Arg 506 Gln factor V mutation (factor V Leiden) in patients with familial hypercholesterolaemia.
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Factor V↗
Biomedical subjects
K Kontula
Publications and source records attributed to K Kontula.
Polymorphism of the beta 3-adrenergic receptor gene in morbid obesity.
OBJECTIVE: The Trp64-->Arg allele of the beta 3-adrenergic receptor gene was recently proposed to be associated with an earlier onset of non-insulin-dependent diabetes mellitus (NIDDM), features of insulin resistance and a tendency to gain weight. We investigated whether the Arg64 allele predisposes to severe obesity. DESIGN AND SUBJECTS: A genetic association study of 254 subjects with morbid obesity [body-mass index (BMI) > or = 40; mean 42.8 +/- 7.0] and 151 lean healthy control subjects [BMI < or = 25; mean BMI 22.3 +/- 1.9]. MEASUREMENTS: beta 3-adrenergic receptor genotyping was carried out with a solid-phase minisequencing technique. Serum lipids, glucose and insulin levels in the obese subjects were also determined. RESULTS: The frequency of the Arg64 did not significantly differ in the morbidly obese patients (9.1%) and lean controls (8.9%), nor was there any statistically significant association between the mean BMI values and the beta 3-adrenergic receptor genotype. However, obese subjects carrying the Arg64 allele developed obesity more often before the age of 15 y than those without it (P < 0.05, adjusted for multiple comparisons). The frequency of the Arg64 allele was similar in nondiabetic and diabetic patients; the mean age at the onset of NIDDM did not differ according to the beta 3-adrenergic receptor genotype. There was no significant association between the receptor genotype and the level of the serum cholesterol, HDL-cholesterol, triglyceride, glucose or insulin, nor was this polymorphism associated with the behavioural or psychopathological characteristics of the morbidly obese subjects. Response to a 16 w treatment program including a very-low calorie diet (VLCD) regimen, dietary and exercise counseling, as well as behavioural modifications, did not differ according to the genotype. CONCLUSION: Our data do not support a significant role for the codon 64 polymorphism of the beta 3-adrenergic receptor as a genetic marker of morbid obesity. Although there was an association between the Arg64 allele and an earlier onset of obesity in individuals subsequently developing morbid obesity, this allele was not associated with the actual BMI gained or response to weight-loss therapy on a hypocaloric diet.
Adult↗
Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein.
BACKGROUND: The epsilon 4 allele of apolipoprotein E has been associated with an increased risk of late-onset Alzheimer's disease. In a cohort of elderly subjects we prospectively investigated the relation between the apolipoprotein E genotype, dementia, and the accumulation of beta-amyloid protein in the cerebral cortex. METHODS: Autopsy involving neuropathological analysis and DNA analysis of frozen blood samples were performed in 92 of 271 persons who were at least 85 years of age, who had been living in Vantaa, Finland, on April 1, 1991, and who had died between that time and the end of 1993. All subjects had been tested for dementia. Apolipoprotein E genotyping was done with a solid-phase minisequencing technique. The percentage of the cortex occupied by methenamine silver-stained plaques was used as an estimate of the extent of beta-amyloid protein deposition. RESULTS: The frequency of the epsilon 4 allele was significantly higher in the subjects with Alzheimer's disease than in the subjects without dementia (30 percent vs. 8 percent, P < 0.001). There was a greater accumulation of beta-amyloid protein in the brain and more neurofibrillary tangles in the subjects with the epsilon 4 allele than in those without it (P < 0.001). The deposition of beta-amyloid protein varied according to the genotype in both the subjects with dementia and those without dementia: it was lowest in those with the epsilon 2/epsilon 3 genotype, intermediate in those with the epsilon 3/epsilon 3 genotype, and highest in those with the epsilon 3/epsilon 4 genotype. A single subject had the epsilon 4/epsilon 4 genotype and had dementia. CONCLUSIONS: The epsilon 4 allele of apolipoprotein E is significantly associated with Alzheimer's disease. Even in elderly subjects without dementia, the apolipoprotein E genotype is related to the degree of deposition of beta-amyloid protein in the cerebral cortex.
Aged↗
High-dose folic acid treatment for red-cell aplasia.
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Aged↗
Linkage of the long QT syndrome to the short arm of chromosome 11: use of five highly polymorphic markers towards more detailed localization of the mutant gene.
