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Jussi Mikkelsson

Publications and source records attributed to Jussi Mikkelsson.

At least 19 recordsLinked to original sources
PubMed2006

Smoking and the platelet fibrinogen receptor glycoprotein IIb/IIIA PlA1/A2 polymorphism interact in the risk of lacunar stroke and midterm survival.

BACKGROUND AND PURPOSE: Smoking, increased fibrinogen levels, and platelet activation are related to the risk of ischemic stroke. The platelet fibrinogen receptor glycoprotein (Gp) IIb/IIIa Pl(A1/A2) polymorphism affects the binding of platelets to fibrinogen and is suggested to interact with smoking. METHODS: We explored the association of smoking and the Pl(A1/A2) polymorphism with ischemic stroke and survival in the Stroke Aging Memory cohort, comprising 486 consecutive patients (55 to 85 years old) who were analyzed 3 months after an ischemic stroke and followed up for 15 months. Stroke subtype determined by magnetic resonance imaging and GpIIb/IIIa Pl(A1/A2) genotype data were available for 272 patients. RESULTS: In multivariate analysis, smoking was the only factor related to the risk of lacunar infarcts (odds ratio [OR]=1.87, 95% CI=1.05 to 3.31; P=0.033), and it was also a predictor of death (n=24, 8.8%) at 15 months (OR=5.13, 95% CI=1.61 to 16.36; P=0.006), along with age (OR=1.10, 95% CI=1.01 to 1.19; P=0.008). The GpIIb/IIIa Pl(A1/A2) polymorphism alone showed no association with stroke subtype or survival. However, there was a smoking-by-genotype association with the risk of lacunar infarcts (OR=2.10, 95% CI=0.90 to 4.89; P=0.087) and with survival (OR=2.78, 95% CI=0.89 to 8.61; P=0.077). Among younger (55 to 69 years) stroke patients, smokers carrying the Pl(A2) allele were at a higher (OR=5.81, 95% CI=1.26 to 26.80; P=0.024) risk of lacunar infarcts than noncarrier smokers (OR=3.12, 95% CI=1.06 to 9.24; P=0.039). The effect of Pl(A2) and smoking combined on survival was also stronger (OR=8.86, 95% CI=1.68 to 46.55; P=0.010) than the effect of smoking alone (OR=5.06, 95% CI=1.20 to 21.35; P=0.027). CONCLUSIONS: Our results indicate that prothrombotic genetic factors may interact with smoking by modifying the stroke phenotype and affecting midterm survival.

Age Distribution↗
PubMed2006

Age-dependent association between hepatic lipase gene C-480T polymorphism and the risk of pre-hospital sudden cardiac death: the Helsinki Sudden Death Study.

OBJECTIVE: We investigated the association between hepatic lipase (HL) C-480T polymorphism and the risk of acute myocardial infarction (AMI) as well as pre-hospital sudden cardiac death (SCD). METHODS: Seven hundred sudden or unnatural pre-hospital deaths of middle-aged (33-70 years, mean 53 years) Caucasian Finnish men were subjected to detailed autopsy (Helsinki Sudden Death Study). Genotype data were obtained for 682 men. RESULTS: In logistic regression analysis with age, body mass index, hypertension, diabetes, smoking and alcohol consumption as covariates, men with the TT genotype had an increased risk for SCD and AMI compared to CC carriers (OR=3.0, P=0.011; and OR=3.7, P=0.003). There was a significant age-by-genotype interaction (P<0.05) on the risk of SCD. Compared to CC genotype carriers, the association between the TT genotype and SCD was particularly strong (P=0.001) among men <53 years of age, but this association was non-significant among older men. This was mainly due to a strong association between the TT genotype and AMI due to severe coronary disease in the absence of thrombosis. Carriers of the TT genotype were more likely to have severe coronary stenoses (> or =50%) than men with the CT or CC genotype (P=0.019). CONCLUSIONS: The results suggest that HL C-480T polymorphism is a strong age-dependent risk factor of SCD in early middle-aged men.

Adult↗
PubMed2006

Genetic variation in platelet integrin alphabeta (GPIIb/IIIa) and the metastatic potential of renal cell carcinoma.

