Biomedical subjects

M Perola

Publications and source records attributed to M Perola.

46 records · Page 3Linked to original sources

PubMed1997

Phenotype expression in familial combined hyperlipidemia.

Familial combined hyperlipidaemia (FCHL) is one of the most common hereditary disorders predisposing to early coronary death. The affected family members have elevations of serum total cholesterol, triglycerides or both. Despite intensive research efforts the genetic and metabolic defects underlying this complex disorder are still unknown. To dissect the metabolism and genetics of FCHL the phenotype of an individual must be precisely defined. We assessed the influence of different diagnostic criteria on the phenotype definition and studied factors affecting the phenotype expression in 16 large Finnish families (n = 255) with FCHL. The fractile cut-points used to define abnormal lipid values had a profound influence on the diagnosis of FCHL. If the 90th percentile cut-point was used, approximately 45% of the family members were affected, in concord with the presumed dominant mode of transmission for FCHL. If the 95th percentile was used only 22% of study subjects were affected. To characterize the metabolic differences or similarities between the different lipid phenotypes, we determined very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and high density lipoprotein (HDL) particles separated by ultracentrifugation. In linkage analysis no single ultracentrifugation variable could discriminate reliably affected family members from non-affected family members. Our data emphasizes the need for re-evaluation of FCHL diagnostic criteria. Preferably, the diagnosis should be based on a single, reliable metabolic marker.

Adolescent↗

PubMed1997

Polymorphism in the cytochrome P450 2E1 gene and the risk of alcoholic liver disease.

BACKGROUND/AIMS: To study the genetic susceptibility to alcoholic liver disease, we investigated the association between genetic polymorphism in the cytochrome P450 2E1 gene and the occurrence of alcoholic liver disease. METHODS: Four previously described restriction fragment length polymorphisms (RFLPs) in the cytochrome P 450 2E1 gene were analyzed by restriction endonuclease (Dra I, Msp I, Pst I and Rsa I) digestion of polymerase chain reaction amplified DNA segments. Polymorphisms in these loci were compared to the occurrence of fatty liver, alcoholic hepatitis and liver fibrosis in 319 males comprising total abstainers, moderate alcohol consumers and chronic alcoholics. RESULTS: The allelic frequencies for each RFLP in this series were: 0.89 and 0.11 (Dra I), 0.98 and 0.02 (Msp I) and 0.99 and 0.01 (Pst I and Rsa I). The distribution of the alleles did not vary significantly between the different consumption groups. The allelic frequencies among patients with fatty liver, alcoholic hepatitis or liver fibrosis were not significantly different from the allelic frequencies among patients with normal liver histology. Comparison of different genotypes among moderate alcohol consumers (n = 43) or chronic alcoholics (n = 243) with or without liver disease showed no statistically significant associations. However, the rare polymorphic (d2) allele in the Dra I RFLP was found slightly more often among moderate consumers as well as alcoholics with alcoholic liver disease. CONCLUSIONS: These results indicate that the Msp I, Pst I and Rsa I RFLPs were very rare in the Finnish population, suggesting at most minor contribution to the inherited susceptibility to alcoholic liver disease. Polymorphism in the Dra I locus was more common in this study population, but showed no statistically significant association with alcoholic liver disease.

Adult↗

PubMed1997

No evidence of linkage between familial combined hyperlipidemia and genes encoding lipolytic enzymes in Finnish families.

