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

Abstract

Abstract 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.