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Biomedical subjects

M Perola

Publications and source records attributed to M Perola.

At least 19 recordsLinked to original sources
PubMed2006

Thrombomodulin gene polymorphisms and haplotypes and the risk of cardiovascular events: a prospective follow-up study.

BACKGROUND: Thrombomodulin is an anticoagulant expressed during endothelial activation and damage. To address the potential role of allelic variants of thrombomodulin gene in the pathogenesis of cardiovascular diseases, we analyzed in a prospective follow-up study 8 single-nucleotide polymorphisms (SNPs) across the thrombomodulin locus, covering all common (>5%) haplotypes. METHODS AND RESULTS: Two separate, stratified random samples of men and women 25 to 74 years of age were examined in Finland in 1992 and 1997. The total sample size was 14 140 individuals, with 7 (1997 cohort) to 10 (1992 cohort) years of follow-up. Altogether, 662 individuals had a history of cardiovascular events already at baseline. During the follow-up, 401 incident coronary events and 148 incident ischemic strokes were observed. The alleles and common haplotypes of 8 SNPs were tested in Cox proportional hazards models using incident coronary events, incident ischemic strokes, and total mortality as end points. None of the SNPs or major SNP haplotypes showed consistent association with the end points analyzed in the combined data. CONCLUSIONS: Results from this prospective, population-based study suggest that common allelic variants of the thrombomodulin gene may not significantly contribute to the risk of cardiovascular events at the population level.

Adult↗
PubMed2006

Radiographic assessment of dental health in middle-aged men following sudden cardiac death.

Poor oral health has been suggested to be a risk factor for myocardial infarction. To study if dental pathology might predispose to pre-hospital sudden cardiac death, and using a sum index of panoramic tomography findings, we compared the oral health of middle-aged (33-69 yrs) male victims (Helsinki Sudden Death Study) of sudden cardiac death (n = 117) with that of controls, who died of non-cardiac diseases (n = 63) or suffered unnatural sudden death (n = 120). The mean number of teeth was 15.2, and 17.4% of the men were edentulous. Frequent age-associated findings in dentate victims were fillings (79.9%), horizontal bone loss (72.1%), periapical lesions (45.6%), residual roots (38.2%), and vertical pockets (30.9%). In multivariate analysis with coronary heart disease risk factors and number of teeth as covariates, poor oral health was associated (p = 0.053) with the risk of sudden cardiac death along with age, smoking, and body mass index. This association was especially strong (p = 0.009) among victims < 50 yrs.

Adult↗
PubMed2005

A male-specific quantitative trait locus on 1p21 controlling human stature.

BACKGROUND: Many genome-wide scans aimed at complex traits have been statistically underpowered due to small sample size. Combining data from several genome-wide screens with comparable quantitative phenotype data should improve statistical power for the localisation of genomic regions contributing to these traits. OBJECTIVE: To perform a genome-wide screen for loci affecting adult stature by combined analysis of four previously performed genome-wide scans. METHODS: We developed a web based computer tool, Cartographer, for combining genetic marker maps which positions genetic markers accurately using the July 2003 release of the human genome sequence and the deCODE genetic map. Using Cartographer, we combined the primary genotype data from four genome-wide scans and performed variance components (VC) linkage analyses for human stature on the pooled dataset of 1417 individuals from 277 families and performed VC analyses for males and females separately. RESULTS: We found significant linkage to stature on 1p21 (multipoint LOD score 4.25) and suggestive linkages on 9p24 and 18q21 (multipoint LOD scores 2.57 and 2.39, respectively) in males-only analyses. We also found suggestive linkage to 4q35 and 22q13 (multipoint LOD scores 2.18 and 2.85, respectively) when we analysed both females and males and to 13q12 (multipoint LOD score 2.66) in females-only analyses. CONCLUSIONS: We strengthened the evidence for linkage to previously reported quantitative trait loci (QTL) for stature and also found significant evidence of a novel male-specific QTL on 1p21. Further investigation of several interesting candidate genes in this region will help towards characterisation of this first sex-specific locus affecting human stature.

