Smoking and a complement gene polymorphism interact in promoting cardiovascular disease morbidity and mortality

Abstract

We have demonstrated previously that carriers of a genotype called C4B*Q0 (silent allele of the C4B gene) have a substantially increased risk to suffer from myocardial infarction or stroke, and are selected out from the healthy elderly population. Because smoking carries a major risk for cardiovascular disease (CVD), it seemed worthwhile to study if these two factors interact. Study 1 involved 74 patients with angina pectoris (AP), 85 patients with recent acute myocardial infarction (AMI) and 112 survivors of a previous AMI and 382 controls from Iceland. Study 2 involved 233 patients with severe CVD and 274 controls from Hungary. Smoking habits were registered for each subject. The number of C4A and C4B genes was determined by phenotyping or genotyping. Compared to controls, C4B*Q0 carrier frequency was significantly higher at diagnosis in Icelandic smokers with AP (P = 0.005) and AMI (P = 0.0003) and Hungarian smokers with severe coronary artery disease (P = 0.023), while no such difference was observed in non-smoking subjects. Age-associated decrease in C4B*Q0 observed previously in two remote Caucasian populations was found, in the present study, to be associated strongly with smoking, and to already occur in smokers after age 50 years both in Iceland and Hungary. Our findings indicate that the C4B*Q0 genotype can be considered as a major covariate of smoking in precipitating the risk for AMI and associated deaths.

Fig. 1

Carrier frequencies of C4B*Q0 in smoking (current smokers + quitters in < 3 years) and non-smoking (never smokers + quitters in ≥ 3 years) healthy Icelandic people at different ages. The decrease in smokers with age is significant (P = 0·008, χ² test for trend), while no significant changes (P = 0·395) occurred in the group of non-smokers (never smokers and former smokers).

Fig. 2

Carrier frequency of C4B*Q0 in currently smoking (a) and never smoking Icelandic patients (b) compared to controls; new acute myocardial infarction (AMI): patients entering the study with their first lifetime acute myocardial infarction; remote AMI: survivors of a myocardial infarction that occurred 7 years (4·3–11·0) previously. Only ≥ 50-year-old subjects were included in the analysis.