Else M Balke1, Simke Demeester2, DaHae Lee2,3, Pieter Gillard2,3, Robert Hilbrands2, Ursule Van de Velde2, Bart J Van der Auwera2, Zhidong Ling2, Bart O Roep4,5, Daniël G Pipeleers2, Bart Keymeulen2, Frans K Gorus2. 1. Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium. else.balke@vub.be. 2. Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium. 3. Department of Endocrinology, University Hospitals Leuven, Leuven, Belgium. 4. Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands. 5. Department of Diabetes Immunology, Diabetes and Metabolism Research Institute, Beckman Research Institute at the City of Hope, Duarte, CA, USA.
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.
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.
Entities:
Keywords:
Body mass index; Genetics of type 1 diabetes; HLA class I; Human islet transplantation; Zinc transporter 8
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