Adult↗
PubMed2005

Meta-analysis of five genome-wide linkage studies for body mass index reveals significant evidence for linkage to chromosome 8p.

OBJECTIVE: To perform a meta-analysis of genome-wide linkage scans using body mass index (BMI) to identify genetic loci predisposing to obesity. DATA: A total of 13 published genome scans on obesity have used BMI as their primary end point. Five of these 13 groups agreed to provide detailed results from their scans that were required for a meta-analysis. Collectively, these five studies included a total of 2814 individuals from 505 families. METHODS: The results of the five studies were analysed using the GSMA (genome scans meta-analysis) method. RESULTS: The analysis revealed significant evidence for linkage of the quantitative phenotype BMI to 8p (P<0.0005).

Adult↗
PubMed2003

Minimum description length block finder, a method to identify haplotype blocks and to compare the strength of block boundaries.

We describe a new probabilistic method for finding haplotype blocks that is based on the use of the minimum description length (MDL) principle. We give a rigorous definition of the quality of a segmentation of a genomic region into blocks and describe a dynamic programming algorithm for finding the optimal segmentation with respect to this measure. We also describe a method for finding the probability of a block boundary for each pair of adjacent markers: this gives a tool for evaluating the significance of each block boundary. We have applied the method to the published data of Daly and colleagues. The results expose some problems that exist in the current methods for the evaluation of the significance of predicted block boundaries. Our method, MDL block finder, can be used to compare block borders in different sample sets, and we demonstrate this by applying the MDL-based method to define the block structure in chromosomes from population isolates.

Haplotypes↗
PubMed2003

A functional variant of the iNOS gene flanking region is associated with LAD coronary artery disease: an autopsy study.

BACKGROUND: Recent studies using reporter gene constructs have indicated significant differences in the promoter activity of inducible nitric oxide synthase (iNOS) gene variants. Although the exact role of iNOS in atherogenesis is unclear, it is possible that this variation site may influence the extent of coronary artery disease (CAD). METHODS: We amplified these (AAAT) repeat variants from the NOS2A gene (denoted iNOS R4 and iNOS R5) from 325 Finnish men included in the Helsinki Sudden Death Study, and studied their association with indices of stenosis and atherosclerosis of the left anterior descending artery (LAD), right coronary artery (RCA) and left circumflex artery (LCX). In order to understand the effect of iNOS genotype on different stages of CAD, our study population was divided into age groups. RESULTS: In the LAD, the progression of atherosclerosis seemed to be more pronounced in the 4/5 genotype carriers than in those with the 4/4 genotype when the different age groups were compared. More specifically, statistically significant differences between the genotypes were found in the subgroup of men aged > 55 years. In this group, men carrying the rare R4/5 genotype presented higher mean values of stenosis percentages (55% vs. 42%, P = 0.008), larger areas of fatty streaks (10.4% vs. 5.9%; P = 0.01) and complicated lesions (3.5% vs. 1.3%; P = 0.001) compared with the R4/4 carriers. No significant association of iNOS genotypes with stenosis and atherosclerosis of RCA and LCX was found. CONCLUSIONS: It appears unlikely the R4/5 genotype plays a major role in the pathogenesis of CAD, as it was not associated with stenosis and atherosclerosis in RCA and LCX. However this genotype may have some role in more pronounced CAD, as seen in the LAD.

Adult↗
PubMed2003

An MDL method for finding haplotype blocks and for estimating the strength of haplotype block boundaries.

We describe a new method for finding haplotype blocks based on the use of the minimum description length principle. We give a rigorous definition of the quality of a segmentation of a genomic region into blocks, and describe a dynamic programming algorithm for finding the optimal segmentation with respect to this measure. We also describe a method for finding the probability of a block boundary for each pair of adjacent markers: this gives a tool for evaluating the significance of each block boundary. We have applied the method to the published data of Daly et al. The results are in relatively good agreement with the published results, but also show clear differences in the predicted block boundaries and their strengths. We also give results on the block structure in population isolates.

Algorithms↗
PubMed2002

Bipolar disorder susceptibility region on Xq24-q27.1 in Finnish families.

