Effect of the PCSK9 R46L genetic variant on plasma insulin and glucose levels, risk of diabetes mellitus and cardiovascular disease: A meta-analysis

Background and Aim The impact of the loss-of-function (LOF) genetic variant PCSK9 R46L on glucose homeostasis and cardiovascular disease (CVD) remains uncertain, despite its established correlation with diminished blood cholesterol levels. This meta-analysis aimed at exploring the effect of the PCSK9 R46L genetic variant on plasma insulin and glucose levels, risk of diabetes mellitus and CVD. Methods and Results PubMed, Embase, and the Cochrane Library were searched for cohort and case–control studies published until October 1, 2023. The studies should report the association of the PCSK9 R46L genetic variant with one of the following: fasting plasma insulin, blood glucose levels, diabetes mellitus, and CVD risk. A dominant model of the PCSK9 R46L genetic variant was employed to statistical analysis. The meta-analyses were performed for continuous variables with standard mean difference (SMD), categorical variables with odds ratio (OR) using a random-effects model. A total of 17 articles with 20 studies engaging 1186861 population were identified and mobilized for these analyses. The overall results indicated that, compared with non-carriers of the PCSK9 R46L genetic variant, carriers of the PCSK9 R46L genetic variant did not increase or decrease the levels of fasting plasma insulin (3 studies with 7277 population; SMD, 0.08; 95% CI, -0.04 to 0.19; P=0.270), and the levels of fasting plasma glucose (7 studies with 9331 population; SMD, 0.03; 95% CI, -0.08 to 0.13; P=0.610). However, carriers of the PCSK9 R46L genetic variant indeed had 17% reduction in the risk of CVD (11 studies with 558263 population; OR, 0.83; 95% CI, 0.71 to 0.98; P=0.030), and 9% increase in the risk of diabetes mellitus (10 studies with 744466 population; OR, 1.09; 95% CI, 1.04 to 1.14; P<0.01). Meta-regression analyses indicated that the increased risk of diabetes mellitus and the reduced risk of CVD were positively correlated with reduction in LDL-C (P=0.004 and 0.033, respectively). Conclusions PCSK9 R46L genetic variant exhibited an elevated susceptibility to diabetes mellitus alongside a reduced vulnerability to CVD.