Cardiometabolic & Genetic Risk Factors for Early Atherosclerosis
Acta Universitatis Tamperensis, No. 1582

By Kalle Sipilä
Febuary 2011
Tampere University Press
Distributed by Coronet Books Inc.
ISBN: 9789514483219
167 pages
$87.50 Paper Original

Background: Overweight has become a major health issue in modern Western society. Obesity and a sedentary lifestyle are closely related to metabolic syndrome, its components and different stages of glucose metabolism impairment. These are well-known cardiovascular risk factors and they have also been related to early stages of atherosclerosis. The independent roles of these particular risk factors in the development of atherosclerosis are not, however, fully understood. It is known that type 2 diabetes has a more pronounced effect on cardiovascular risk in women than in men. Therefore, it is reasonable to hypothesize that milder impairment in glucose metabolism and metabolic syndrome might also have similar sex-related differences in their relationships to early atherosclerosis. This has not been studied extensively Genetics is another field in cardiovascular research that has gained a tremendous amount of attention in recent years. Large genome-wide association studies have revealed several gene polymorphisms relating to cardiovascular risk. Several different studies have identified a genetic locus on chromosome 9p21.3 that has an influence on the risk of coronary heart disease.

The single nucleotide polymorphism on chromosome 9p21.3 showing the strongest association with coronary heart disease is known as rs1333049. A polymorphism located in the promoter region of inflammatory cytokine interleukin-6, known as IL6?174 G>C, has been studied in a number of candidate gene studies. It has been associated with the incidence of cardiovascular events, such as myocardial infarction, and several risk factors for cardiovascular disease. Interleukin-6 is closely related to inflammation, which is believed to be the driving force behind metabolic syndrome, type 2 diabetes and the atherosclerosis process in general. Overall, the results regarding IL6?174 G>C genotype and its associations with cardiovascular risk have been very controversial. The role of these two above-mentioned genotypes in the early stages of atherosclerosis is not clear. Aims: In the present study, the independent associations of metabolic syndrome and different stages of glucose intolerance with the markers of early atherosclerosis were studied.

Specifically, possible sex-related differences in these associations were investigated. Another study aim was to evaluate the associations of some contemporary candidate genes with cardiovascular risk factors and the markers of early atherosclerosis. Two approaches were used in the selection of the genetic variants of interest: the polymorphism showing the strongest association with coronary heart disease in genome-wide association studies and a polymorphism strongly associating with cardiovascular risk factors and coronary heart disease in candidate gene studies were selected to be studied in detail. A single nucleotide polymorphism on chromosome 9p21.3 (rs1333049) as well as IL6-174 G>C genotype represent these two approaches in the present study.

Subjects and Methods: A subpopulation of the Health 2000 Survey, which is a large Finnish cross-sectional health examination survey carried out in 2000–2001, formed the main population of the current study (sample size 1,353). The subjects were over 45 years old (age range 46–76 years). The population of the Cardiovascular Risk in Young Finns Study, a multi-centre study of atherosclerotic risk factors in children and young adults, was used as a second cohort in the investigation regarding the association of the rs1333049 polymorphism and early atherosclerosis. Subjects in the Young Finns Study were 24–39 years old (sample size 2,251). In both cohorts subjects underwent a physical examination and a variety of measurements used as markers for early atherosclerosis. Carotid artery intima-media thickness, carotid artery elasticity and brachial artery flow-mediated dilatation measured by ultrasound as well as pulse wave velocity measured by whole-body impedance cardiography were used in this study. Medical history, medication and lifestyle-related factors were evaluated with questionnaires, and a comprehensive selection of blood sample measurements, including genotyping for the genetic variants of interest, was carried out for both cohorts. Glucose tolerance status was evaluated using medical history and the oral glucose tolerance test, and it was defined using the American Diabetes Association criteria. Metabolic syndrome was defined using the National Cholesterol Education Program criteria (used in most of the calculations) and the International Diabetes Federation criteria.

Results: Metabolic syndrome was associated with increased pulse wave velocity and carotid artery intima-media thickness independently of other cardiovascular risk factors in both sexes. This association, however, appeared to be stronger in women, which was seen especially regarding carotid artery intima-media thickness. After the components of metabolic syndrome were taken into account, the association between metabolic syndome and carotid artery intima-media thickness remained significant in women but not in men. In men, traditional cardiovascular risk factors were strongly associated with carotid artery intima-media thickness, and metabolic syndrome seemed to offer little additional information. In women, however, metabolic syndrome was associated with an additional risk of increased intima-media thickness, especially when the risk according to the traditional risk factors was relatively low. There was a trend of increasing carotid artery intima-media thickness and decreasing carotid artery elasticity according to the worsening of glucose tolerance in both sexes. This trend was weakened markedly after the adjustment for other cardiovascular risk factors. The association of glucose tolerance status and carotid artery elasticity remained significant in women but not in men after the other risk factors were taken into account. The association of glucose tolerance status and carotid artery intima-media thickness was not significant in either sex after these adjustments.

The rs1333049 polymorphism was not associated with carotid artery intima-media thickness in either of the study cohorts, and it was not associated with brachial artery flow-mediated dilatation in the Young Finns Study cohort either.

IL6?174 G>C genotype was not associated with carotid artery intima-media thickness. It was, however, associated with the levels of total cholesterol, LDL cholesterol and fasting plasma glucose as well as with body mass index and systolic blood pressure in men.

Conclusions: Metabolic syndrome is associated with early atherosclerosis in both sexes. This association seems to be stronger in women, especially if the risk for cardiovascular disease defined by traditional risk factors is low. There is a trend of increasing early atherosclerosis according to the worsening of the glucose tolerance in both sexes. This association is at least partly mediated by other risk factors and may be stronger in women than in men. The rs1333049 polymorphism is not related to the markers of early atherosclerosis, suggesting that its effect on the risk of coronary heart disease might be mediated by different mechanism than simply promoting atherosclerotic changes in the vascular wall. The association of IL6?174 G>C genotype with cardiovascular risk factors seems to be different in men and women. This may partly explain the previous controversial results regarding its effect on cardiovascular risk. The effect of this genotype may also depend on factors such as body fat mass as well as the metabolic and inflammatory state. At the population level, this polymorphism seems to have an impact as a genetic risk factor. However, future research is needed to evaluate its effect in different populations.

Many of the results of the present study emphasize the fact that in the evaluation of overall cardiovascular risk, it is important to take the subjects’ sex as well as other characteristics into account. Many of the known risk factors may act differently depending on these characteristics. This kind of approach will be extremely important in the future cardiovascular research as well. Some of the traditional risk factors may even have to be re-evaluated in specific populations.

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