Familial combined hyperlipidemia (FCHL) is characterized by different lipid phenotypes (IIa, IIb, IV) and elevated apolipoprotein B (apo B) levels in affected family members. Despite intensive research, the genes involved in the expression of this complex disorder have not been identified, probably because of problems associated with phenotype definition, unknown mode of inheritance, and most probably genetic heterogeneity. To explore the genetics of FCHL in the genetically homogeneous Finnish population, we collected 14 well-documented Finnish pedigrees with premature coronary heart disease and FCHL-like dyslipidemia. The lipolytic enzymes lipoprotein lipase (LPL), hepatic lipase (HL), and hormone-sensitive lipase (HSL) were selected as initial candidate genes because of their central roles in apo B and triglyceride metabolism. On the basis of the pedigree structures, a dominant mode of inheritance was adopted for linkage analyses, and serum total cholesterol and/or triglyceride levels exceeding the 90th percentile level were set as diagnostic criteria (criterion 1). In pairwise linkage analyses with intragenic markers, no evidence for linkage was found. Instead, the significantly negative LOD scores suggested exclusion of all three loci for single major gene effect. LOD scores were -14.63, -5.03, and -5.70 for the three LPL polymorphisms (theta=0.00); -9.40, -6.30, and -4.74 for the three HL polymorphisms (theta=0.00); and -15.29 for the HSL polymorphism (theta=0.00). The results were very similar when apo B levels over the 90th percentile were used as criteria for affected status (criterion 2). Also, when linkage calculations were carried out using an intermediate or recessive mode of inheritance, the results of pairwise linkage analysis remained negative. Furthermore, when haplotypes were constructed from multiple polymorphisms of the LPL and HL genes, no segregation with the FCHL phenotype could be observed in the 14 Finnish families. Data obtained by the affected sib-pair method supported these findings, suggesting that the LPL, HL, or HSL genes do not represent major loci influencing the expression of the FCHL phenotype.

Adult↗

PubMed1996

Glutathione S-transferase-M1 'null' genotype and alcohol-induced disorders of human spermatogenesis.

The association between alcohol-induced disorders of human spermatogenesis and glutathione S-transferase-M1 genotype was investigated in an autopsy study comprising 271 subjects, including interviews with relatives or close acquaintances on the alcohol consumption of the deceased. Of the 50 moderate drinking men (reported mean daily alcohol consumption < 40 g), 21 (42.0%) had normal spermatogenesis, whereas 24 men (48.0%) had partial, and five (10.0%) complete arrest of spermatogenesis. Of the 21 men with normal spermatogenesis, nine (42.9%) had GST M1 'null' genotype, while this genotype was found in 13 (44.8%) of the 29 men with partial or complete spermatogenic arrest. Of 212 heavy-drinking men (reported mean daily alcohol consumption > 80 g), only 45 (21.2%) had normal spermatogenesis, whereas 77 (36.3%) had partial spermatogenic arrest. Complete arrest of spermatogenesis was found in 81 men (38.2%) and nine men had Sertoli-cell-only syndrome (4.2%). Of the 45 heavy drinkers with normal spermatogenesis, 27 (60%) men had GST M1 'null' genotype (OR 2.7 with 95% confidence intervals: 1.0-4.0, when compared to those with disorders of spermatogenesis). The frequency of GST M1 'null' genotype in heavy drinkers with normal spermatogenesis also differed from that of corresponding moderate drinkers, whereas the frequency of GST M1 'null' genotype in heavy drinkers with disorders of spermatogenesis was similar to moderate drinkers with or without disorders of spermatogenesis. The finding that > 20% of men in the heavy-drinking group had normal spermatogenesis suggests individual variations in sensitivity to alcohol-induced disorders of this process. Heavy drinkers with GST M1 'null' genotype were slightly less prone to develop disorders of spermatogenesis. Thus, the GST M1 locus may be associated with susceptibility to develop alcohol-induced disorders of spermatogenesis.

Adult↗

PubMed1996

Polymorphism in the cytochrome P450 2E1 gene and alcohol-induced disorders of human spermatogenesis.

The association between alcohol-induced disorders of human spermatogenesis and four restriction fragment polymorphisms (DraI, MspI, PstI and RsaI) of the cytochrome P450 2E1 gene was investigated in an autopsy study on 254 men. Acquaintances were interviewed and the mean daily alcohol consumption of the subjects was calculated on the basis of the interviews. Spermatogenesis score and testicular morphology were assessed by light-microscopy, and cytochrome 2E1 polymorphic genotypes were determined using the polymerase chain reaction. Of the 204 heavy-drinking men, 42 (20.6%) men had normal spermatogenesis (p < 0.001, compared to moderate drinkers). Partial spermatogenic arrest was observed in 76 (37.3%) men and complete spermatogenic arrest in 79 (38.7%) men (p < 0.001, compared to moderate drinkers), whereas seven men (3.4%) had Sertoli cell only syndrome. The overall allelic frequencies for the common and rare polymorphic alleles were 0.98 and 0.02 (MspI) and 0.99 and 0.01 (PstI and RsaI), respectively. No associations between heterozygosity in the MspI, PstI or RsaI loci, or the allelic frequencies of common and rare alleles, and disorders of spermatogenesis were observed. The allelic frequencies for the common and rare polymorphic alleles in the DraI locus were 0.90 and 0.10, respectively. No significant difference was observed, either among moderate or heavy drinkers, in the frequency of the rare allele between men with disorders of spermatogenesis and those with normal spermatogenesis in the respective group, although men with disorders of spermatogenesis in general had a slightly lower frequency of the rare allele when compared to those with normal spermatogenesis. In conclusion, we were unable to demonstrate a significant association between any polymorphisms in the CYP2E1 gene and disorders of spermatogenesis. RsaI, MspI and PstI polymorphisms were extremely rare in our population and could thus possibly be excluded as reasons for genetic susceptibility to disorders of spermatogenesis in our series.

