Haplotypes of the interleukin-1 receptor antagonist gene, interleukin-1 receptor antagonist mRNA levels and the risk of myocardial infarction.
BACKGROUND
The overall effect of the major pro-inflammatory cytokine interleukin-1 (IL-1) on coagulation and fibrinolysis is prothrombotic. We recently found that haplotype 5 (H5) of the gene (IL1RN) coding for the interleukin-1 receptor antagonist (IL-1Ra), the natural inhibitor of IL-1, is associated with an increased risk of venous thrombosis. It is unclear whether variations in IL1RN affect the risk of myocardial infarction.


OBJECTIVE
The aim of this study was to investigate the effect of the five most common haplotype groups of IL1RN on the risk of myocardial infarction and on IL1RN mRNA levels.


METHODS
We genotyped 5 single nucleotide polymorphisms (SNPs) in IL1RN in 560 male patients and 646 male control subjects of a population-based case-control study on myocardial infarction, enabling us to tag the five common haplotype groups of IL1RN. For all haplotype groups the relationship with the risk of myocardial infarction and IL1RN mRNA levels was determined.


RESULTS
An increased risk of myocardial infarction was found for haplotype 3 (H3) carriers (tagged by SNP 13760T/C, odds ratio=1.3; 95% confidence interval: 1.1-1.7) compared to non-H3 carriers. No effect on myocardial infarction risk was found for the other haplotypes. H3 carriers had decreased IL1RN mRNA levels compared to non-H3 carriers (p<0.01), whereas mRNA levels were higher in H2 carriers compared to non-H2 carriers (p<0.01).


CONCLUSIONS
We found that H3 carriership increases the risk of myocardial infarction. This effect could be explained by the reduced IL1RN expression in H3 carriers, which is expected to result in reduced levels of IL-1Ra, the principal antagonist of IL-1.
van Minkelen
Rick
R
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
Wettinger
Stephanie Bezzina
SB
de Visser
Marieke C H
MC
Vos
Hans L
HL
Reitsma
Pieter H
PH
Rosendaal
Frits R
FR
Bertina
Rogier M
RM
Doggen
Carine J M
CJ
D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D005838:Genotype; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000096:biosynthesis* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism; D012306:Risk; D020246:Venous Thrombosis / Q000175:diagnosis* / Q000235:genetics
D053590:Interleukin 1 Receptor Antagonist Protein; D012333:RNA, Messenger