Bipolar disorder (BPD) is a common disorder characterized by episodes of mania, hypomania and depression. The genetic background of BPD remains undefined, although several putative loci predisposing to BPD have been identified. We have earlier reported significant evidence of linkage for BPD to chromosome Xq24-q27.1 in an extended pedigree from the late settlement region of the genetically isolated population of Finland. Further, we established a distinct chromosomal haplotype covering a 19 cM region on Xq24-q27.1 co-segregating with the disorder. Here, we have further analyzed this X-chromosomal region using a denser marker map and monitored X-chromosomal haplotypes in a study sample of 41 Finnish bipolar families. Only a fraction of the families provided any evidence of linkage to this region, suggesting that a relatively rare gene predisposing to BPD is enriched in this linked pedigree. The genome-wide scan for BPD predisposing loci in this large pedigree indicated that this particular X-chromosomal region provides the best evidence of linkage genome-wide, suggesting an X-chromosomal gene with a major role for the genetic predisposition of BPD in this family.

Bipolar Disorder↗
PubMed2001

Dissecting a population genome for targeted screening of disease mutations.

Compared to mixed populations, population isolates such as Finland show distinct differences in the prevalence of disease mutations. However, little information exists of the differences on the prevalence of different disease alleles in regional populations with different history of multiple bottlenecks. We constructed a DNA-array and monitored the prevalence of 31 rare and common disease mutations underlying 27 clinical phenotypes in a large population-based study sample. Over 64 000 genotypes were assigned in 2151 samples from four geographical areas representing early and late settlement regions of Finland. Each sample was analyzed in duplicate and a total of 142 000 array-derived genotyping calls were made. On average one in three individuals was found to be a carrier of one of the 31 monitored mutations. This should remove fears of the stigmatizing effect of a carrier-screening program monitoring multiple diseases. Regional differences were found in the prevalence of mutations, providing molecular evidence for the deviating population histories of regional subisolates. The mutations introduced early into the population revealed relatively even distribution in different subregions. More recently introduced rare mutations showed local clustering of disease alleles, indicating the persistence of population subisolates and the effect of multiple bottlenecks in molding the population gene pool. Regional differences were observed also for common disease alleles. Such precise information of the carrier frequencies could form the basis for targeted genetic screens in this population. Our approach describes a general paradigm for large-scale carrier-screening programs also in other populations.

Alleles↗
PubMed2001

Platelet glycoprotein Ibalpha HPA-2 Met/VNTR B haplotype as a genetic predictor of myocardial infarction and sudden cardiac death.

BACKGROUND: Sudden cardiac death (SCD) is one of the leading manifestations of coronary heart disease in early middle age. Platelet glycoprotein (GP) Ib-IX-V receptor complexes play a key role in the initial adhesion of platelets to collagen during the formation of a coronary thrombus. The HPA-2 (Thr145 Met) and VNTR polymorphisms of the gene for GP Ibalpha have been studied previously in hospitalized patients with acute coronary syndromes. The significance of these polymorphisms in victims of sudden cardiac death is not known. METHODS AND RESULTS: The association of these 2 polymorphisms with coronary atherosclerosis, coronary artery stenosis, coronary thrombosis, myocardial infarction (MI), and SCD was studied in the Helsinki Sudden Death Study, which comprised 2 large autopsy series, collected 10 years apart during 1981 to 1982 and 1991 to 1992, of 700 middle-aged white Finnish men who suffered sudden or violent out-of-hospital death. The 2 polymorphisms showed an almost complete linkage disequilibrium. Men with acute MI (n=80) and coronary thrombosis (n=65) were more likely to be carriers of the HPA-2 Met allele (OR 2.0 and 2.6, respectively, P<0.005 for both) than were control subjects who died of noncardiac causes (n=367). In men <55 years old, the Met allele was overrepresented (OR 2.2) among victims of SCD (n=98) compared with control subjects (n=249). In men <55 years old, 17 of 29 men with acute MI (58.6%) and 16 of 23 men with coronary thrombosis (69.6%) were carriers of the HPA-2 Met allele compared with the 49 of 249 (19.7%) who had died of noncardiac causes (ORs 5.6 and 9.2, respectively). Similar associations were observed in the separate analyses of both autopsy series. CONCLUSIONS: Our results suggest that the HPA-2 Met/VNTR B haplotype of the platelet von Willebrand factor and thrombin receptor protein GP Ib-V-IX may be considered to be a major risk factor of coronary thrombosis, fatal MI, and SCD in early middle age.

