Serum gamma-glutamyl transferase and risk of type 2 diabetes in the general Korean population: A Mendelian randomization study

Elevated gamma-glutamyl transferase (GGT) levels are associated with higher risk of type 2 diabetes in observational studies, but the underlying causal relationship is still unclear. Here,we tested a hypothesis that GGT levels have a causal effect on type 2 diabetes risk using Mendelian randomization. Datawere collected from7640 participants in a South Korean population. In a single instrumental variable (IV) analysis using two stage least squares regression with the rs4820599 in the GGT1 gene regionas an instrument, one unit of GGT levels (IU/L)was associatedwith 11% higher risk of type 2 diabetes (odds ratio (OR)=1.11, 95% confidence interval (CI): 1.04 to 1.19). In a multiple IV analysis using seven genetic variants that have previously been demonstrated to be associated with GGT at a genome-wide level of significance, the corresponding estimate suggested a 2.6% increase in risk (OR=1.026, 95% CI: 1.001 to 1.052). In a two-sampleMendelian randomization analysis using genetic associationswith type 2 diabetes taken from a trans-ethnic GWAS study of 110 452 independent samples, the single IV analysis confirmed an association between the rs4820599 and type 2 diabetes risk (P-value=0.04); however, the estimate from themultiple IV analysis was compatiblewith the null (OR=1.007, 95% CI: 0.993 to 1.022)with considerable heterogeneity between the causal effects estimated using different genetic variants. Overall, there isweak genetic evidence that GGT levelsmay have a causal role in the development of type 2 diabetes.