The long QT syndrome is an autosomally dominantly inherited cardiac disorder characterized by abnormalities of myocardial repolarization, exercise- or stress-related syncopal attacks and risk of sudden death due to cardiac arrhythmias. Genetic linkage studies have defined three LQT loci on chromosomes 11p15.5, 3q21-24 and 7p35-36. We performed linkage analyses in three Finnish LQT families using five amplifiable markers assigned to chromosome 11p15. By multipoint linkage analyses we obtained a maximal lod score of 5.503, suggesting that the LQT1 locus maps between D11S922 and D11S1338 on chromosome 11. Our data provide a step towards closer definition of the exact borderlines of the LQT1 locus in chromosome 11 and demonstrate markers with high utility in identification of gene carriers in the affected families.
Adolescent↗
Heterozygous familial hypercholesterolaemia: the influence of the mutation type of the low-density-lipoprotein receptor gene and PvuII polymorphism of the normal allele on serum lipid levels and response to lovastatin treatment.
OBJECTIVES: To study whether (i) the low-density-lipoprotein (LDL)-receptor gene mutation type itself or (ii) the PvuII restriction-fragment-length polymorphism (RFLP) of the intact LDL-receptor gene affects serum lipid levels and their responses to lovastatin treatment in heterozygous familial hypercholesterolaemia (FH). DESIGN: Comparison of serum lipid levels in 149 heterozygous FH patients, including 79 patients with the FH Helsinki gene and 70 patients with the FH North Karelia gene, grouped according to the PvuII RFLP status of their nonmutated LDL-receptor allele; studies of lovastatin responses in 23 FH patients with different mutation types. SUBJECTS: Molecularly defined heterozygous FH patients. INTERVENTIONS: DNA analysis by polymerase chain-reaction assay (PCR) and Southern blotting, fasting serum lipid measurements in all patients, and administration of lovastatin 40-80 mg daily to 16 FH Helsinki patients and seven FH North Karelia patients. MAIN OUTCOME MEASURES: Baseline and post-treatment serum cholesterol. LDL cholesterol, high-density-lipoprotein (HDL) cholesterol and triglyceride levels. RESULTS: There were no significant differences in serum total or LDL-cholesterol levels in FH patients with the FH Helsinki gene compared with those carrying the FH North Karelia gene. Regardless of the mutation type, patients without the PvuII site in the normal LDL-receptor gene (P--subjects) tended to have 6-8% higher serum and LDL-cholesterol levels than patients possessing this restriction site (P+ subjects). Although not statistically significant, this difference is qualitatively and quantitatively similar to that reported in three different non-FH populations. Treatment with lovastatin brought about similar hypolipidaemic responses in FH patients with either mutation type (FH Helsinki or FH North Karelia) or PvuII RFLP status (P+ or P-). CONCLUSIONS: Two LDL-receptor gene mutations with dissimilar phenotypic characteristics are associated with similar serum lipid levels and response to statin treatment. Our data also support the previous assumption that the PvuII RFLP of the LDL-receptor gene locus is associated with variation of serum cholesterol levels.
Alleles↗
Cholesterol absorption and metabolism and LDL kinetics in healthy men with different apoprotein E phenotypes and apoprotein B Xba I and LDL receptor Pvu II genotypes.
Apoprotein (apo) E, apoB Xba I, and LDL receptor gene Pvu II polymorphisms are associated with LDL cholesterol level, but little is known about cholesterol and LDL metabolism in subjects with the latter two genetic polymorphisms alone or in combination with different apoE phenotypes. We studied cholesterol absorption efficiency, cholesterol and bile acid synthesis, and LDL apoB kinetics in 52 healthy men and related the metabolic results to the apoB Xba I and LDL receptor Pvu II restriction fragment length polymorphism (RFLP) and apoE phenotypes. New findings were as follows. ApoB Xba I polymorphism was not associated with the metabolic variables of cholesterol, but LDL receptor Pvu II RFLP was associated with fractional catabolic rate for LDL apoB, cholesterol absorption, and cholesterol and bile acid synthesis. ApoE polymorphism exerted the most powerful effect on the LDL cholesterol concentration, so that the apoE2 subjects had the lowest LDL cholesterol and apoB levels and cholesterol absorption, and the highest fractional catabolic rate and bile acid and cholesterol synthesis compared with the apoE3 or especially apoE4 phenotypes in different genetic combinations. In multiple stepwise regression analysis with LDL cholesterol as the dependent and the genetic and metabolic parameters as the independent variables, 47.0% (n = 35, P < .001) of the variability of LDL cholesterol was explained by the apoE polymorphism, 7.1% (P < .05) by the LDL receptor Pvu II RFLP, and 11.3% (P < .01) by bile acid synthesis, while the contribution of the apoB Xba I RFLP was nonsignificant.(ABSTRACT TRUNCATED AT 250 WORDS)
Apolipoproteins B↗
Two different allelic mutations in a Finnish family with lecithin:cholesterol acyltransferase deficiency.