OBJECTIVE: To explore whether genetic polymorphisms in platelet receptors known to be associated with platelet activity have any association with haematogenous metastases in renal cell carcinoma (RCC), as platelets and their fibrinogen receptors may be central to haematogenous cancer spread, in addition to various adhesive proteins on both platelets and tumour cells on themselves. PATIENTS AND METHODS: The glycoprotein alpha(IIb)beta3 (GPIIb/IIIa) is the main fibrinogen receptor on platelets, with GPIb-IX-V and GPIa/IIa being the von Willebrand Factor and collagen receptors, respectively. In a cross-sectional survey of 128 men treated for RCC (55 with disseminated disease and 73 with a local disease), they were genotyped using DNA extracted from freshly drawn blood, and central clinical data were recorded. RESULTS: The frequency of possessing the GPIIIaPl(A2) allele among patients with metastatic RCC was 43.6%, and with local disease was 24.7% (P = 0.024). The frequencies of the different alleles of the GIB-IX-V, C3550T and GPIa/IIa C807T polymorphisms did not differ between the groups. In a stepwise logistic regression (metastatic vs local RCC) the Pl(A2) allele remained a significant risk factor, with an odds ratio of 2.7 (95% confidence interval, 1.1-6.5; P = 0.02). CONCLUSION: The prothrombotic Pl(A2) allele of platelet fibrinogen receptor GPIIb/IIIa increased the risk of metastases in RCC in men.

Carcinoma, Renal Cell↗
PubMed2006

Polymorphisms of COX-1 and GPVI associate with the antiplatelet effect of aspirin in coronary artery disease patients.

The antiplatelet effect of aspirin varies individually. This study evaluated whether the antiplatelet effect of aspirin associates with polymorphisms in the genes coding for cyclo-oxygenase-1 (COX-1) and several platelet glycoprotein (GP) receptors in patients with stable coronary artery disease (CAD). Blood samples were collected from 101 aspirin-treated (mean 100 mg/d) patients. Compliance to treatment was assessed by plasma salicylate measurement. Platelet functions were assessed by two methods: 1) Response to arachidonic acid (AA, 1.5 mmol/L in aggregometry, and 2) PFA-100, evaluating platelet activation under high shear stress in the presence of collagen and epinephrine (CEPI). Aspirin non-response was defined as: 1) slope steeper than 12%/min in AA-aggregations, and 2) by closure time shorter than 170 s in PFA-100. The methods used detected different individuals as being aspirin non-responders. Five and 21 patients, respectively, were non-responders according to AA-induced aggregation and PFA-100. Increased plasma thromboxane B2 levels correlated with poor aspirin-response measured with both AA-induced aggregations and PFA-100 (P = 0.02 and P = 0.003, respectively). Of the non-responders detected by AA, 3 of 5 (60%) carried the rare G allele for the -A842G polymorphism of COX-1 in contrast to 16 of 96 (17%) responders (P = 0.016). Diabetes was associated with poor response. Aspirin non-response detected by PFA-100 associated with C13254T polymorphism of GP VI and female gender (P = 0.012 and P = 0.019, respectively). Although two patients were possibly non-compliant, this did not effect present conclusions. Evaluation of aspirin efficacy by AA-induced aggregation and PFA-100 detected different individuals, with different genotypic profiles, as being aspirin non-responders.

Adult↗
PubMed2006

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Journal Article↗
PubMed2005

The effect of glycoprotein IIIa PIA 1/A2 polymorphism on the PFA-100 response to GP IIb IIa receptor inhibitors-the importance of anticoagulants used.

Antithrombotic drugs including glycoprotein (GP) IIb IIIa receptor inhibitors have significantly reduced ischaemic events in coronary disease. Variability in the response to GP receptor inhibitors has been observed both with healthy individuals and in clinical studies. One single nucleotide polymorphism on GP IIIa (PI(A1/A2)) correlates with increased risk for cardiovascular events in many studies. In this study we investigated whether this polymorphism associates with individual differences in the response to GP IIb IIIa receptor inhibitors in healthy individuals. Fresh blood samples were collected randomly from individuals without a history of coronary disease. Blood samples were anticoagulated with either sodium citrate or with PPACK. The ability of different GP IIb IIIa receptor inhibitors (tirofiban, eptifibatide and abciximab) to inhibit platelet aggregation was investigated using a commercial PFA-100 analyser. At baseline, the function of platelets with different PI(A) genotypes did not differ from each other. With sodium citrate anticoagulated samples, tirofiban prolonged the closure time slightly more rapidly when platelets with PI(A 2 A 2) genotype were used than with other genotypes (p<0.05) both on epinephrine-collagen and ADP-collagen coated membranes. With eptifibatide or abciximab no differences were observed. If an anticoagulant not affecting Ca(2+) concentration (PPACK) was used, no differences were observed between different GP IIIa genotypes and the ability of any of the GP IIb IIIa receptor inhibitors to prolong the closure time. The effect of tirofiban and eptifibatide was significantly affected by the anticoagulant used (p<0.001), whereas abciximab functioned equally regardless of the anticoagulant. Glycoprotein IIIa PI(A2) allele has been found in many studies to associate with risk of thrombosis. In healthy controls the function of GP IIb IIIa receptor inhibitors on platelets with different PI(A) genotypes was modified by anticoagulants used. PI(A) polymorphism does not explain the interindividual variance in the response to GP IIb IIIa receptor inhibitors in healthy individuals. The study, however, demonstrates the importance of the anticoagulant used in in vitro studies and the important role of Ca(2+) concentration with tirofiban and eptifibatide, but not with abciximab.

