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

Abstract

Plasma kallikrein formed from prekallikrein (PK) produces bradykinin from kininogens and activates factor XII. Plasma PK is activated by factors αXIIa, βXIIa, or prolylcarboxypeptidase (PRCP). A cross-sectional investigation determined if there is an association of PRCP and KLKB1 polymorphisms with cardiovascular disease (CVD). DNA was obtained from 2243 individuals from the Prevention of Events with Angiotensin Converting Enzyme trial. Two PRCP SNPs, rs7104980 and rs2298668, and two KLKB1 SNPs, rs3733402 and rs3087505, were genotyped. Logistic regression models were performed for history of diabetes, myocardial infarction, stroke, angina, angiographic coronary disease, CABG, intermittent claudication, percutaneous transluminal coronary angioplasty (PTCA), and transient ischemic attack. The PRCP SNP rs7104980 increased the odds of having a history of PTCA by 21% [odds ratio (OR) = 1.211; 95% confidence intervals (CI) = (1.008, 1.454)]; P = 0.041, but was non-significant after Bonferroni correction. Alternatively, having the G allele for rs3733402 (KLKB1 gene) decreased the odds of having a history of angiographic coronary disease by 24% [OR = 0.759; 95% CI = (0.622, 0.927)]; P = 0.007 that was statistically significant (P < 0.01) after Bonferroni correction for multiple hypothesis testing. When the best-fit model based on the Akaike information criterion controlled for age, weight, gender, hypertension, and history of angina, the G allele of KLKB1 rs3733402 that is associated with less plasma kallikrein activity correlated with reduced history of CVD.

Antithrombotic potential of the contact activation pathway

“…This observation suggests that another mechanism is occurring for thrombosis inhibition. This observation also supports the epidemiologic data that PK has an additional role in accelerating cardiovascular disease 45–47 . Several recent epidemiologic studies indicate that PK contributes to cardiovascular disease especially in diabetics 45–47 .…”

“…This observation also supports the epidemiologic data that PK has an additional role in accelerating cardiovascular disease 45–47 . Several recent epidemiologic studies indicate that PK contributes to cardiovascular disease especially in diabetics 45–47 . The mechanism(s) by which PK contributes to stroke protection is not completely known but it may be related to an influence of PK on leukocyte function 43 .…”

Genetic Determinants of C1 Inhibitor Deficiency Angioedema Age of Onset

“…Moreover, given that PK converts prorenin to renin, albeit in low pH [20] , this variant has been shown to be linked to disruption of enzymatic cascade events leading to a diminished formation of active renin [10] . Finally, this variant exhibits a strong association with pre-pro-endothelin-1 and prepro-adrenomedullin [21] , and with a reduced history of cardiovascular disease [11] . With regard to the functionality of the F12 -46C/T polymorphism, located in the promoter region of the F12 gene at nt46, it is known that it creates a new initiation codon (ATG) for transcription of the mRNA and a frameshift that produces a truncated protein.…”

“…Most of the reported KLKB1 polymorphisms are located in noncoding regions. The KLKB1 -428G/A polymorphism (rs3733402), however, is located in exon 5, where it leads to the amino acid substitution Asn124Ser [8,9] , and strong evidence indicates that this mutation is linked to functional consequences [10,11] .…”

Plasma contact factors as therapeutic targets

“…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]. …”