Adult↗

PubMed1996

Glutathione-S-transferase GST M1 "null" genotype and the risk of alcoholic liver disease.

The present study was conducted to investigate possible association between the occurrence of glutathione-S-transferase GST M1 "null" genotype and alcoholic liver disease (ALD). The"null" genotype indicating absent activity of class mu glutathione transferase was assessed in 33 abstainers, 43 moderate alcohol consumers, and 313 heavy alcohol consumers by polymerase chain reaction. The genotypes were compared with occurrence of alcoholic fatty liver, alcoholic hepatitis, and alcoholic liver fibrosis. The "null" genotype was found among 44.7% of patients in the series, with no significant differences between different consumption groups: controls, 36.4%; moderate consumers, 39.5%; and heavy consumers, 46.3%. Occurrence of GST M1 "null" genotype was not associated with occurrence ALD among moderate alcohol consumers. Frequency of the "null" genotype was, however, statistically nearly significantly [p = 0.07, odds ratio (OR) = 1.75] lower among heavy consumers with normal liver histology than in alcoholics with ALD. Furthermore, when compared with heavy consumers without ALD, the "null" genotype was nearly significantly more frequent among heavy consumers with at least slight liver fibrosis (p = 0.05, OR = 1.8) and statistically significantly more frequent among among alcoholics with advanced liver fibrosis (p < 0.025, OR = 2.3). Results of the present Finnish association study suggest that homozygous deletion of the GST M1 gene may indicate increased susceptibility to develop irreversible liver damage in response to the toxic effects of ethanol. Significant association was found between the occurrence of the "null" genotype and the occurrence of alcoholic liver cirrhosis.

Adult↗

PubMed1995

Angiotensin-converting enzyme genotypes in the high- and low-risk area for coronary heart disease in Finland.

The deletion/deletion genotype of the insertion (I)/deletion (D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been suggested to be a risk factor for myocardial infarction (MI). The objective of this study was to evaluate whether genotype distributions of the I/D polymorphism of the ACE gene are different between individuals from high-risk and low-risk areas for coronary heart disease in the genetically isolated population of Finland and to assess the impact of this genetic risk factor by comparing individuals with different parental histories of MI. Representative population-based samples of middle-aged men (n = 363) and women (n = 358) from two areas of Finland were used. The area had a borderline significant effect on the prevalence of the genotype DD (beta = 0.35, SE = 0.16, X2 = 470, df = 1, P = 0.03), the DD genotype being more prevalent in eastern Finland (the high-risk area). The II genotype was more prevalent in women with parental history of MI, so we could not replicate the previous findings of the risk-increasing effect of DD genotype in this sample. Although the observed difference in the ACE DD genotype between the high-risk and low-risk areas for coronary heart disease might represent one of the genetic factors contributing to the difference in risk of coronary heart disease between eastern and southwestern Finland, the data emphasize the fact that also other risk factors, including other genes, contribute to this difference and the high incidence of MI in Finland.

Adult↗

PubMed1995

Early perivenular fibrogenesis--precirrhotic lesions among moderate alcohol consumers and chronic alcoholics.

