Vermeulen I et al (2013) HLA-A*24 is an independent predictor of 5-year progression to diabetes in autoantibody-positive first-degree relatives of type 1 diabetic patients. Diabetes 62:1345–1350CrossRefPubMedPubMedCentral
28.
Zurück zum Zitat Schleinitz D, Distefano JK, Kovacs P (2011) Targeted SNP genotyping using the TaqMan® assay. Methods Mol Biol 700:77–87CrossRefPubMed Schleinitz D, Distefano JK, Kovacs P (2011) Targeted SNP genotyping using the TaqMan® assay. Methods Mol Biol 700:77–87CrossRefPubMed
29.
Zurück zum Zitat Vittinghoff E, McCulloch CE (2007) Relaxing the rule of ten events per variable in logistic and cox regression. Am J Epidemiol 165:710–718CrossRefPubMed Vittinghoff E, McCulloch CE (2007) Relaxing the rule of ten events per variable in logistic and cox regression. Am J Epidemiol 165:710–718CrossRefPubMed
31.
Zurück zum Zitat Piemonti L, Everly MJ, Maffi P et al (2013) Alloantibody and autoantibody monitoring predicts islet transplantation outcome in human type 1 diabetes. Diabetes 62:1656–1664CrossRefPubMedPubMedCentral Piemonti L, Everly MJ, Maffi P et al (2013) Alloantibody and autoantibody monitoring predicts islet transplantation outcome in human type 1 diabetes. Diabetes 62:1656–1664CrossRefPubMedPubMedCentral
32.
Zurück zum Zitat Braghi S, Bonifacio E, Secchi A et al (2000) Modulation of humoral islet autoimmunity by pancreas allotransplantation influences allograft outcome in patients with type 1 diabetes. Diabetes 49:218–224CrossRefPubMed Braghi S, Bonifacio E, Secchi A et al (2000) Modulation of humoral islet autoimmunity by pancreas allotransplantation influences allograft outcome in patients with type 1 diabetes. Diabetes 49:218–224CrossRefPubMed
33.
Zurück zum Zitat Vantyghem MC, Defrance F, Quintin D et al (2014) Treating diabetes with islet transplantation: lessons from the past decade in Lille. Diabetes Metab 40:108–119CrossRefPubMed Vantyghem MC, Defrance F, Quintin D et al (2014) Treating diabetes with islet transplantation: lessons from the past decade in Lille. Diabetes Metab 40:108–119CrossRefPubMed
34.
Zurück zum Zitat Shapiro AM, Ricordi C, Hering BJ et al (2006) International trial of the Edmonton protocol for islet transplantation. N Engl J Med 355:1318–1330CrossRefPubMed Shapiro AM, Ricordi C, Hering BJ et al (2006) International trial of the Edmonton protocol for islet transplantation. N Engl J Med 355:1318–1330CrossRefPubMed
36.
Zurück zum Zitat Huurman V, Hilbrands R, Pinkse C et al (2008) Cellular islet autoimmunity associates with clinical outcome of islet cell transplantation. PLoS One 3:e2435CrossRefPubMedPubMedCentral Huurman V, Hilbrands R, Pinkse C et al (2008) Cellular islet autoimmunity associates with clinical outcome of islet cell transplantation. PLoS One 3:e2435CrossRefPubMedPubMedCentral
37.
Zurück zum Zitat Hilbrands R, Huurman VA, Gillard P et al (2009) Differences in baseline lymphocyte counts and autoreactivity are associated with differences in outcome of islet cell transplantation in type 1 diabetic patients. Diabetes 58:2267–2276CrossRefPubMedPubMedCentral Hilbrands R, Huurman VA, Gillard P et al (2009) Differences in baseline lymphocyte counts and autoreactivity are associated with differences in outcome of islet cell transplantation in type 1 diabetic patients. Diabetes 58:2267–2276CrossRefPubMedPubMedCentral
38.
Zurück zum Zitat Ling Z, De Pauw P, Jacobs-Tulleneers D et al (2015) Plasma GAD65, a marker for early β-cell loss after intraportal islet cell transplantation in diabetic patients. J Clin Endocrinol Metab 100:2314–2321CrossRefPubMedPubMedCentral Ling Z, De Pauw P, Jacobs-Tulleneers D et al (2015) Plasma GAD65, a marker for early β-cell loss after intraportal islet cell transplantation in diabetic patients. J Clin Endocrinol Metab 100:2314–2321CrossRefPubMedPubMedCentral
