Haplotypes of the caspase-1 gene, plasma caspase-1 levels, and cardiovascular risk

Circ Res. 2006 Jul 7;99(1):102-8. doi: 10.1161/01.RES.0000232324.87983.4b. Epub 2006 Jun 15.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Cardiovascular Diseases / etiology*
  • Cardiovascular Diseases / genetics
  • Cardiovascular Diseases / mortality
  • Case-Control Studies
  • Caspase 1 / blood*
  • Caspase 1 / genetics*
  • Cohort Studies
  • Coronary Artery Disease / blood*
  • Female
  • Follow-Up Studies
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genetic Variation*
  • Genotype
  • Haplotypes
  • Humans
  • Interleukin-18 / blood
  • Male
  • Middle Aged
  • Myocardial Infarction / genetics
  • Polymorphism, Single Nucleotide
  • Prospective Studies
  • Risk Assessment

Substances

  • Interleukin-18
  • Caspase 1