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M Perola

Publications and source records attributed to M Perola.

At least 37 records · Page 2Linked to original sources
PubMed2000

Heritability and risk factors of uterine fibroids--the Finnish Twin Cohort study.

OBJECTIVES: Our aim was to study heritability, risk factors and hospitalization for uterine fibroids. METHODS: A random sample of 80 MZ and 80 DZ twins from the Finnish Twin Cohort were invited and 51% of the eligible women (n=82, 17 MZ and 16 DZ pairs, 40-47 years, mean age 43.0), underwent a transvaginal ultrasound. The entire cohort of 13872 women was linked to the national hospital discharge registry 1972-1990. RESULTS: Prevalence of fibroids was 66% and the average number of fibroids 1.7. The casewise concordance for being hospitalized for uterine fibroids was higher in MZ (0.31, 95% CI 0.24-0.37) than in DZ pairs (0.18, 95% CI 0.14-0.22). The proportion of variance in liability to fibroid hospitalization accounted for by genetic factors was 54.8% (95% CI 46.2-62.7%). Women with fibroids had higher body mass index (23.7 vs 21.7, P=0.0086), lower age at first birth (25.7 vs 29.3, P=0.012) and higher parity (3+ children 48.2 vs 29.6%, P=0.009) than women without fibroids. Risk ratio (RR) for fibroids in a MZ twin whose sister had been diagnosed with fibroids was 1.1 (95% CI 0.08;15), for a DZ twin 1.1 (95% CI 0.16;8.8) and for all twins 1.3 (95% CI 0.3; 6.1). Intraclass correlation for the number of fibroids was 0.24 for MZ and 0.11 for DZ twins, yielding an heritability estimate of 0.26. CONCLUSION: Reproductive and anthropometric factors may have at least as large role in pathogenesis of fibroids than genetic factors.

Adult↗
PubMed2000

Two loci on chromosomes 2 and X for premature coronary heart disease identified in early- and late-settlement populations of Finland.

Coronary heart disease (CHD) is a complex disorder constituting a major health problem in Western societies. To assess the genetic background of CHD, we performed a genomewide linkage scan in two study samples from the genetically isolated population of Finland. An initial study sample consisted of family material from the northeastern part of Finland, settled by a small number of founders approximately 300 years ago. A second study sample originated from the southwestern region of Finland, settled approximately 2,000 years ago. Families were ascertained through probands exhibiting premature CHD, defined as >50% stenosis of at least two coronary arteries at a young age, as verified by coronary angiography. Both study samples and the pooled data set provided evidence for linkage in two chromosomal regions. A region on chromosome 2q21.1-22 yielded two-point LOD scores of 3.2, 1.9, and 3.7, in the affected sib-pair (ASP) analyses of the northeastern, southwestern, and pooled study samples. The corresponding multipoint maximum-likelihood scores (MLSs) for these three study samples were 2.4, 1.3, and 3.0. In addition, a region on chromosome Xq23-26 resulted in two-point LOD scores of 1.9, 3.5, and 2.9 and in multipoint MLSs of 3.4, 3.1, and 2.5, respectively. In conclusion, this study identifies two loci likely to contribute to premature CHD: one on chromosome 2q21.1-22 and another on chromosome Xq23-26.

Age of Onset↗
PubMed2000

Apolipoprotein E variation at the sequence haplotype level: implications for the origin and maintenance of a major human polymorphism.

