Interleukin 18 gene promoter polymorphism: a link between hypertension and pre-hospital sudden cardiac death: the Helsinki Sudden Death Study.
OBJECTIVE
The interleukin 18 (IL-18) gene has a single nucleotide promoter region (-137) G-to-C polymorphism (rs187238) which leads to attenuated transcriptional activity of the gene and to lower production of pro-atherogenic IL-18. The C allele of this polymorphism is associated with a lower risk of sudden cardiac death (SCD). We examined the process by which this polymorphism alters the risk of SCD and coronary artery disease (CAD) by analysing the interactions between this polymorphism and environmental factors.


RESULTS
TaqMan 5' nuclease assay was used to genotype the study population of the Helsinki Sudden Death Study, comprising medicolegal autopsies of 700 men. According to adjusted logistic regression analysis, there was a significant interaction between IL-18 genotype and hypertension impacting on the risk of SCD due to coronary heart disease (CHD) (P = 0.011) and the severity of autopsy-verified CAD (P = 0.026). Among GG homozygotes, hypertension was a major risk factor for SCD due to CHD [adjusted odds ratio (OR) 3.75 with 95% CI 1.78-7.91, P < 0.001] and hypertension also associated with larger coronary atherosclerotic plaque areas (P = 0.002) and the occurrence of complicated plaques (adjusted OR 8.38 with 95% CI 2.39-29.33, P < 0.001). Among C allele carriers, hypertension was not a significant risk factor for CHD-related SCD or CAD and did not associate with the development of coronary atherosclerotic plaques. According to gene expression analysis of atherosclerotic tissue samples obtained from live patients, hypertension also interacted significantly with IL-18 genotype affecting the expression of IL-18 (P = 0.030) mRNA and interferon-gamma mRNA (P = 0.004).


CONCLUSIONS
Hypertension interacts with IL-18 gene promoter -137 G/C polymorphism, affecting the risk of SCD and the development of coronary atherosclerosis.
Hernesniemi
Jussi A
JA
Laboratory of Atherosclerosis Genetics, Department of Clinical Chemistry, Tampere University Hospital, Centre for Laboratory Medicine, University of Tampere, Medical School, Finn Medi 2, FI-33521 Tampere, Finland. jussi.hernesniemi@uta.fi
Karhunen
Pekka J
PJ
Oksala
Niku
N
Kähönen
Mika
M
Levula
Mari
M
Rontu
Riikka
R
Ilveskoski
Erkki
E
Kajander
Olli
O
Goebeler
Sirkka
S
Viiri
Leena E
LE
Hurme
Mikko
M
Lehtimäki
Terho
T
D000328:Adult; D000368:Aged; D000483:Alleles; D001344:Autopsy; D003327:Coronary Disease / Q000235:genetics* / Q000401:mortality; D016757:Death, Sudden, Cardiac / Q000453:epidemiology / Q000209:etiology*; D005387:Finland / Q000453:epidemiology; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006760:Hospitalization; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000401:mortality; D020382:Interleukin-18 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*
D020382:Interleukin-18