Adult↗
PubMed2005

Apolipoprotein E polymorphism is not a predictor for repeated coronary artery bypass surgery.

OBJECTIVES: Factors leading to the occlusion of coronary grafts are diverse and may at least partially be inherited. We aimed to study the possible genetic predisposition and especially the role of apoE epsilon4 allele as a risk factor for repeated coronary artery bypass grafting (CABG) in a case-control setting. DESIGN: All patients (n=184) who underwent repeated CABG between 1990 and 1998 were identified in the computed registry of the Department of Cardiothoracic Surgery in Tampere University Hospital. Age, sex and operation date matched controls with first time CABG were selected from the same registry. DNA samples were collected by sample stick sent via the mail for buccal smear. The final analysis included 137 surviving matched pairs. RESULTS: In patients <62 years of age (median age), family history emerged as the only significant (OR=3.4; 95% CI=1.5-7.8, p=0.004) predictor for repeated surgery. Among older patients, repeated CABG was no longer predicted by family history but by hypercholesterolemia (OR=2.1; 95% CI=1.1-4.0, p=0.027), modified by apoE genotype. CONCLUSIONS: Our results suggest that medium-term survivors after redo CABG have a strong genetic predisposition unrelated to hypercholesterolemia or apoE genotype, leading to more severe coronary artery disease at earlier age. In the older age group, redo coronary artery bypass surgery is associated with hypercholesterolemia, which, although modified by apoE genotype, may mainly be due to other genetic or acquired factors.

Aged↗
PubMed2005

Genetics of platelet glycoprotein receptors: risk of thrombotic events and pharmacogenetic implications.

Platelet aggregation and coronary thrombosis have a central role in the development of acute coronary syndromes and myocardial infarction (MI). Therapies aimed at inhibiting platelet aggregation have shown great benefit in individuals with coronary disease or with multiple risk factors for coronary disease. Genetic variation in platelet surface receptors mediating thrombus formation has been suggested to be associated with platelet hyperreactivity, with increased risk of MI and possibly with the benefit received from various antithrombotic drug treatments. This review focuses on discrepancies and their likely explanations in studies on platelet glycoprotein genetics. Current knowledge on important issues concerning coronary event phenotypes and pharmacogenetics is analyzed. Possible future applicability of these data to patient treatment is also discussed.

Humans↗
PubMed2004

Matrix metalloproteinase3 and 9 gene promoter polymorphisms: joint action of two loci as a risk factor for coronary artery complicated plaques.

OBJECTIVE: Matrix metalloproteinases 3 and 9 (MMP3 and MMP9) are present in atherosclerotic plaques and co-operate in the degradation of the fibrous cap of the atheroma, leading to fissuring and ultimately to acute coronary thrombosis. The functional genetic polymorphisms in the promoters of MMP3 and MMP9, which lead to low- and high-transcription activity genotypes, have been shown to be associated with myocardial infarction and angiographically measured atherosclerosis individually, whereas their effects in combination are not yet known. In order to assess the two disease loci simultaneously, we investigated the association of combined low and high promoter activity genotypes with different types of coronary lesions in an autopsy cohort of 300 Caucasian males aged 33-69 years (Helsinki Sudden Death Study). METHODS: Genotyping at these loci was performed by PCR, restriction enzyme digestion and minisequencing, and areas of the coronary wall covered with atherosclerotic lesions were measured using computer-assisted morphometry. RESULTS: In analysis of covariance (ANCOVA) with age, body mass index, hypertension, diabetes, smoking and alcohol consumption as covariates, a significant interaction between the MMP3 and MMP9 genotypes was observed on area of complicated lesions (P=0.012). Men with high promoter activity genotypes for both loci had, on average, more than two times larger area of complicated lesions (250%) compared with those men who had low promoter activity genotypes (P=0.008), but these loci showed no association with myocardial infarction. CONCLUSIONS: The joint action of two susceptibility loci, rather than single MMP genes alone, and the particular combination of MMP3 and MMP9 genotypes present at these loci may contribute to heterogeneity in the presentation of atherosclerosis.