Three common protein isoforms of apolipoprotein E (apoE), encoded by the epsilon2, epsilon3, and epsilon4 alleles of the APOE gene, differ in their association with cardiovascular and Alzheimer's disease risk. To gain a better understanding of the genetic variation underlying this important polymorphism, we identified sequence haplotype variation in 5.5 kb of genomic DNA encompassing the whole of the APOE locus and adjoining flanking regions in 96 individuals from four populations: blacks from Jackson, MS (n=48 chromosomes), Mayans from Campeche, Mexico (n=48), Finns from North Karelia, Finland (n=48), and non-Hispanic whites from Rochester, MN (n=48). In the region sequenced, 23 sites varied (21 single nucleotide polymorphisms, or SNPs, 1 diallelic indel, and 1 multiallelic indel). The 22 diallelic sites defined 31 distinct haplotypes in the sample. The estimate of nucleotide diversity (site-specific heterozygosity) for the locus was 0.0005+/-0.0003. Sequence analysis of the chimpanzee APOE gene showed that it was most closely related to human epsilon4-type haplotypes, differing from the human consensus sequence at 67 synonymous (54 substitutions and 13 indels) and 9 nonsynonymous fixed positions. The evolutionary history of allelic divergence within humans was inferred from the pattern of haplotype relationships. This analysis suggests that haplotypes defining the epsilon3 and epsilon2 alleles are derived from the ancestral epsilon4s and that the epsilon3 group of haplotypes have increased in frequency, relative to epsilon4s, in the past 200,000 years. Substantial heterogeneity exists within all three classes of sequence haplotypes, and there are important interpopulation differences in the sequence variation underlying the protein isoforms that may be relevant to interpreting conflicting reports of phenotypic associations with variation in the common protein isoforms.

Alleles↗
PubMed2000

Glycoprotein IIIa Pl(A1/A2) polymorphism and sudden cardiac death.

OBJECTIVES: We studied the association of the Pl(A1/A2) polymorphism with coronary thrombosis, myocardial infarction (MI) and sudden cardiac death (SCD) in autopsied victims of sudden death. BACKGROUND: Sudden cardiac death is one of the leading symptoms of coronary heart disease in early middle age. Platelet glycoprotein (GP)IIb/IIIa fibrinogen receptors play a key role in coronary thrombosis and MI. Pl(A1/A2) polymorphism of the gene for GPIIIa has been previously studied in hospital MI patients. Significance of the Pl(A1/A2) polymorphism in victims of SCD is not known. METHODS: The Pl(A1/A2) polymorphism was studied in the Helsinki Sudden Death Study comprising 700 autopsied middle-aged white Finnish men (33 to 70 years, mean 53 years) who suffered sudden or violent out-of-hospital death. RESULTS: Prevalence of the A2 allele decreased with age in the series. This decrease was observed among victims of SCD (n = 281) but not in men who died violently (n = 258) or of other diseases (n = 127). Of SCD victims below 50 years, 39.7% were carriers of the A2 allele compared with 28.3% among men under 50 who died of other causes (odds ratio [OR] 2.5, p = 0.01). Men with acute fatal coronary thrombosis (n = 39) were more often (OR 3.4, p < 0.01) carriers of the A2 allele than were men (n = 242) with SCD in the absence of acute coronary thrombosis (48.7% vs. 24.4%, respectively). In addition, men with MI and recent or old thrombosis (n = 67) were more often (OR 3.6, p = 0.005) carriers of the A2 allele than were men (n = 123) with MI in the absence of thrombosis (44.8% vs. 20.3%, respectively). These associations were especially strong in men under 60. CONCLUSIONS: Our results suggest that the A2 allele of the Pl(A1/A2) polymorphism of GPIIIa is a major risk factor of coronary thrombosis and may be one important predictor of SCD in early middle age.

Adult↗
PubMed2000

Genome-wide scan of predisposing loci for increased diastolic blood pressure in Finnish siblings.

OBJECTIVES: To review, on a genome-wide scale, a linkage result obtained in an earlier candidate gene analysis in this same study sample, and to look for other possible contributing genetic loci predisposing to hypertension in this population. DESIGN: An affected sibpair linkage study with highly polymorphic genetic markers spanning the genome at an average intermarker density of 10 cM. PARTICIPANTS: A total of 47 families with two affected siblings (mostly dizygotic twins) and all available additional family members from the genetic isolate of Finland. The families were identified through the Finnish Twin Cohort Study, the total number of this follow-up cohort being 13,888. The study sample was selected on the basis of early-onset hypertension with minimal presence of other phenotypic risk factors such as obesity. RESULTS: The AT1 locus stood out as the most significant locus in this population (maximum likelihood score 4.04). Some evidence for linkage was also detected with markers on chromosomes 2q (maximum likelihood score 2.96), 22q (2.07), and Xp (2.41). CONCLUSIONS: Our results establish the role of the AT1 locus, on a genome-wide scale, as a major contributing locus to essential hypertension in this study sample.

