Context: Following major surgery, post-operative hyperglycemia (POHG) is associated with suboptimal outcomes, among diabetics and non-diabetics. A specific genetic variant, rs13266634 (c.973C>T; p.ARG325TRP) in zinc transporter SLC30A8/ZnT8, is associated with protection against Type-2 Diabetes, 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 abdominal ventral hernia repair (cVHR). Patients and Methods: For 110 patients (mean BMI 34.95.8, T2D history 28%) undergoing cVHR at a tertiary referral center (January 2012 to March 2017), multivariate regression was used to correlate the rs13266634 variant to pre-operative 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 to patients with rs13266634, the homozygous wild-genotype (C/C, n=49) was associated with significantly higher risks of POHG (OR= 0.30 95%CI =0.14, 0.67, P=0.0038). Multivariate regression indicated that the association was independent (OR= 0.39 95%CI 0.15-0.97, p=0.040). In addition, 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 risk of POHG and potentially as a therapeutic target.
- Paddy Ssentongo
- ZnT8, Post-operative hyperglycemia, Type-2 Diabetes, Obesity, Non-Alcoholic Fatty Liver Disease (NAFLD), Causal Mediation Analysis
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