Laboratory of Atherosclerosis Genetics, Centre for Laboratory Medicine, Tampere University Hospital and Department of Clinical Chemistry, Medical School, University of Tampere, Finland. email@example.com
Previously, we scanned all 23,000 human genes for differential expression between normal and atherosclerotic tissues and found the involvement of ADAM8.
We investigated the expression of ADAM8 mRNA and protein level in human atherosclerotic tissues and non-atherosclerotic internal thoracic arteries as well as the association of ADAM8 2662 T/G single nucleotide polymorphism (SNP) with the extent of coronary atherosclerosis and with the risk of fatal myocardial infarction.
ADAM8 mRNA was up-regulated in carotid, aortic, and femoral atherosclerotic plaques (n=24) when compared with non-atherosclerotic arteries. ADAM8 protein expression was increased in advanced atherosclerotic plaques as compared to control vessels wherein it was localized to macrophages and smooth muscle cells The G allele carriers of the ADAM8 2662 T/G SNP had significantly larger areas of fibrotic, calcified, and complicated plaques in coronary arteries (P=0.027, P=0.011, and P=0.011, respectively) and significantly higher occurrence of myocardial infarction (MI) (P=0.004) and fatal pre-hospital MI (P=0.003) than did the TT homozygotes.
ADAM8 is a promising candidate to be involved in atherosclerosis, and its 2662 T/G allelic variant significantly associates with advanced atherosclerotic lesion areas and MI.
Apolipoprotein A-IV (apoA-IV) is a glycoprotein constituent of triglyceride-rich and high-density lipoproteins (HDL) and may thus play an important role in lipid metabolism. In Finland two common isoforms (A-IV-1 and A-IV-2) of apoA-IV have been found. The isoforms are the result of the G to T substitution in the third base of the codon 360 in the apoA-IV-2 allele of the apoA-IV gene. The purpose of the study was to determine the apoA-IV allele frequencies in the Saami and the Finns, and to relate the apoA-IV phenotypes to serum lipids. The sample was drawn in connection with a Reindeer Herders' Health Survey performed in northern Finland in 1989. The study group included 248 men with known ethnic origin, Saami and Finns, who lived in the area of the nine northernmost municipalities of Finland. ApoA-IV phenotypes from 71 Saami (both parents Saami) and 177 Finns (both parents Finns) were determined by isoelectric focusing and Western blotting. Serum lipids were determined enzymatically. ApoA-IV allele frequencies in the Saami and the Finns were for A-IV-1 0.894 vs 0.944 and for A-IV-2 0.106 vs 0.056, respectively (chi2-test, P
The apoE phenotype of 83 patients with probable Alzheimer's disease (AD) and of 164 non-demented controls was determined by isoelectric focusing and Western blotting. The proportion of the epsilon 4 allele was 0.548 in AD and 0.202 in controls (P
Apolipoprotein E (apoE) phenotype is a genetic determinant of plasma total cholesterol and low density lipoprotein (LDL) cholesterol concentrations, that are classical coronary heart disease risk factors. ApoE appears in three major isoforms E2, E3, and E4, coded by corresponding alleles epsilon 2, epsilon 3, and epsilon 4. These give rise to six different phenotypes.
To study the associations of apoE phenotype with cord serum lipids (during minimal enteral nutrition), and with serum lipids of 3-year-old children.
We determined serum lipid levels and apoE phenotypes in 206 newborns and 259 3-year-old children in connection with a larger follow-up study of atherosclerosis precursors in children and young adults. ApoE phenotyping was done directly from plasma by isoelectric focusing followed by immunoblotting.
The effect of apoE phenotype on serum total and LDL cholesterol was significantly different in newborns and 3-year-old children (two-way ANOVA, interaction between apoE phenotype and age group: P .05) either in males or in females. The mean serum levels of triglycerides and high density lipoprotein cholesterol did not differ between apoE phenotypes either in 3-year-old children or newborns.
The results show that the differences in serum total and LDL cholesterol levels between apoE phenotypes are formed after birth by the influence of environmental factors and suggest that both genetic and external factors influence the levels of serum cholesterol concentrations during the first years of life.
Apolipoprotein E (apoE) polymorphism is a genetic determinant of plasma lipid levels and of coronary heart disease (CHD) risk. We determined the apoE phenotypes and plasma lipid levels in 1577 youths aged 3 to 18 years in 1980. The subjects were randomly selected from five areas of Finland. ApoE phenotyping was performed directly from plasma by isoelectric focusing and immunoblotting. The apoE allele frequencies in the population sample were epsilon 2 = 0.039, epsilon 3 = 0.767, and epsilon 4 = 0.194. There were no differences in the apoE phenotype distribution between East and West Finland or between sexes. The concentrations of serum total cholesterol, low density lipoprotein cholesterol, and apolipoprotein B increased with apoE phenotype in the order of E2/2, E3/2, E4/2, E3/3, E4/3, and E4/4. This increase was already seen in 3-year-old children; it was observed in both sexes, but was clearer in males than in females. The mean levels of high density lipoprotein (HDL) cholesterol, apolipoprotein A-I, triglyceride, Lp[a] lipoprotein, and the activity of lecithin:cholesterol acyltransferase did not differ between the apoE phenotypes. The observed differences in serum cholesterol remained fairly stable during the 6-year follow-up from 1980 to 1986, while the mean serum cholesterol concentration in the whole study population decreased by 6.3%. This study confirms the reported higher frequency of the epsilon 4 allele in Finns as compared to most other populations; this may contribute to the high rates of CHD in Finland as compared to most other populations. The results do not, however, explain the higher rate of CHD in East Finland in comparison to the western part of the country.