Blood Pressure↗
PubMed2000

Plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism, coronary thrombosis, and myocardial infarction in middle-aged Finnish men who died suddenly.

High plasminogen activator inhibitor-1 (PAI-1) plasma levels increase future risk of myocardial infarction (MI). The 4G allele of the 4G/5G polymorphism of the PAI-1 gene has been associated with increased plasma levels of PAI-1. The association of the PAI-1 polymorphism with coronary narrowings, coronary thrombosis and myocardial infarction (MI) was studied in a prospective autopsy series of 300 middle-aged Caucasian Finnish men (33 to 69 yrs) suffering sudden out-of-hospital death (Helsinki Sudden Death Study). The 4G allele was found in 76.8% of men with sudden cardiac death (SCD) compared to 67.5% in men who died accidentally and 63.2% in men who died of other diseases (p = 0.08 and p = 0.055, respectively). Men possessing the 4G allele had more often acute MI (OR 3.5; p <0.05) and coronary thrombosis (OR 5.5. p = 0.01) compared to 5G homozygotes. 5G homozygotes, comprising one third of the men in our study, seem to be at a decreased risk of thrombosis, whereas carriers of the common 4G allele have an increased risk of thrombosis, AMI and possibly SCD compared to 5G homozygotes.

Accidents↗
PubMed1999

The GPIIIa Pl(A) polymorphism in the progression of abdominal aortic atherosclerosis.

Glycoprotein IIIa is expressed in platelets as part of the fibrinogen receptor and also in vascular endothelium where it mediates smooth muscle cell proliferation. The association between the glycoprotein GPIIIa Pl(A) polymorphism and the stage of atherosclerosis in the abdominal aorta was studied in a prospective autopsy study series of 300 middle-aged men (33-69 years). The Pl(A) genotype was determined by RFLP-PCR. The stage of atherosclerosis in the abdominal aorta was determined by computer-assisted morphometry. Elevated, fibrous lesions were more frequently (P=0.05) found in the abdominal aortas of men with the Pl(A1) homozygous genotype compared to men with the A2 allele (OR 2.3; 95% CI 0.99-5.2). The area of complicated lesions was significantly greater in men with Pl(A2)-positive genotypes compared to A1 homozygotes. The association with complicated lesions was especially strong in men over 60 (P=0.002). These results suggest that Pl(A) polymorphism is involved in the progression of atherosclerosis in the abdominal aorta. The association of men possessing the Pl(A2) allele with slower development of fibrous lesions and with greater area of complicated lesions in the abdominal aorta may result from genotypic differences in the smooth muscle cell proliferation after slight injuries to the endothelium mediated by glycoprotein IIIa or from genotypic differences in platelet fibrinogen binding or both.

Adult↗
PubMed1999

Age-dependent association of apolipoprotein E genotype with coronary and aortic atherosclerosis in middle-aged men: an autopsy study.

BACKGROUND: Apolipoprotein E (apoE) polymorphism is one of the genetic determinants of serum cholesterol values. The apoE epsilon4 allele has been associated with advanced coronary heart disease (CHD) diagnosed by angiography, but the role of the apoE genotype in atherosclerosis has not been confirmed at vessel-wall level, nor is any age-dependent effect of the apoE genotype on the development of CHD known. METHODS AND RESULTS: The right and left anterior descending coronary arteries (RCA and LAD) and the aorta from 700 male autopsy cases (Helsinki Sudden Death Study) in 1981-1982 and 1991-1992 (average age 53 years, range 33 to 70 years) were stained for fat, and all areas covered with fatty streaks, fibrotic plaques, and complicated lesions were measured. In the RCA and LAD, the apoE genotype was significantly associated with the area of total atherosclerotic lesions in men <53 years old but not with that in older men (P=0.0085 and P=0.041, respectively, for age-by-genotype interaction). Men <53 years old with the epsilon4/3 genotype showed 61% larger total atherosclerotic lesion area in the RCA (P=0.0027) and 26% larger area in the LAD (P=0.12) than did men with the epsilon3/3. The apoE epsilon4/3 was also associated with atherosclerotic lesions in the abdominal (P=0.014) and thoracic (P=0.12) aorta, but this effect, unlike that of the coronary arteries, was not age-related. CONCLUSIONS: In men, the apoE epsilon4 allele is a significant genetic risk factor for coronary atherosclerosis in early middle age. This suggests that at older age, other known risk factors of CHD play a more important role in the atherosclerotic process than apoE polymorphisms.

