No causal association between plasma cystatin C and cardiovascular diseases: Mendelian randomization analyses in UK biobank

Abstract

Background: We aimed to determine whether the plasma cystatin C is a causal risk factor for cardiovascular events, stroke, myocardial infarction (MI), and cardiovascular disease (CVD) mortality by conducting Mendelian randomization (MR) designs.

Methods: Our study included 277,057 individuals free of CVDs or cancer at baseline in the UK Biobank. The genetic scores of plasma cystatin C comprising 67 single-nucleotide polymorphisms were calculated on the basis of data from a large genome-wide association study. By stratifying the genetic score, we conducted cox regression to assess the relationship between plasma cystatin C and CVDs. In this study, linear MR analysis was used to estimate the causal association between plasma cystatin C and CVDs.

Results: Observational analyses showed that plasma cystatin C concentrations were associated with the risk of CVDs [hazard ratios (HR) per standard deviation (SD) 1.09, 95% confidence interval (CI); 1.07-1.10] and CVD mortality (1.14, 1.11-1.17). Among CVDs, plasma cystatin C were associated with stroke (1.10, 1.08-1.11) and MI (1.08, 1.07-1.10). Linear MR analysis did not provide evidence of a causal association between plasma cystatin C and the risk of CVDs [odds ratio (OR) per SD 0.96, 95% CI;0.90-1.03], stroke (0.96, 0.93-1.01), MI (0.97, 0.91-1.03), and CVD mortality (0.98, 0.96-1.01), with consistent estimates from sensitivity analyses.

Conclusion: Observational findings indicated that higher plasma cystatin C is associated with a higher risk of CVDs; According to MR studies, there is no causal association between plasma cystatin C and the risk of CVDs and CVD mortality.

Keywords: Mendelian randomization; cardiovascular disease; genetic risk; myocardial infarction; plasma cystatin C; stroke.

Figure 1

The association between plasma cystatin C and CVD events and CVD mortality in the UK Biobank study. Results were adjusted for age, sex, Townsend Deprivation Index (continuous), household income (<£18 000, £18 000-£52000, £52000-£100000, or >£100000), physical activity (<250 min/week, 250-550 min/week, >550 min/week), smoking status (never, former, current), drinking status (never, former, current), employment (no, yes), BMI (continuous), HDL cholesterol (continuous), LDL cholesterol (continuous), total cholesterol, diabetes (yes or no), hypertension (yes or no) and chronic kidney disease (yes or no). Hazard Ratios (HRs) at each category Q2-Q5 (compared with Q1) and per 1-standard deviation (SD) of each plasma cystatin C, estimated from Cox regression models. P value for trend was calculated as the trend per group.

Figure 2

The association between plasma cystatin C with CVD events stratified by Cystatin C–GRS. Model were adjusted for age, sex, TDI (continuous), household income (<£18 000, £18 000-£52000, £52000-£100000, or >£100000), physical activity (<250 min/week, 250-550 min/week, >550 min/week), smoking status (never, former, current), drinking status (never, former, current), employment (no, yes), BMI (continuous), HDL cholesterol (continuous), LDL cholesterol (continuous) and total cholesterol, diabetes (yes or no), hypertension (yes or no) and chronic kidney disease (yes or no).

Figure 3

Linear Mendelian randomization estimates for the associations of genetically predicted plasma cystatin C with CVD events and CVD mortality in the UK Biobank. Odds ratios were estimated by two-stage least squares regression method. Model1:adjusted for age, sex, Townsend Deprivation Index (continuous), household income (<£18 000, £18 000-£52000, £52000-£100000, or >£100000), physical activity (<250 min/week, 250-550 min/week, >550 min/week), smoking status (never, former, current), drinking status (never, former, current), employment (no, yes). Model2: model1 + BMI (continuous), HDL cholesterol (continuous), LDL cholesterol (continuous) and total cholesterol. Model3: model2 + diabetes (yes or no), hypertension (yes or no) and chronic kidney disease (yes or no).