Adult↗
PubMed2001

Quantitative-trait-locus analysis of body-mass index and of stature, by combined analysis of genome scans of five Finnish study groups.

In recent years, many genomewide screens have been performed, to identify novel loci predisposing to various complex diseases. Often, only a portion of the collected clinical data from the study subjects is used in the actual analysis of the trait, and much of the phenotypic data is ignored. With proper consent, these data could subsequently be used in studies of common quantitative traits influencing human biology, and such a reanalysis method would be further justified by the nonbiased ascertainment of study individuals. To make our point, we report here a quantitative-trait-locus (QTL) analysis of body-mass index (BMI) and stature (i.e., height), with genotypic data from genome scans of five Finnish study groups. The combined study group was composed of 614 individuals from 247 families. Five study groups were originally ascertained in genetic studies on hypertension, obesity, osteoarthritis, migraine, and familial combined hyperlipidemia. Most of the families are from the Finnish Twin Cohort, which represents a population-wide sample. In each of the five genome scans, approximately 350 evenly spaced markers were genotyped on 22 autosomes. In analyzing the genotype data by a variance-component method, we found, on chromosome 7pter (maximum multipoint LOD score of 2.91), evidence for QTLs affecting stature, and a second locus, with suggestive evidence for linkage to stature, was detected on chromosome 9q (maximum multipoint LOD score of 2.61). Encouragingly, the locus on chromosome 7 is supported by the data reported by Hirschhorn et al. (in this issue), who used a similar method. We found no evidence for QTLs affecting BMI.

Body Height↗
PubMed2001

Polymorphisms within the tumor necrosis factor locus and prevalence of coronary artery disease in middle-aged men.

Tumor necrosis factor (TNF) is an important cytokine in the inflammation process of atherosclerosis and is also involved in lipid metabolism. Two biallelic polymorphisms within TNF gene locus-TNFA at the position -308 in the promoter region of the TNF gene and TNFB in the first intron of the lymphotoxin-alpha (LT-alpha) have been reported to be associated with TNF production and with susceptibility to inflammatory diseases. We studied the association of these polymorphisms within the major histocompatibility complex (MHC) III region with coronary atherosclerosis and its manifestations. The autopsy series comprised 700 Caucasian Finnish men, aged 33-70 years (The Helsinki Sudden Death Study). Coronary stenosis and surface area of atherosclerotic changes (fatty streaks, fibrous plaques, complicated lesions and calcification) were measured and the presence of myocardial infarction and coronary thrombosis recorded. TNFA and TNFB genotypes were determined by the PCR-RFLP technique. The allele frequencies were TNFA1/TNFA2=0.88/0.12 and TNFB1/TNFB2=0.30/0.70. There was a strong linkage disequilibrium between the two polymorphisms. There were no differences in coronary stenosis and in the frequency of old or recent myocardial infarction or coronary thrombosis between men with different genotype status in either locus. Men with TNFA22 or TNFB11 genotype tended to have more fibrous lesions and calcification in their coronary arteries. TNFA and TNFB polymorphisms are unlikely to contribute to progression of atherosclerosis in a way clinically important.

Adult↗
PubMed2001

The GPIIIa (beta3 integrin) PlA polymorphism in the early development of coronary atherosclerosis.

