The Role of Genetic Variant rs13266634 in SLC30A8/ZnT8 in Postoperative Hyperglycemia after Major Abdominal Surgery

Context: Following major surgery, postoperative hyperglycemia (POHG) is associated with suboptimal outcomes among patients with diabetes and nondiabetic patients. A specific genetic variant, rs13266634 (c.973C>T; p.ARG325TRP) in zinc transporter SLC30A8/ZnT8, is associated with protection against type 2 diabetes (T2D), suggesting it may be actionable for predicting and preventing POHG. Objective: To determine independent and mediated influences of a genetic variant on POHG in patients undergoing a model major operation, complex ventral hernia repair (cVHR). Patients and Design: For 110 patients (mean body mass index, 34.9 ± 5.8; T2D history, 28%) undergoing cVHR at a tertiary referral center (January 2012 to March 2017), multivariable regression was used to correlate the rs13266634 variant to preoperative clinical, laboratory, and imaging-based indices of liver steatosis and central abdominal adiposity to POHG. Causal mediation analysis (CMA) was used to determine direct and mediated contributions of SLC30A8/ZnT8 status to POHG. Results: Variant rs13266634 was present in 61 patients (55.4%). In univariate models, when compared with patients with homozygous wild-type genotype (C/C, n = 49), rs13266634 was associated with significantly lower risks of POHG (OR, 0.30; 95% CI, 0.14 to 0.67; P = 0.0038). Multivariable regression indicated that the association was independent (OR, 0.39; 95% CI, 0.15 to 0.97; P = 0.040). Additionally, CMA suggested that rs13266634 protects against POHG directly and indirectly through its influence on liver steatosis and central adiposity. Conclusions: In medically complex patients undergoing major operations, the rs13266634 variant protects against POHG and its associated outcomes, through independent and mediated contributions. In C/C patients undergoing major operations, SLC30A8/ZnT8 may prove useful to stratify the risk of POHG and potentially as a therapeutic target.