A Mendelian randomization approach to assess the causal relationship of gamma-glutamyl transferase with blood pressure and insulin

Background: Elevated levels of g-glutamyl transferase (GGT) have been associated with subsequent risk of elevated blood pressure (BP), hypertension and diabetes. However, the causality of these relationships has not been addressed. Mendelian randomization refers to the random allocation of alleles at the time of gamete formation. Such allocation is expected to be independent of any behavioural and environmental factors (known or unknown), allowing the analysis of largely unconfounded risk associations that are not due to reverse causation. Methods: We performed a cross-sectional analysis among 4361 participants to the population based CoLaus study. Associations of sex-specific GGT quartiles with systolic BP, diastolic BP and insulin levels were assessed using multivariable linear regression analyses. The rs2017869 GGT1 variant, which explained 1.6% of the variance in GGT levels, was used as an instrument to perform a Mendelian randomization analysis. Results: Median age of the study population was 53 years. After age and sex adjustment, GGT quartiles were strongly associated with systolic and diastolic BP (all p for linear trend <0.0001). After multivariable adjustment, these relationships were significantly attenuated, but remained significant for systolic (b(95%CI)¼1.30 (0.32;2.03), p¼0.007) and diastolic BP (b (95%CI)¼0.57 (0.02;1.13), p¼0.04). Using Mendelian randomization, we observed no positive association of GGT with either systolic BP (b (95%CI)¼-5.68 (-11.51-0.16), p¼0.06) or diastolic BP (b (95%CI)¼ -2.24 (-5.98;1.49) p¼0.24). The association of GGT with insulin was also attenuated after multivariable adjustment. Nevertheless, a strong linear trend persisted in the fully adjusted model (b (95%CI)¼0.07 (0.04;0.09), p<0.0001). Using Mendelian randomization, we observed a similar positive association of GGT with insulin (b (95%CI)¼0.19 (0.01-0.37), p¼0.04). Conclusion: In this study, we found evidence for a direct causal relationship between GGT and insulin, suggesting that oxidative stress may be causally implicated in the pathogenesis of type 2 diabetes mellitus.