Relationship of age-related myocardial infarction risk and Gln/Arg 192 variants of the human paraoxonase1 gene: the REGICOR study.
Paraoxonase1 (PON1) seems to exert a major antioxidant effect by removing lipid-peroxidation products. A common polymorphism of the PON1 gene, the PON1-192 genetic polymorphism, modulates PON1 activity and has been related in some studies to coronary heart disease. Oxidized LDL is believed to play a crucial role in the pathogenesis of atherosclerosis and there are studies providing support for the oxidative stress theory of aging. We have conducted a case-control study to determine whether PON1 activity and PON1-192 genetic variants have a different impact on myocardial infarction (MI) risk among individuals stratified by tertiles of age distribution. PON1-192 genotypes and PON1 activity were determined in 280 consecutive MI patients and 396 control subjects. Serum PON1 activity levels were significantly higher in controls than in MI patients [226 U/l (159-351) vs. 216 U/l (146-298), median (interquartile range), P=0.005]. A decline of PON1 activity levels with advancing age in subjects carrying the low-activity QQ genotype was observed, particularly in MI patients. PON1 activity and age negatively correlated in MI patients but not in controls. In the entire population, middle-aged and older subjects showed MI risks of 1.89 (P=0.012) and 2.69 (P<0.001) respectively, compared with young subjects. These risks increased to 2.41 (P=0.016) and 4.39 (P<0.001), respectively, in QQ homozygotes in comparison with younger QQ homozygotes, decreased to 1.53 (P=0.314) and 2.08 (P=0.112), respectively, in QR heterozygotes, and also lowered to 1.95 (P=0.410) and 0.51 (P=0.508) in RR homozygotes who were middle-aged and older, respectively, compared with younger RR carriers. The effect of PON1-192 genotypes on the association of the older age-category and MI risk was gene-dosage related. PON1 activity decreases as a function of age in subjects homozygous for the Q allele. Age may also act on MI risk as a function of PON1-192 alleles. The risk of MI increases with advancing age, principally among subjects carrying the low-activity QQ genotype.
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Lipids and Cardiovascular Epidemiology Unit, Institut Municipal d'Investigació Mèdica, IMIM and Universitat Pompeu Fabra, Dr Aiguader 80, E-08003, Barcelona, Spain. msenti@imim.es
Tomás
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Vila
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Marrugat
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Elosua
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Sala
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Masiá
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D000328:Adult; D017677:Age Distribution; D000704:Analysis of Variance; D043303:Aryldialkylphosphatase; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D015331:Cohort Studies; D004950:Esterases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D015994:Incidence; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000201:enzymology* / Q000453:epidemiology* / Q000235:genetics; D011110:Polymorphism, Genetic; D011247:Pregnancy; D012016:Reference Values; D018570:Risk Assessment; D012307:Risk Factors; D017678:Sex Distribution
D004950:Esterases; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human