Modeling premature occurrence of acute coronary syndrome with atherogenic and thrombogenic risk factors and gene markers in extended families.
BACKGROUND
The interaction between genetic and environmental risk factors in determining premature cardiovascular events has been largely investigated in case-control association studies. By contrast, few family based analyses have been performed so far.


METHODS
From a series of 2936 subjects aged 45-64, we selected probands who died for a premature (<50 years) ischemic heart disease (IHD) and with at least one family member with a history of IHD also occurring under the age of 50. Ninety-four families from 32 pedigrees including 296 subjects were identified. In this population, we analyzed the relationship between background risk factors [age, gender, the G1691A polymorphisms of factor V gene, the C677T polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene, the 844ins68bp polymorphisms of the cystathionine-beta-synthase (CBS) gene, and the apolipoprotein E (APOE) polymorphisms] and environmental risk factors, both atherogenic (smoke, hypertension, diabetes, dyslipidemia, obesity) and thrombogenic (smoke, homocysteine, fibrinogen) by a Markov block-recursive modeling approach.


RESULTS
None of the studied polymorphisms had an independent direct effect on the risk of IHD. As opposed to atherogenic factors, thrombogenic factors (homocysteine and fibrinogen) turned out to be possible mediators of the indirect effect of the MTHFR gene on IHD risk (OR: 1.30; 95% CI: 1.01-1.69, for every 8 mm increase in plasma levels of homocysteine in TT-carriers compared with CT/CC-carriers (OR: 1.11; 95% CI: 1.01-1.22), for every 20 g L(-1) increase in plasma levels of fibrinogen in TT-carriers compared with CT/CC-carriers).


CONCLUSIONS
Plasma levels of homocysteine and fibrinogen may be interpreted as intermediate factors mediating the effect of predisposing genes on the risk premature cardiovascular disease.
Grassi
M
M
Department of Health Sciences, Section of Medical Statistics and Epidemiology, University of Pavia, Pavia, Italy.
Assanelli
D
D
Mozzini
C
C
Albertini
F
F
Salvadori
G
G
Archetti
S
S
Negrini
R
R
Galeazzi
G
G
Pezzini
A
A
D017668:Age of Onset; D050197:Atherosclerosis / Q000453:epidemiology* / Q000209:etiology / Q000235:genetics; D005192:Family Health; D005260:Female; D005340:Fibrinogen / Q000032:analysis; D005819:Genetic Markers; D005838:Genotype; D006710:Homocysteine / Q000097:blood; D006801:Humans; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D009203:Myocardial Infarction / Q000453:epidemiology* / Q000209:etiology* / Q000235:genetics; D010375:Pedigree; D012307:Risk Factors; D013927:Thrombosis / Q000453:epidemiology* / Q000209:etiology / Q000235:genetics
D005819:Genetic Markers; D006710:Homocysteine; D005340:Fibrinogen