Association between serum lipids and apolipoprotein E phenotype is influenced by diet in a population-based sample of free-living children and young adults: the Cardiovascular Risk in Young Finns Study.
Apolipoprotein E (apoE) is a genetic determinant of coronary heart disease and lipid levels in several populations. We studied whether the association of apoE alleles with serum lipids varies with diet in a population of free-living young Finns. One thousand twelve subjects, aged 9-24 years, were studied as a part of the Cardiovascular Risk in Young Finns Study in 1986. Serum lipid concentrations and apoE phenotypes were determined, and the composition of the diet was assessed by the 48-h recall method. The subjects were divided into three groups according to the intake of dietary saturated fatty acids (SAFA, g/1000 kcal) and cholesterol (mg/1000 kcal). Group one (high SAFA-cholesterol group) was formed from subjects belonging to the highest tertiles of both cholesterol and SAFA intakes (n = 175); group two (middle SAFA-cholesterol group) consisted of subjects belonging to the middle respective tertiles (n = 119); and group three (low SAFA-cholesterol group) consisted of subjects belonging to the lowest respective tertiles (n = 192). The statistical significance of the association of serum total cholesterol and low density lipoprotein (LDL) concentration with apoE phenotype increased from the low SAFA-cholesterol group (P = 0.024 for total cholesterol and P = 0.015 for LDL-cholesterol, respectively) to the high SAFA-cholesterol group (P = 0.0022 and P = 0.00073, respectively). The middle SAFA-cholesterol group fell between these two groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Moderate consumption of alcohol may reduce mortality from vascular diseases. The beneficial effects of alcohol may partly be mediated by its effects on lipoprotein metabolism. We studied the connection between alcohol consumption and the serum lipid profile from a well-documented national health program study.
Carbohydrate-deficient transferrin (CDT) and gamma-glutamyl-transferase (GGT) were used as biochemical markers for alcohol consumption. The laboratory analyses were carried out on 5675 subjects (3097 males and 2578 females). The subjects were divided into quartiles on the basis of CDT or GGT value. The highest CDT quartile and the lowest GGT quartile seemed to be associated with a favorable lipid profile and the lowest CDT quartile and the highest GGT quartile were associated with an unfavorable lipid profile. Serum high density lipoprotein (HDL) cholesterol values were significantly higher and triglycerides lower with increasing serum CDT concentrations for both men and women. Increasing serum GGT was associated with higher serum total cholesterol and higher triglycerides in both men and women and lower HDL cholesterol in men.
CDT and GGT seem to detect different populations of subjects in regard to lipid metabolism. These observations may lead to a better understanding of the effects of alcohol consumption on lipids as well as mechanisms behind favorable and detrimental effects of alcohol on vascular diseases.
Carbohydrate-deficient transferrin (CDT) and gamma-glutamyl-transferase (GGT) were used as biochemical markers for alcohol consumption. A total of 3097 males and 2578 females were divided into quartiles on the basis of their CDT or GGT values. The highest CDT quartiles had higher HDL and lower triglycerides, whereas the highest GGT quartiles appeared to be associated with higher total cholesterol and triglycerides in both genders and lower HDL in men. CDT and GGT seem to detect different populations of subjects in regard to lipid metabolism. These observations may have important clinical and public health implications.
We examined the association of three known genome-wide association study loci for blood lipids that have lead traits for triglycerides with hypertension in the Tampere adult population cardiovascular risk study.
A Finnish cohort of 190 men with diagnosed hypertension and 279 controls were analyzed. Samples were genotyped for low-density lipoprotein receptor-related protein 1 rs11613352 (C>T), angiopoietin-like 3 rs2131925 (T>G), and fatty acid desaturase 1 rs174546 (C>T) polymorphisms using competitive allele-specific polymerase chain reaction technique.
At the age of 50, subjects with low-density lipoprotein receptor-related protein 1 rs11613352 (C>T) minor genotype TT had significantly more hypertension than those with the C allele (OR 5.17, CI 2.03-12.74, p G) T allele had more hypertension than those with the minor genotype GG (OR 5.02, CI 1.40-17.98, p = 0.013). Fatty acid desaturase 1 rs174546 (C>T) did not associate with hypertension.
Association of low-density lipoprotein receptor-related protein 1 rs11613352 and angiopoietin-like 3 rs2131925 with hypertension might imply a direct effect at the artery wall.
Monocyte-derived macrophages in atherosclerotic plaques secrete matrix metalloproteinases (MMPs), which may contribute to plaque rupture. There has been much speculation as to which factors precipitate in the arterial inflammation. Oxidized low density lipoprotein (oxLDL) has been suggested to have proinflammatory properties, and it has been shown to increase matrix metalloproteinase-9 (MMP-9) secretion by macrophages in vitro. We determined serum MMP-9 concentration and autoantibodies against oxLDL by ELISA in men with angina pectoris (n=243) and age-matched controls (n=238). The association between serum MMP-9 concentration and autoantibodies against oxLDL was evaluated. Autoantibody level against oxLDL, expressed in optical density units, was significantly higher in subjects with angina pectoris compared to controls (0.100+/-0.064 versus 0.088+/-0.051, respectively, P=0.030), but serum levels of MMP-9 did not differ significantly between these groups (54.2+/-29.9 versus 50.6+/-23.1 microg/l). However, autoantibodies against oxLDL correlated positively with serum MMP-9 (r=0.21, P