A Polymorphism in the Zinc Transporter Gene SLC30A8 Confers Resistance Against Posttransplantation Diabetes Mellitus in Renal Allograft Recipients

Abstract

OBJECTIVE—Posttransplantation diabetes mellitus (PTDM) is a major metabolic complication in renal transplant recipients, and insulin secretory defects play an important role in the pathogenesis of PTDM. The R325W (rs13266634) nonsynonymous polymorphism in the islet-specific zinc transporter protein gene, SLC30A8, has been reported to be associated with type 2 diabetes and possibly with a defect in insulin secretion. This study investigated the association between genetic variations in the SLC30A8 gene and PTDM in renal allograft recipients. RESEARCH DESIGN AND METHODS—A total of 624 unrelated renal allograft recipients without previously diagnosed diabetes were enrolled. Rs13266634 was genotyped in the cohort, which consisted of 174 posttransplantation diabetic patients and 450 non-posttransplantation diabetic subjects. The genotyping of the SLC30A8 polymorphism was performed using real-time PCR. RESULTS—The prevalence of PTDM was 33.8% in patients carrying the R/R genotype, 26.8% in patients with the R/W genotype, and 19.8% in patients with the W/W genotype. There was a strong association between the number of W-alleles and PTDM risk reduction (P for trend = 0.007). Patients with at least one T-allele showed a decreased risk of PTDM compared with those with the R/R genotype (R/W, risk ratio [RR] 0.78, P = 0.126; W/W, RR 0.52, P = 0.007). The effect of the SLC30A8 genotype remained significant after adjustments for age, sex, body weight gain, and type of immunosuppressant (R/W, hazard ratio [HR] 0.77, P = 0.114; W/W, HR 0.58, P = 0.026). CONCLUSIONS—These data provide evidence that the SLC30A8 rs13266634 gene variation is associated with protection from the development of PTDM in renal allograft recipients.

A low-risk ZnT-8 allele (W325) for post-transplantation diabetes mellitus is protective against cyclosporin A-induced impairment of insulin secretion

“…The unexpected interaction between ZnT-8 and CsA or calcineurin was inferred from our previous human genetic association study. 8 It has long been known that CsA treatment is correlated with the onset of PTDM, for reasons that remain to be elucidated. 3,29,30 The differing effects of two ZnT-8 variants on GSIS suggest that patients undergoing CsA immunosuppressive treatment who have the 'low-risk' ZnT-8 variant (W325) may retain insulin-secreting capacity compared with those who have the 'high-risk' variant; this may account for the protective ZnT-8 polymorphism and cyclosporin A I Kim et al effect of the W325 allele with respect to PTDM.…”

“…[4][5][6] Notably, SLC30A8 encodes the b-cell-specific zinc transporter-8 (ZnT-8). 7 We recently reported that the same allelic variant (which is a substitution of tryptophan for arginine at residue 325) of ZnT-8 is also associated with reduced incidence of PTDM in renal allograft recipients 8 (see Figure 1). To date, the molecular basis for PTDM has not been elucidated.…”

Zinc, pancreatic islet cell function and diabetes: new insights into an old story

“…Similarly, Staiger et al demonstrated that rs13266634 is associated with reduced insulin secretion stimulated by intravenously administered glucose (54) , suggesting that rs13266634 in SLC30A8 is a crucial allele for b-cell function. Moreover, the R325W non-synonymous polymorphism in ZnT8 has been shown to protect against post-transplantation diabetes mellitus (55) , a major metabolic complication in renal transplant recipients, for which insulin-secretory defects play an important role in pathogenesis. The same polymorphism in SLC30A8, rs13266634, has eventually been associated with glycated Hb (HbA1c), a marker of long-term blood glucose levels, in a non-diabetic population (56) .…”

Association of leptin receptor gene polymorphisms with post-transplant diabetes mellitus: Short report and literature review

“…In the last decade, numerous other genetic studies for PTDM have been conducted in renal transplant recipients, and nearly 50 loci have been established as suspected loci (Table 4) [7][8][9][10]13,[22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41]. Polymorphisms in AIPOQ, CAPN10, CDKAL1, CDKN2A/B, HHEX, KCN11, KCNQ1, SLC30A8, and TCFL2 are known to be associated with T2DM.…”