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

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. 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. 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). 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. ClinicalTrials.gov NCT00798785 and NCT00623610.