The GPIIIa (beta3 integrin) is an integral part of two glycoprotein receptors - the GP(IIb/IIIa) fibrinogen receptors in platelets and the GP(V/IIIa) vitronectin receptors in endothelium and vascular smooth muscle cells (vSMC). The PlA polymorphism of the gene for GPIIIa (beta3 integrin) has been suggested to play an important role in the progression of coronary artery disease (CAD) and in coronary thrombosis. Whether the action of the PlA polymorphism is due to differences in platelet aggregability or function of the vSMC and endothelial GPIIIa is not known. The association of the PlA polymorphism with the early, non-complicated atherosclerosis and CAD was studied in the Helsinki Sudden Death Study (HSDS) comprising two independent, autopsy series of altogether 700 middle-aged Caucasian Finnish men (33-70 year) suffering sudden out-of-hospital death. The burden of complicated lesions was greater in men with the A2 allele (heterozygotes or homozygotes for A2) (P=0.01) compared with PlA1/A1 homozygotes in the entire series. To further estimate the role of platelet-independent GPIIIa receptors, we excluded all cases with coronary thrombosis and thrombus-overlaid complicated lesions. In this subset of men, fibrous coronary lesions were more frequent (OR 2.9; P<0.01) in the coronary arteries of PlA1/A1 homozygotes compared with men with the PlA2 allele. Moreover, men with the PlA1/A1 genotype also had more stenotic coronary arteries (P<0.05) compared with men with the A2 allele at this early, non-complicated stage of atherosclerosis. The findings of this study suggest that Pl(A1/A1) homozygotes may be prone to early atherosclerosis and more rapid progression of stable CAD whereas carriers of the PlA2 allele are more prone to thrombotic complications. We hypothesize that the PlA polymorphism may account for the early atherosclerosis by affecting the function of endothelial and vSMC GP(V/IIIa) receptors, whereas the PlA polymorphism on platelet GP(IIb/IIIa) receptors may play a major role in coronary thrombosis.

Adult↗
PubMed2001

Promoter polymorphism of the CD14 endotoxin receptor gene as a risk factor for alcoholic liver disease.

Twin concordance studies indicate that genetic factors influence the individual susceptibility for alcoholic liver disease (ALD). Both clinical and experimental data suggest that Kupffer cell activation by gut-derived endotoxins and other bacterial products is an important pathogenic factor. Activated Kupffer cells release proinflammatory cytokines, a process that is regulated by the CD14 endotoxin receptor (CD14). Recently, a C-->T (-159) polymorphism in the promoter region of the CD14 gene was detected and found to confer increased CD14 expression. In the present study, the association of CD14 promoter polymorphism with different forms of ALD was examined in 3 separate autopsy series. Among 442 men with valid alcohol-consumption data, 381 men had been moderate or heavy alcohol consumers. The allele frequency of the CD14 promoter genotype, determined by a modified cycle minisequencing technique, was 0.34 (CC), 0.51 (CT), and 0.16 (TT). The T allele was found to be associated with advanced ALD, i.e., with alcoholic hepatitis (odds ratio [OR]: 2.48; P = .018), and especially with cirrhosis (OR: 3.45; P = .004), but not with fatty liver, periportal fibrosis, or bridging fibrosis. The overall age-adjusted risk for cirrhosis was 3.08 (P = .01) for the carriers of the CT genotype, and 4.17 (P = .005) for the homozygous TT genotype. These results suggest that in the relatively isolated Finnish population, the T allele confers increased risk of alcoholic liver damage. In particular, TT homozygotes are at a high risk to develop cirrhosis.

Adult↗
PubMed2001

Testing genetic susceptibility loci for alcoholic heart muscle disease.