Lecithin:cholesterol acyltransferase (LCAT) deficiency is a genetic disorder associated with low levels of serum HDL cholesterol. The proband of the Finnish LCAT-deficient family had corneal opacities, proteinuria, anemia with stomatocytosis, low serum HDL cholesterol (0.27 mmol/L), and low LCAT activity. Sequence analysis of his LCAT gene revealed compound heterozygosity for two different mutations: a C insertion in exon 1 between nucleotides 932 and 937 and a C-to-T point mutation in exon 6 at position 4976. The C insertion in exon 1 is predicted to result in premature termination and a truncated polypeptide containing only 16 amino acids. The C-to-T point mutation in exon 6 substitutes cysteine for arginine at residue 399. The functional significance of the Arg399-->Cys mutation was examined by expressing the mutated and wild-type LCAT cDNAs in COS cells. COS cells transfected with mutated and wild-type cDNAs showed comparable levels of mature LCAT mRNA. However, LCAT activity in the cell media of COS cells transfected with the mutant LCAT cDNA was significantly lower than that of COS cells transfected with the wild-type cDNA (1.4% versus 12.0% cholesterol esterified, respectively). A polymerase chain reaction-based duplex assay, in which both mutations can be detected simultaneously, was used for preliminary screening of Finnish subjects with serum HDL levels below 0.9 mmol/L; two additional individuals heterozygous for the Arg399-->Cys mutation were identified.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Lack of association of apolipoprotein E allele epsilon 4 with late-onset Alzheimer's disease among Finnish centenarians.
No association between Alzheimer's disease (AD) and apolipoprotein E type epsilon 4 (ApoE epsilon 4) phenotype was found among centenarians in Finland (N = 179). The data are based on ascertainment of all centenarians in Finland in 1991. All examinations were conducted during 1991. The diagnoses of dementia and AD were based on clinical grounds, conforming to DSM-III-R and NINCDS-ADRDA criteria. The percentage of ApoE epsilon 4 alleles among the centenarians was 8.7% (31 of 358 alleles). This is significantly lower than percentages found in younger Finnish populations. Thirty (16.8%) of the 179 centenarians were epsilon 4 allele carriers. One hundred fifty-one (84.4%) of the centenarians were women. Twenty-eight (18.5%) of the women had at least one epsilon 4 allele, as did two (7.1%) of the men. The prevalence of clinically diagnosed AD was 26.8%; 44% of the subjects were cognitively normal, 23% had signs of cognitive decline or at most mild dementia (with no differential diagnosis), and 6% had a dementia clinically diagnosed as being due to some cause other than AD. For AD cases versus cognitively normal subjects, the odds ratio associated with being a carrier of the epsilon 4 allele was 1.34 (p = 0.64; 95% CI = [0.5, 3.3]). Among women, the odds ratio was 0.99 (p = 1.0; 95% CI = [0.4, 2.6]). There were fewer, but not significantly so, epsilon 4 carriers among subjects with cognitive decline or at most mild dementia (12.2%) than there were among the cognitively normal subjects (16.5%). The AD patients had no evidence of difficulty standing on a flat stationary surface unless the surface suddenly moved.(ABSTRACT TRUNCATED AT 250 WORDS)
Age of Onset↗
Arg506Gln factor V mutation (factor V Leiden) in patients with ischaemic cerebrovascular disease and survivors of myocardial infarction.
