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

Abstract

SummaryWe 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.

Low complement C4B gene copy number predicts short-term mortality after acute myocardial infarction

“…This finding is most probable due to the so-called smoker's paradox (25): compared with persistent smoker patients with AMI, non-smokers are younger and have fewer underlying medical problems, therefore at univariate analysis they have an apparently lower risk of death which, however, turns to the opposite after adjustment to the confounding variables. Higher mortality rate of the smoking AMI patients with low C4B copy number is in line with our previous findings (15) indicating that smoking carriers of this genotype exhibit an increased susceptibility for coronary artery disease and AMI and they are selected out for the healthy elderly population.…”

“…Interaction between smoking habits and C4B gene copy number in prediction of short-term mortality Previously, we reported an interaction between smoking and the C4B*Q0 carrier state for determining risk of CAD and myocardial infarction (15). In addition, in the present study we observed that smoking is weakly associated with mortality (Table 2).…”

“…This difference, however, could be detected only in patients who ever smoked and was the highest in the group of current smokers. Low copy number of the C4B gene can be considered nearly equal to the carrier state of C4B*Q0, determined by phenotyping 15 . Therefore, our present findings confirm our previous results obtained in Hungarian patients with AMI in which 3/6 (50%) of homozygote and 8/38 (21%) of heterozygote carriers compared with only 17/137 (12.4%) of non-carriers had a lethal outcome (P = 0.024).…”

“…Elderly C4B*Q0 carriers were found to have significantly higher risk for myocardial infarction (9) and stroke (12) and were selected out from the healthy elderly population both in Hungary (13) and Iceland (14). Moreover, recently (15) we reported on a significant interaction between carrier state of C4B*Q0 and smoking in promoting CVD morbidity: smoking C4B*Q0 carriers were found to have a highly increased risk of coronary artery disease and myocardial infarction whereas no such risk was observed in patients who never smoked or stopped to smoke in time. These findings were confirmed recently by an other group in Finland (16): they found that smokers who carry the C4B*Q0 genotype together with HLA-DRB1*01 are prone to the risk of CVD.…”

AMBIENCE: A Novel Approach and Efficient Algorithm for Identifying Informative Genetic and Environmental Associations With Complex Phenotypes

“…T HE risk of developing many chronic diseases such as cancer, cardiovascular diseases, autoimmune diseases, and mental disorders may involve interactions among a number of genetic, endogenous, and exogenous environmental factors (Shields and Harris 2000;Talmud and Stephens 2004;Caspi and Moffitt 2006;Ambrosone et al 2007;Arason et al 2007). The successful identification of critical gene-environment interactions (GEI) may provide the scientific basis for preventative public health measures to help individuals with particular genetic susceptibilities reduce their exposure to disease risk-increasing environmental variables.…”