Adult↗
PubMed2004

Platelet membrane collagen receptor glycoprotein VI polymorphism is associated with coronary thrombosis and fatal myocardial infarction in middle-aged men.

Glycoprotein VI is a platelet collagen receptor binding to subendothelial collagen after a rupture of an atherosclerotic plaque. The GPVI gene is polymorphic with several SNPs and the T13254C polymorphism predicting amino acid substitution (serine to proline) has been associated with the risk of MI in a preliminary study. We studied the association of the GPVI T13254C with fatal myocardial infarction (MI) and coronary artery disease among the 300 men of the Helsinki Sudden Death Study (HSDS). Genotype frequencies were 77.9% for TT, 20.7% for CT and 1.4% for CC. We found a significant association (P = 0.02) between the C-allele carriers (CT or CC) and coronary thrombosis (OR 2.5, 95% CI: 1.05-6.2). There was also a tendency (P = 0.07) for an association between the C-allele and acute myocardial infarction (AMI) (OR 2.2). The average area of complicated coronary lesions was also significantly (P = 0.01) larger in carriers compared to non-carriers of the C-allele. Our findings support previous results on the role of this GPVI polymorphism, or another linked polymorphism, as a possible predictor of the risk of coronary thrombosis.

Adult↗
PubMed2004

Fatality of myocardial infarction in relation to the coronary anatomy: role of culprit lesion location.

OBJECTIVE: We set out to study the effect of the location of the culprit coronary lesion on myocardial infarction (MI) fatality by combining data from MI survivors in the coronary care unit (CCU) and autopsied patients with pre-hospital fatal MI. DESIGN: We studied two simultaneous series of men under 70 years with fatal pre-hospital MI (n = 36) and men admitted for acute ST-elevation-MI (n = 92). The culprit lesion was identified by the presence of thrombus at autopsy and by coronary angiography in patients admitted to the CCU. RESULTS: The culprit lesion was located in the right coronary artery (RCA) in 22 (61%) of 36 men with fatal MI compared to 30 (33%) of 92 men with non-fatal MI (P = 0.01). Seventy-three percent of fatal RCA occlusions were proximal as opposed to only 30% of non-fatal RCA occlusions (P < 0.001). Forty-four percent of all fatal MI were due to proximal RCA occlusion as opposed to only 10% of non-fatal MI (P < 0.005). CONCLUSIONS: Proximal RCA occlusions were very often found among men with fatal pre-hospital MI, whereas left-sided coronary occlusions were significantly more frequent in hospital-admitted survivors of MI. Left-sided coronary occlusions may be associated with a more favourable pre-hospital phase of acute MI compared to proximal RCA occlusions.

Autopsy↗
PubMed2004

Association of paraoxonase-1 M55L genotype and alcohol consumption with coronary atherosclerosis: the Helsinki Sudden Death Study.

High-density lipoprotein (HDL) level is inversely correlated with coronary heart disease risk. Paraoxonase-1 (PON1) is an HDL-associated anti-atherogenic enzyme. The activity of PON1 is affected by the methionine for leucine substitution at position 55 (M55L) and increased during regular moderate alcohol consumption, consistent with increased HDL cholesterol concentration. We related the PON1 M55L genotypes to the extent of atherosclerosis in left anterior descending coronary artery (LAD) in alcohol abstainers (0-1 g of alcohol/day), moderate consumers (1-36 g of alcohol/day) and drinkers (> 36 g of alcohol/day). The study subjects included an autopsy series of total of 700 middle-aged Finnish men from the Helsinki Sudden Death Study. The LAD was stained for fat and the areas covered with fatty streaks and fibrotic and complicated plaques were measured. Data on coronary artery disease risk factors were obtained from relatives or close friends of the deceased. Compared to the LL homozygotes, carriers of the M55 allele tended to have larger areas of atherosclerotic lesions, the size of which decreased dose-dependently by reported alcohol consumption. Moderate consumers carrying the M55 allele had significantly larger complicated plaques compared to the LL homozygotes drinking as much (P = 0.009). Among the M55 allele carriers, drinkers showed significantly smaller areas of fatty streaks compared to abstainers (P = 0.042) and moderate consumers (P < 0.001) (for the PON1 genotype by alcohol interaction, P = 0.078). Similarly, drinkers with the M55 allele also had statistically significantly smaller areas of complicated lesions than moderate consumers with the M55 allele (P < 0.0001) (for the PON1 genotype by alcohol interaction, P = 0.009). The areas of atherosclerotic lesions in LAD appear to be dependent on the amount of alcohol consumption, especially in men carrying the PON1 M55 allele.