39.
Zurück zum Zitat Shapiro AMJ (2011) State of the art of clinical islet transplantation and novel protocols of immunosuppression. Curr Diab Rep 11:345–354CrossRefPubMed Shapiro AMJ (2011) State of the art of clinical islet transplantation and novel protocols of immunosuppression. Curr Diab Rep 11:345–354CrossRefPubMed
40.
Zurück zum Zitat Nakanishi K, Inoko H (2006) Combination of HLA-A*24, -DQA1*03, and -DR9 contributes to acute-onset and early complete beta-cell destruction in type 1 diabetes: longitudinal study of residual beta-cell function. Diabetes 55:1862–1868CrossRefPubMed Nakanishi K, Inoko H (2006) Combination of HLA-A*24, -DQA1*03, and -DR9 contributes to acute-onset and early complete beta-cell destruction in type 1 diabetes: longitudinal study of residual beta-cell function. Diabetes 55:1862–1868CrossRefPubMed
41.
Zurück zum Zitat Chatenoud L (2008) Chemical immunosuppression in islet transplantation—friend or foe? N Engl J Med 358:1192–1193CrossRefPubMed Chatenoud L (2008) Chemical immunosuppression in islet transplantation—friend or foe? N Engl J Med 358:1192–1193CrossRefPubMed
42.
Zurück zum Zitat Nielsen LB, Vaziri-Sani F, Pörksen S et al (2011) Relationship between ZnT8, the SLC30A8 gene and disease progression in children with newly diagnosed type 1 diabetes. Autoimmunity 44:616–623CrossRefPubMed Nielsen LB, Vaziri-Sani F, Pörksen S et al (2011) Relationship between ZnT8, the SLC30A8 gene and disease progression in children with newly diagnosed type 1 diabetes. Autoimmunity 44:616–623CrossRefPubMed
43.
Zurück zum Zitat Moosavi M, Séguin J, Li Q, Polychronakos C (2012) The effect of type 2 diabetes risk loci on insulin requirements in type 1 diabetes. Horm Res Paediatr 77:305–308CrossRefPubMed Moosavi M, Séguin J, Li Q, Polychronakos C (2012) The effect of type 2 diabetes risk loci on insulin requirements in type 1 diabetes. Horm Res Paediatr 77:305–308CrossRefPubMed
44.
Zurück zum Zitat Nicolson TJ, Bellomo EA, Wijesekara N et al (2009) Insulin storage and glucose homeostasis in mice null for the granule zinc transporter ZnT8 and studies of the type 2 diabetes-associated variants. Diabetes 58:2070–2083CrossRefPubMedPubMedCentral Nicolson TJ, Bellomo EA, Wijesekara N et al (2009) Insulin storage and glucose homeostasis in mice null for the granule zinc transporter ZnT8 and studies of the type 2 diabetes-associated variants. Diabetes 58:2070–2083CrossRefPubMedPubMedCentral
45.
Zurück zum Zitat Leitão CB, Bernetti K, Tharavanij T et al (2009) Type 2 diabetes mellitus phenotype and graft survival after islet transplantation. Transplantation 88:57–61CrossRefPubMedPubMedCentral Leitão CB, Bernetti K, Tharavanij T et al (2009) Type 2 diabetes mellitus phenotype and graft survival after islet transplantation. Transplantation 88:57–61CrossRefPubMedPubMedCentral
46.
Zurück zum Zitat Al-Adra DP, Gill RS, Imes S et al (2014) Single-donor transplantation and long-term insulin-independence in select patients with type 1 diabetes mellitus. Transplantation 98:1007–1012CrossRefPubMed Al-Adra DP, Gill RS, Imes S et al (2014) Single-donor transplantation and long-term insulin-independence in select patients with type 1 diabetes mellitus. Transplantation 98:1007–1012CrossRefPubMed
Metadaten
Titel
SLC30A8 polymorphism and BMI complement HLA-A*24 as risk factors for poor graft function in islet allograft recipients
verfasst von
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
Publikationsdatum
20.04.2018
Verlag
Springer Berlin Heidelberg
Erschienen in
Diabetologia / Ausgabe 7/2018
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-018-4609-z

Weitere Artikel der Ausgabe 7/2018

Diabetologia 7/2018 Zur Ausgabe

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.