Haplotypes of the caspase-1 gene, plasma caspase-1 levels, and cardiovascular risk.
Caspase-1 processes the interleukin (IL)-1beta and IL-18 inactive precursors to the biologically active cytokines that are known to have proatherogenic effects. The present study investigated the genetic variability of the CASP1 gene and plasma levels of caspase-1 in relation to cardiovascular risk. In Europeans, 3 tag SNPs captured 4 common haplotypes of the CASP1 gene. Among these, the A(in6) allele of the G+7/in6A polymorphism was less frequent in 246 cases with myocardial infarction and a parental history of disease than in 253 controls free of familial history of disease (0.13+/-0.02 versus 0.20+/-0.02; P=0.005). However, in a larger case/control study (n=1774), these effects are borderline restricted to the UK population. In a prospective cohort of 1168 patients with coronary artery disease followed up during a median period of 6.0 years, the A(in6) allele exhibited a borderline association with future cardiovascular death (hazard ratio [HR]: 0.64, 0.41 to 1.01; P=0.053) and was associated with lower serum IL-18 levels (P=0.014). Baseline caspase-1 levels in the top quartile of the distribution were predictive of cardiovascular deaths (HR=3.62, 1.81 to 7.27; P=0.0003 compared with the bottom quartile). Finally, in vitro assays of allelic imbalance showed that the CASP1 haplotype carrying the A(in6) allele was associated with a lower mRNA expression. These results indicate that caspase-1 levels are predictive of future cardiovascular death in patients with coronary artery disease. The role of CASP1 genetic variations in the susceptibility to myocardial infarction requires further investigation.
Blankenberg
Stefan
S
Department of Medicine II, Johannes Gutenberg-University Mainz, Mainz, Germany. blankenberg@2-med.klinik.uni-mainz.de
Godefroy
Tiphaine
T
Poirier
Odette
O
Rupprecht
Hans J
HJ
Barbaux
Sandrine
S
Bickel
Christoph
C
Nicaud
Viviane
V
Schnabel
Renate
R
Kee
Frank
F
Morrison
Caroline
C
Evans
Alun
A
Lackner
Karl J
KJ
Cambien
François
F
Münzel
Thomas
T
Tiret
Laurence
L
D000328:Adult; D000368:Aged; D002318:Cardiovascular Diseases / Q000209:etiology* / Q000235:genetics / Q000401:mortality; D016022:Case-Control Studies; D020170:Caspase 1 / Q000097:blood* / Q000235:genetics*; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000097:blood*; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D020382:Interleukin-18 / Q000097:blood; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D018570:Risk Assessment
D020382:Interleukin-18; D020170:Caspase 1