BACKGROUND: Although many heavy alcohol users have subclinical alcoholic heart muscle disease, only a very few develop severe dilated cardiomyopathy. Therefore, and because cardiac abnormalities correlate only weakly with the duration or quantity of drinking, individual susceptibility differences may exist. In this work we examined whether common gene variants previously associated with cardiac hypertrophy or altered alcohol metabolism could modify the effects of alcohol on the heart. METHODS: We studied 700 middle-aged male victims of sudden death who underwent a medicolegal autopsy. In addition to routine postmortem examination, the weights and the cavity and wall dimensions of the left and right ventricle were measured. Coronary artery stenoses were determined from a silicone rubber cast of the arteries. Alcohol consumption and cardiovascular risk factors were assessed by a structured interview of the spouse. The following gene polymorphisms were determined by using polymerase chain reaction restriction fragment length polymorphism and solid-phase minisequencing techniques: angiotensin converting enzyme I/D, angiotensin II type 1 receptor 1166A/C, aldosterone synthase -344C/T, alcohol dehydrogenases 2 and 3, acetaldehyde dehydrogenase 2, and cytochrome P-450 2E1 DraI, PstI, RsaI, and MspI. RESULTS: The most consistent effects of alcohol (p < 0.05) were a higher total heart weight and a larger right ventricle size with increasing daily drinking. However, these and other effects of alcohol were statistically fully independent of the studied genotypes. CONCLUSIONS: The gene polymorphisms selected for and analyzed in our study are unlikely to modify the effects of alcohol on the heart. Other unknown factors determine the individual susceptibility to alcoholic heart muscle disease.

Adult↗
PubMed2001

Utility of the Arg/Gln polymorphism of the factor VII (FVII) gene, serum lipid levels and body mass index in the prediction of the FVII:C and FVII:Ag in North Karelia; a cross-sectional and prospective study.

The arginine/glutamine (Arg/Gln) polymorphism of the factor VII (FVII) gene is associated with variation in coagulation activity (FVII:C) and antigen concentration (FVII:Ag) of the FVII protein. We estimated frequency distributions of the Arg and Gln alleles and respective genotypes in North Karelia, and evaluated the utility of this polymorphism, serum lipids, and body mass index (BMI) in the prediction of the distributions of FVII:C and FVII:Ag in a cross-sectional study and in a prospective cohort study. The sample comprised 203 males and 262 females (aged 45-64 years) who were seen twice, in 1992 and 1995. The Arg/Arg genotype and the Arg allele frequencies were among the highest reported so far (86 and 93% respectively, in men; and 89 and 94% respectively, in women). Intragenotypic means of both FVII:C and FVII:Ag were significantly higher in the Arg/Arg genotype than in the Arg/Gln genotype in both genders. Also, intragenotypic variances were different in different genotypes in females. Regression relationships between the FVII:C and FVII:Ag and serum triglyceride, and total cholesterol levels and BMI were positive in both genotypes in both genders, which has not been found in other populations. In prospective analyses, average changes in the FVII:C and FVII:Ag were genotype specific in both genders, as were also regression relationships between these changes and changes in triglyceride level in females (P = 0.065 for FVII:C and P = 0.061 for FVII:Ag). A consequence of these complex genetic architectures is that predictive utility of the Arg/Gln genotypes depends on population, gender, serum lipid levels, and BMI, and changes in these factors over time.

Alleles↗
PubMed2001

Coronary artery complicated lesion area is related to functional polymorphism of matrix metalloproteinase 9 gene: an autopsy study.

Matrix metalloproteinase 9 (MMP9) is expressed in human atherosclerotic plaques, and the protein is localized in human coronary atherosclerotic lesions. The MMP9 gene has a C-to-T promoter polymorphism at position -1562, which affects transcription and leads to promoter low-activity (C/C) and high-activity (C/T, T/T) genotypes. To determine whether these genotypes exert an influence on the atherosclerotic lesion area, we investigated their association with different types of coronary lesions in an autopsy cohort of 276 men aged 33 to 69 years. Areas of the coronary wall covered with fatty streaks and fibrotic, calcified, and complicated lesions were measured, and the percentage of coronary narrowing was determined. MMP9 genotypes were determined by polymerase chain reaction and restriction enzyme digestion. In men aged >/=53 years, the mean area of complicated lesions in 3 coronaries was significantly associated with the MMP9 genotype (P=0.008). Subjects with high promoter activity genotypes had, on average, larger complicated lesion areas than did those with the low-activity genotype. The MMP9 genotype persisted as an independent predictor of complicated lesion area after adjustment for age, body mass index, hypertension, diabetes, and smoking (P=0.012). These data provide evidence that the proposed effect of MMP9 in the process of atherosclerotic lesion development may be modified by the MMP9 genotype.

Adult↗