Age Factors↗
PubMed1999

Long-extension PCR to detect deleted mitochondrial DNA molecules is compromized by technical artefacts.

Long-extension PCR (LX-PCR), followed by Southern hybridization to probes for two different regions of the mitochondrial genome, was used to evaluate the presence of deleted mtDNA molecules in heart muscle samples from alcoholic cardiomyopathy patients compared with age-matched controls. Two different primer pairs capable of amplifying the entire genome, as well as a variety of other primer pairs predicted to amplify the genome in large, overlapping fragments, were tested. Products indicating the presence of a variety of subgenomic, deleted molecules were detected in variable amounts from patient and control myocardial samples alike. Most of these hybridized with a probe for the 16S/ND1 region, but not with a probe for the ND4/ND5 region that is commonly deleted. Dilution of a given template DNA in which deleted products were prominent resulted in the disappearance of the subgenomic bands in favour of the full-length, undeleted product. Therefore, the appearance and amount of such products is subject to template concentration or quality. The results indicate that the application of LX-PCR to the detection and quantitation of deleted mtDNAs is inherently unreliable, and findings using this technique should be treated with caution unless supported by an independent method.

Adult↗
PubMed1999

Association of FXIII Val34Leu with decreased risk of myocardial infarction in Finnish males.

Factor XIII is a transglutaminase that crosslinks fibrin in the last steps of the coagulation process. A few polymorphic sites have been identified in this gene, one of them being a point mutation (FXIII Val34Leu), leading to an amino acid change of valine to leucine. Recently, in British patients, FXIII 34Leu allele was suggested to be associated with a decreased incidence of myocardial infarction (MI). PAI-1 4G/4G genotype seemed to lessen the beneficial effect of FXIII 34Leu allele. The aim of our study was to further investigate the possible protective role of the FXIII 34Leu allele against MI and its suggested interaction with the PAI-1 4G/5G polymorphism. We carried out genotype analyses for FXIII Val34Leu using solid-phase minisequencing in two independent Finnish study groups. In our study, the FXIII 34Leu allele was associated with a lower risk of MI (P = 0.009), however, the PAI-1 4G allele showed no interaction with this polymorphism. To establish the population frequency of the FXIII 34Leu allele and to study the possible variations in Finland four DNA pools from different geographical areas of Finland were genotyped. No significant differences in the allele frequencies were observed (21-28%) except in the Eastern Kainuu area (13%), an area with an increased risk of mortality from coronary artery disease (CAD), supporting the results presented above. The association of FXIII 34Leu variant with a lower incidence of myocardial infarction suggests a new role for FXIII in a polygenic thrombotic disease.

Alleles↗
PubMed1999

Genomewide scan for familial combined hyperlipidemia genes in finnish families, suggesting multiple susceptibility loci influencing triglyceride, cholesterol, and apolipoprotein B levels.

Familial combined hyperlipidemia (FCHL) is a common dyslipidemia predisposing to premature coronary heart disease (CHD). The disease is characterized by increased levels of serum total cholesterol (TC), triglycerides (TGs), or both. We recently localized the first locus for FCHL, on chromosome 1q21-q23. In the present study, a genomewide screen for additional FCHL loci was performed. In stage 1, we genotyped 368 polymorphic markers in 35 carefully characterized Finnish FCHL families. We identified six chromosomal regions with markers showing LOD score (Z) values >1.0, by using a dominant mode of inheritance for the FCHL trait. In addition, two more regions emerged showing Z>2.0 with a TG trait. In stage 2, we genotyped 26 more markers and seven additional FCHL families for these interesting regions. Two chromosomal regions revealed Z>2.0 in the linkage analysis: 10p11.2, Z=3.20 (theta=.00), with the TG trait; and 21q21, Z=2.24 (theta=.10), with the apoB trait. Furthermore, two more chromosomal regions produced Z>2.0 in the affected-sib-pair analysis: 10q11.2-10qter produced Z=2.59 with the TC trait and Z=2.29 with FCHL, and 2q31 produced Z=2.25 with the TG trait. Our results suggest additional putative loci influencing FCHL in Finnish families, some potentially affecting TG levels and some potentially affecting TC or apoB levels.