The point mutation Arg506- > Gln of factor V was recently shown to be an important and relatively common genetic cause of venous thromboembolism. Using a DNA technique based on polymerase chain reaction, we surveyed the blood samples of 236 patients with ischaemic stroke or a transient ischaemic attack, 122 survivors of myocardial infarction and 137 control subjects for the presence of this mutation. Although the frequency of the factor V mutation in patients with arterial disease (4.5%) was not significantly different from that in healthy blood donors (2.9%), a carrier status for this mutant gene was associated with symptoms of migraine and relatively mild angiographic abnormalities among patients with cerebrovascular disease. A more extensive study addressing the occurrence and significance of the mutant factor V mutation in patients with vasospastic cerebrovascular diseases seems to be warranted.
Adult↗
Molecular characterization of minor gene rearrangements in Finnish patients with heterozygous familial hypercholesterolemia: identification of two common missense mutations (Gly823-->Asp and Leu380-->His) and eight rare mutations of the LDL receptor gene.
Two deletions of the low-density lipoprotein (LDL) receptor gene were previously shown to account for about two thirds of all mutations causing familial hypercholesterolemia (FH) in Finland. We screened the DNA samples from a cohort representing the remaining 30% of Finnish heterozygous FH patients by amplifying all the 18 exons of the receptor gene by PCR and searching for DNA variations with the SSCP technique. Ten novel mutations were identified, comprising two nonsense and seven missense mutations as well as one frameshift mutation caused by a 13-bp deletion. A single nucleotide change, substituting adenine for guanidine at position 2533 and resulting in an amino acid change of glycine to aspartic acid at codon 823, was found in DNA samples from 14 unrelated FH probands. This mutation (FH-Turku) affects the sequence encoding the putative basolateral sorting signal of the LDL receptor protein; however, the exact functional consequences of this mutation are yet to be examined. The FH-Turku gene and another point mutation (Leu380-->His or FH-Pori) together account for approximately 8% of the FH-causing genes in Finland and are particularly common among FH patients from the southwestern part of the country (combined, 30%). Primer-introduced restriction analysis was applied for convenient assay of the FH-Turku and FH-Pori point mutations. In conclusion, this paper demonstrates the unique genetic background of FH in Finland and describes a commonly occurring FH gene with a missense mutation closest to the C terminus thus far reported.
Base Sequence↗
[The family of lipoprotein receptors is growing].
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Animals↗
A single-base substitution in the proximal Sp1 site of the human low density lipoprotein receptor promoter as a cause of heterozygous familial hypercholesterolemia.
We have identified a Finnish family with a typical phenotype of heterozygous familial hypercholesterolemia (FH) due to a single-base substitution in the proximal Sp1 binding site of the low density lipoprotein (LDL) receptor gene promoter. The mutation, a C-->T substitution at nucleotide -43, cosegregated with the FH phenotype in six available family members and abolished binding of Sp1 transcription factor to this site. As a consequence, transcriptional activity of the mutated LDL receptor promoter was only about 1/20th of that of the wild-type promoter, as judged by transfection studies in HeLa cells. Studies of primary fibroblast cultures established from a family member revealed a markedly reduced LDL receptor mRNA concentration as well as reduction of binding, internalization, and degradation of 125I-labeled LDL to values < 50% of those in normal fibroblasts. This DNA alteration is thus a naturally occurring promoter mutation causing a severe disorder of human lipoprotein metabolism.
Animals↗
Polymorphisms of the apolipoprotein and angiotensin converting enzyme genes in young North Karelian patients with coronary heart disease.
The genes encoding apolipoproteins (apos) A-I, B, C-III and E as well as that encoding the angiotensin converting enzyme (ACE) have been proposed as candidate genes for coronary heart disease (CHD). We determined the common polymorphisms of the apo genes, previously found to influence serum lipid levels at the population level, and the insertion/deletion polymorphism of the ACE gene, recently reported to reflect the risk of myocardial infarction, in 82 very young (mean, 41 years) North Karelian Finns with symptomatic CHD and 50 controls of similar age. Patients with familial hypercholesterolemia had been excluded from this material. None of the polymorphisms examined, including the apo A-I promoter MspI, apo C-III SstI and apo B XbaI restriction fragment polymorphisms, a common variation of apo E (epsilon 2, epsilon 3 and epsilon 4 alleles) and an ACE insertion/deletion (I/D) polymorphism, was significantly associated with the risk of premature CHD. Patients with CHD had a higher mean serum LDL cholesterol/HDL cholesterol ratio than controls (3.15 +/- 1.30 vs 2.72 +/- 0.98, P < 0.05), but no significant associations between the common apo gene polymorphisms and serum lipid levels were disclosed in either group. It is possible that other genetic loci than those proposed to be associated with accelerated atherosclerosis may be more important as risk factors of symptomatic CHD at the age of 40 years.