Cirrhosis is believed to be preceded by "precirrhotic" lesions indicating initial fibrogenesis in the perivenular area. We investigated three previously described markers of early perivenular fibrogenesis: the thickness of the rim of the terminal hepatic venule, perivenular fibrosis and perivenular fibronectin deposition. The frequencies of these features were evaluated and compared to long-term daily alcohol intake in autopsy series of 120 males comprising abstainers, moderate alcohol consumers and chronic heavy alcohol consumers. Thickening of the rim of the terminal hepatic venule showed no correlation to the long-term daily ethanol intake. In contrast, compared to abstainers, daily alcohol intake between 40 and 80 g for an average of 25 years was associated in an increased number of subjects with perivenular fibrosis (13.3% vs 38.9%, p < 0.05), and with perivenular fibronectin deposition (13.3% vs 44.4%, p < 0.025). Similarly, daily intake exceeding 80 g was associated in an increased number of subjects with perivenular fibrosis (56.1%, p < 0.001) and with perivenular fibronectin deposition (56.1%, p < 0.001). A daily intake exceeding 80 g (110 g/d vs 240 g/d) did not, however, further increase the occurrence of these lesions. A daily intake below 40 g of absolute alcohol was not associated with signs of early perivenular fibrogenesis. In this study, the frequencies of subjects with perivenular fibrosis and perivenular fibronectin deposition correlated with the amount of daily alcohol intake. A daily intake between 40 and 80 g was associated with approximately a three-fold and a daily intake exceeding 80 g with approximately a five-fold increase in the risk of these features. This could suggest that daily intake between 40 and 80 g represents a "threshold" level, beyond which the risk of alcoholic liver fibrosis increases significantly. The majority (50-70%) of chronic heavy alcohol consumers presented signs of early perivenular fibrogenesis, whereas cirrhosis was found in only 20% of heavy consumers. This could suggest that alcohol-induced fibrotic lesions of the liver may develop in the majority of people, but factors other than cumulative alcohol consumpation may have a critical impact on the progression of early liver fibrosis to cirrhosis.

Adult↗

PubMed1994

Abuse of alcohol in sudden out-of-hospital deaths in Finland.

Alcoholism is known to be greatly underdiagnosed in death certificates, a fact that biases in estimates of alcohol-related mortality. An autopsy series of 1658 cases (920 with natural cause of death and 738 nonnatural) was reviewed to evaluate the extent of this bias, and also to see how well different sources of information served as indicators of alcoholism when alcohol-related disease diagnosed at autopsy was considered as a gold standard. A stepwise logistic regression model adjusted by age and sex showed police reports of individual's alcohol usage and blood alcohol concentration (BAC) of > 2.9/1000 at autopsy to be the two most significant predictors of chronic alcohol abuse (p < 0.0001). The specificities of these two parameters as predictors of chronic alcohol abuse were generally high and sensitivities low. The authors see high BAC (> 2.9/1000), due to its high specificity, as particularly suggestive of chronic heavy drinking. However, it is wise to use these parameters only as an aid in decision-making, not as sole indicators of alcoholism. Deaths associated with chronic heavy drinking were frequent, 50.5% of the total series (male 56.4%, female 37.1%). For all but one age-group (male 45-64 years), however, death certificates mentioned alcohol-related diseases in less than half of these cases. Especially evident underdiagnosis was found for female and males 65 years and older. These results indicate that alcoholism is frequent in such a highly selected population as a series of forensic autopsies and suggest that estimates of prevalence of alcoholism based only on review of death certificates are to be considered with great caution.(ABSTRACT TRUNCATED AT 250 WORDS)

Accidents↗

PubMed1994

Left ventricular size, mass, and function in relation to angiotensin-converting enzyme gene polymorphism in humans.

Angiotensin-converting enzyme (ACE) exhibits genetic variation related to insertion/deletion (I/D) polymorphism in intron 16 of the ACE gene. The DD genotype results in high ACE activity and is overrepresented in diseases characterized by left ventricular (LV) hypertrophy and dysfunction. We studied whether the ACE gene polymorphism predicts LV mass or function in the absence of heart disease. Polymerase chain reaction of leukocyte DNA was used to determine the I/D genotype, and M-mode and Doppler echocardiography were used to quantify LV mass and function in 86 human subjects, 36-37 yr of age. All were free of clinical heart disease. The LV mass-to-body height ratio averaged 99 +/- 19 (SD) g/m in subjects with the II genotype (n = 25), 99 +/- 30 g/m in those with the ID genotype (n = 35), and 94 +/- 24 g/m in those with the DD genotype (n = 26; P = 0.790). The indexes of LV systolic and diastolic function were also unrelated to the ACE genotype. We conclude that in the absence of heart disease the ACE gene variation has no major influence on LV mass or function that is detectable at echocardiography.

Adult↗