Adult↗
PubMed1999

Glycoprotein IIIa Pl(A) polymorphism associates with progression of coronary artery disease and with myocardial infarction in an autopsy series of middle-aged men who died suddenly.

Glycoprotein IIIa (GPIIIa) has a key role in the aggregation of thrombocytes, and it also mediates intimal hyperplasia after endothelial injuries; the possible association of the Pl(A1/A2) polymorphism of the gene for GPIIIa with coronary thrombosis and with the progression of coronary artery disease (CAD) is still to be confirmed. Therefore, the association of the Pl(A) polymorphism with the development of coronary atherosclerosis, coronary narrowing, and myocardial infarction (MI) was studied in a prospective, consecutive autopsy series of 300 middle-aged, white Finnish men (33 to 69 years) suffering sudden out-of-hospital or violent death. Coronary atherosclerosis was measured morphometrically and the coronary stenosis percentage determined from a cast rubber model of the coronary tree. We found a significant inverse relation (P=0.01) between the Pl(A2)-positive genotype and coronary artery stenosis. The frequency of possessing the Pl(A2) allele was significantly (odds ratio [OR] 0.45, 95% confidence interval [CI] 0.22 to 0.98) lower among men with >50% coronary stenosis (18.3%) than among those with <25% stenosis (32.9%). Although the Pl(A) polymorphism was not directly associated with MI, the Pl(A2) allele was present in 11 of the 22 men (50%) with MI and coronary thrombosis (OR 6.6, 95% CI 2.1 to 22.8) but in only 6 of the 47 (12.8%) with MI associated with severe stenosis in the absence of thrombosis. In line with this result, men possessing the Pl(A2) allele also had a larger area of fissured and ulcerated complicated lesions in their coronary arteries (P<0.05). The present results suggest that the Pl(A) polymorphism is involved in the development of CAD and MI. Men with the Pl(A2) allele may harbor more thin-walled, vulnerable coronary plaques, plaques prone to rupture, leading to massive, fatal thrombosis. In contrast, men homozygous for the Pl(A1) allele may more often show stable plaques and present with infarction caused by progressive coronary stenosis.

Adult↗
PubMed1999

Evidence for involvement of the type 1 angiotensin II receptor locus in essential hypertension.

Components of the renin-angiotensin system play an important role in the normal regulation of blood pressure. We carried out a comprehensive genetic linkage study of the genes involved in the renin-angiotensin cascade in Finnish hypertensive twins and their affected siblings. We found no evidence for linkage between essential hypertension and the genes coding for renin, angiotensinogen, angiotensin-converting enzyme, or kallikrein 1 in the 329 hypertensive individuals of 142 families studied. In contrast, two intragenic markers for the type 1 angiotensin II receptor (AT1) showed some evidence for linkage in the total sample. A closer examination of this gene locus was carried out using subgroups of nonobese sibpairs with early onset of hypertension and uniform geographical origin. These stratifications yielded suggestive evidence for linkage of hypertension to the genetic area containing the AT1 gene, with a maximal multipoint logarithm of the odds (LOD) score of 2.9. A genetic association study carried out in an independent series of 50 hypertensive cases and 122 normotensive controls showed an increase in the frequency of the A1166-->C allele of the AT1 gene in the hypertensive individuals. In a novel variant of model-free multipoint linkage analysis allowing linkage disequilibrium in the calculations, an LOD score of 5.13 was obtained. Sequence analyses of the entire coding region and 848 bp of promoter region in the DNA sample on 8 index samples did not reveal previously unpublished sequence variations. The data provide evidence that a common genetic variant of the AT1 gene locus influences the risk of essential hypertension in the Finnish population.

