Plasma Prekallikrein Is Associated With Carotid Intima-Media Thickness in Type 1 Diabetes

Abstract

The hypothesis that plasma prekallikrein (PK) is a risk factor for the development of vascular complications was assessed in a study using the Diabetes Control and Complications Trial (DCCT)/Epidemiology and Diabetes Interventions and Complications (EDIC) cohort of subjects with type 1 diabetes. The circulating levels of plasma PK activity were measured in the plasma of 636 subjects with type 1 diabetes (EDIC years 3–5). Common and internal carotid intima-media thickness (IMT) were measured by B-mode ultrasonography in EDIC years 1 and 6. Plasma PK levels were positively and significantly associated with BMI, hemoglobin A1c, systolic blood pressure, total cholesterol, LDL cholesterol, and triglycerides but not with age, sex, duration of diabetes, or HDL cholesterol. Univariate and multivariable statistical models after controlling for other risk factors consistently demonstrated a positive association between plasma PK and progression of internal carotid IMT. Multivariate analysis using a general linear model showed plasma PK to be significantly associated with progression of both internal and combined IMT (Wilks Λ P value of 0.005). In addition, the mean internal carotid IMT levels were higher in subjects with plasma PK levels in the highest 10th percentile compared with subjects with plasma PK levels in the lower 10th percentile (P = 0.048). These novel findings implicate plasma PK as a risk factor for vascular disease in type 1 diabetes.

A Cross-sectional Study of KLKB1 and PRCP Polymorphisms in Patient Samples with Cardiovascular Disease

“…Recent genome-wide meta-analysis studies indicate that the KLKB1 SNP rs3733402 has a positive correlation with circulating B-type natriuretic peptide, a recognized cardioprotective vasodilator in African Americans ( 29 ). Other recent studies show that PK deficient mice ( klkb1 −/− mice) have reduced arterial thrombosis providing support in mouse models to enhance the observation made in human association studies ( 6 – 9 ). It is of interest that mechanism for delayed thrombosis in klkb1 −/− mice is mediated in part through elevated prostacyclin and vasculo-protective transcription factors Sirt1 and KLF4 with reduction of vessel wall tissue factor and not reduced contact activation as is commonly believed ( 7 ).…”

“…Alternatively, the minor G allele of an exonic SNP rs3733402 (N124S) of KLKB1 is significantly associated with reduced CVD. These data suggest that a selected KLKB1 SNP (rs3733402) mirrors the phenotype observed in patient studies with diabetes and on murine deletions of klkb1 ( 7 – 9 ).…”

“…These combined studies suggest that PK contributes to vascular homeostasis. Infact, previous work by our own group demonstrated that elevated plasma PK correlates with accelerated vascular disease and proteinuria in a large population of diabetic patients ( 8 , 9 ).…”

“…Previous studies by us have shown that elevated plasma PK is associated with accelerated diabetic vascular disease ( 8 , 9 ). Elevations of plasma kallikrein may be associated with increased prorenin conversion to renin and renin formation leading to elevated angiotensin II.…”

Plasma contact factors as therapeutic targets

“…Elevated PK levels have been implicated in vascular disease, hypertension and nephropathy in diabetic patients in the Diabetes Control and Complications Trial/Epidemiology and Diabetes Intervention and Complications Study [108,109]. A PK Asn124Ser polymorphism that reduces HK binding was linked to reduced bradykinin and plasma renin concentrations [110,111], and with reduced risks for hypertension and coronary artery disease [112].…”