Adult↗
PubMed2003

Variation in the alpha2B-adrenoceptor gene as a risk factor for prehospital fatal myocardial infarction and sudden cardiac death.

OBJECTIVES: Our aim was to corroborate the observed association between the deletion/deletion (DD) genotype of the insertion/deletion polymorphism in the alpha(2B)-adrenoceptor (AR) and increased risk for acute myocardial infarction (AMI), and to study whether this genotype also confers an increased risk for sudden cardiac death (SCD). BACKGROUND: Vasospasm has been suggested to play a role in AMI. Alpha(2)-AR mediate coronary vasoconstriction in humans, and studies on mice suggest the involvement of the alpha(2)-AR subtype B in vasoconstriction. A deletion variant of the human alpha(2B)-AR has been associated with impaired receptor desensitization in vitro. In a population-based prospective study of 912 middle-aged men, the DD genotype of the alpha(2B)-AR conferred an increased risk for AMI. METHODS: A series of 700 unselected sudden out-of-hospital deaths of middle-aged white men subjected to medico-legal autopsy was analyzed. RESULTS: Genotype information was obtained for 683 men (DD = 22%, insertion/deletion = 51%, insertion/insertion = 27%). Carriers of the DD genotype had an increased risk for SCD (n = 278, odds ratio [OR] = 2.0, p = 0.01) and fatal AMI (n = 84, OR = 2.1, p = 0.04) compared with the other two genotypes combined. The risks for SCD and fatal AMI were higher in carriers of the DD genotype who died before the age of 55 years (OR = 4.5 and 5.0, p < 0.001 for both). CONCLUSIONS: Middle-aged white men carrying the DD genotype of the alpha(2B)-AR have a significantly increased risk for SCD and AMI, especially before the age of 55 years.

Adult↗
PubMed2003

Smoking-dependent association between paraoxonase 1 M/L55 genotype and coronary atherosclerosis in males: an autopsy study.

High-density lipoprotein-associated paraoxonase 1 (PON1) enzyme can retard the oxidation of lipids. The methionine for leucine substitution at position 55 (M/L55) of the PON1 protein is associated with lower (MM genotype) or higher (ML or LL genotype) expression of the gene affecting serum level of PON1. We studied the association of the PON1 M/L55 genotype with the extent of atherosclerosis in an autopsy series of Finnish males. Areas of the coronary arteries and the aorta covered with fatty streaks and fibrotic and complicated lesions were measured from a total of 700 cases. Carriers of the MM genotype (14.4% of subjects) had larger percentual areas of fatty streaks in their left anterior descending coronary artery (P=0.014) and right coronary artery (P=0.004), as well as in thoracic (P<0.001) and abdominal aorta (P=0.010) compared to carriers of the LL or ML genotype. A PON1 genotype-by-smoking interaction was observed on the area of fatty streaks in left anterior descending coronary artery (P=0.011) and right coronary artery (P=0.005); the association between fatty streaks and MM genotype was evident only among non-smokers, whereas in smokers this association was abolished. The areas of more advanced atherosclerotic lesions did not vary significantly between the genotype groups. These data suggest that the genetic variation of PON1 affects the formation of early atherosclerotic lesions and that the effect is modified by smoking.

Adult↗
PubMed2003

Myeloperoxidase gene variation as a determinant of atherosclerosis progression in the abdominal and thoracic aorta: an autopsy study.

Myeloperoxidase (MPO) is an enzyme that transforms low-density lipoprotein into atherogenic particles. The MPO gene has a promoter polymorphism at position -463, which affects gene transcription and leads to high- (G/G) and low-expression (A/A, A/G) genotypes. To determine if these genotypes are associated with the severity of atherosclerosis, we performed an autopsy study of 300 men aged 33 to 69 years (Helsinki Sudden Death Study). We examined the percentage area of fatty streaks and fibrotic, calcified, and complicated lesions using computer-assisted planimetry. The MPO genotypes were determined by PCR. There were significant interactions of MPO genotype with the mean area of fibrotic (p < 0.01) and calcified (p < 0.05) lesions in the abdominal aorta and in fibrotic lesions in the thoracic aorta (p = 0.003). In the abdominal aorta, men < 53 years with low-expression genotypes had on average a 38.6% larger area of fibrotic lesions and a 43.8% larger area of calcified lesions than did the subjects with the G/G genotype. This association weakened with advancing age. Among men < 53 years, the MPO genotype was an independent predictor of fibrotic (p = 0.037) and calcified (p = 0.001) lesion area in the abdominal aorta after adjustment for age, body mass index, diabetes, hypertension, and smoking. MPO gene variation may modify the extent of advanced atherosclerotic lesions in the human aorta in early middle age.

Adult↗