Adult↗
PubMed1998

Dual origins of Finns revealed by Y chromosome haplotype variation.

The Finnish population has often been viewed as an isolate founded 2, 000 years ago via a route across the Gulf of Finland. The founding event has been characterized as involving a limited number of homogeneous founders, isolation, and subsequent rapid population growth. Despite the purported isolation of the population, levels of gene diversity for the Finns at autosomal and mitochondrial DNA loci are indistinguishable from those of other Europeans. Thus, mixed or dual origins for the Finns have been proposed. Here we present genetic evidence for the dual origins of Finns by evaluating the pattern of Y chromosome variation in 280 unrelated males from nine Finnish provinces. Phylogenetic analysis of 77 haplotype configurations revealed two major star-shaped clusters of Y haplotypes, indicative of a population expansion from two common Y haplotypes. Dramatic and quite significant differences in Y haplotype variation were observed between eastern and western regions of Finland, revealing contributions from different paternal types. The geographic distribution and time of expansion for the two common Y haplotypes correlate well with archeological evidence for two culturally and geographically distinct groups of settlers. Also, a northeastern to southwestern gradient of Y haplotype frequencies provides convincing evidence for recent male migration from rural areas into urban Finland.

Evolution, Molecular↗
PubMed1998

Haplotype structure and population genetic inferences from nucleotide-sequence variation in human lipoprotein lipase.

Allelic variation in 9.7 kb of genomic DNA sequence from the human lipoprotein lipase gene (LPL) was scored in 71 healthy individuals (142 chromosomes) from three populations: African Americans (24) from Jackson, MS; Finns (24) from North Karelia, Finland; and non-Hispanic Whites (23) from Rochester, MN. The sequences had a total of 88 variable sites, with a nucleotide diversity (site-specific heterozygosity) of .002+/-.001 across this 9.7-kb region. The frequency spectrum of nucleotide variation exhibited a slight excess of heterozygosity, but, in general, the data fit expectations of the infinite-sites model of mutation and genetic drift. Allele-specific PCR helped resolve linkage phases, and a total of 88 distinct haplotypes were identified. For 1,410 (64%) of the 2,211 site pairs, all four possible gametes were present in these haplotypes, reflecting a rich history of past recombination. Despite the strong evidence for recombination, extensive linkage disequilibrium was observed. The number of haplotypes generally is much greater than the number expected under the infinite-sites model, but there was sufficient multisite linkage disequilibrium to reveal two major clades, which appear to be very old. Variation in this region of LPL may depart from the variation expected under a simple, neutral model, owing to complex historical patterns of population founding, drift, selection, and recombination. These data suggest that the design and interpretation of disease-association studies may not be as straightforward as often is assumed.

Animals↗
PubMed1998

Array-based multiplex analysis of candidate genes reveals two independent and additive genetic risk factors for myocardial infarction in the Finnish population.

We analysed common variants of eight genes implicated previously as risk factors for coronary heart disease or myocardial infarction (MI) in a cross-sectional study on patients with a history of MI and in carefully matched controls from the Finnish population. The most common low density lipoprotein receptor mutations in Finland were also included in our analysis. Multiplex genotyping of the target genes was performed using a specific and efficient array-based minisequencing system. The 4G allele of the plasminogen activator inhibitor gene (P < 0.05) and the PlA2 allele of the glycoprotein IIIa gene (P < 0.01) were associated with an increased risk of MI in our study population. We analysed the combined effect of these risk alleles and found that the concurrent carrier status of the two genetic variants conferred a high risk for the development of MI in our sample (OR = 4.5, P = 0.001), which was particularly prominent in male subjects (OR = 6.4, P = 0.0005). This study demonstrates the application of a new powerful tool for genome analysis to yield information on the inherited determinants of susceptibility to MI. The observation of two separate genes contributing an additive risk of developing MI exemplifies the advantages of multiplex analysis of genetic variation.

Adult↗