Adult↗
No evidence for linkage between familial hypertriglyceridemia and apolipoprotein B, apolipoprotein C-III or lipoprotein lipase genes.
Familial hypertriglyceridemia has been suggested to be an autosomal dominant condition with age-dependent penetrance, but so far the underlying defective gene has not been elucidated. We examined the possible role of three candidate gene loci by linkage analysis in six Finnish families with familial clustering of hypertriglyceridemia. The probands were initially recruited from a group of hyperlipidemic outpatients after measurement of serum triglyceride concentrations exceeding 2.00 mmol/l on two occasions. Altogether, 71 subjects were included in the linkage analyses. Bi- or multiallelic DNA polymorphisms were used as markers for the apolipoprotein B gene (chromosome 2), lipoprotein lipase gene (chromosome 8), and apolipoprotein A-I/C-III/A-IV gene cluster (chromosome 11). Linkage analysis was performed by applying two alternative phenotyping models, one adopting quantitative serum triglyceride concentrations and another using qualitative classification of the subjects into hypertriglyceridemic, normotriglyceridemic, and borderline hypertriglyceridemic groups. Using either approach, the cumulative lod scores of each of the three candidate genes in the six families were less than -2.0 at the recombination fraction 0.0. These results suggest that none of the candidate genes investigated is involved in familial clustering of hypertriglyceridemia in our study.
Adult↗
Variability gene effects of DNA polymorphisms at the apo B, apo A I/C III and apo E loci on serum lipids: the Cardiovascular Risk in Young Finns Study.
We studied the influence of selected genetic markers on the intra-individual long-term variability in serum lipid levels. The study cohort consisted of a sub-sample from a large follow-up study of atherosclerosis precursors in children and young adults. A total of 320 subjects had determinations of apo B XbaI RFLP genotypes, 305 subjects had apo AI/CIII SstI RFLP genotype determinations and 1581 subjects had their apo E phenotypes determined. Complete data on serum lipids were available at 3-year intervals over a 6-year follow-up period. The subjects were healthy and aged 3-18 years at baseline. Intra-individual variability was assessed with a nested analysis of variance procedure. Each of the genetic markers studied here significantly affected intra-individual variability of serum lipid levels. No clear sex influence was observed, although the differences in variability tended to be more significant in males. Apo B XbaI genotypes significantly influenced intra-individual variability of total and LDL-cholesterol levels in both sexes. A marked effect of the XbaI genotype was also found on triglyceride variability. In males the standardized intra-individual triglyceride variances were 0.71 and 0.34 in genotypes X1X1 and X2X2, respectively (p < 0.001), with a clear gene dosage effect. The apo AI/CIII genotype had an influence only on the variability of total cholesterol and LDL-cholesterol levels and only in males. The apo E phenotypes were associated with intra-individual variability in total and LDL-cholesterol levels but again, only in males.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Aging and genetic variation of plasma apolipoproteins. Relative loss of the apolipoprotein E4 phenotype in centenarians.
We determined the common polymorphism of apolipoprotein E (E2, E3, and E4), apolipoprotein B Xba I polymorphism, and apolipoprotein C-III Sst I polymorphism in almost all Finnish centenarians alive in 1991 (n = 179/185). Plasma lipid and lipoprotein levels in different apolipoprotein genotypes were also measured. In comparison with younger Finnish populations studied previously, the frequency of the apolipoprotein E epsilon 2 allele was almost twice as high (7.0% versus 4.1%; P < .05) and that of the epsilon 4 allele only approximately one third as high (8.4% versus 22.7%; P < .001) in the centenarians. Plasma cholesterol and high-density lipoprotein cholesterol levels tended to be lowest in the group with the epsilon 2 allele (4.33 mmol/L and 1.41 mmol/L, respectively), intermediate in those with the epsilon 3 allele (4.57 mmol/L and 1.48 mmol/L, respectively), and highest in those with the epsilon 4 allele (4.82 mmol/L and 1.60 mmol/L, respectively). The frequencies of the apolipoprotein B X1 and X2 alleles (Xba I restriction site absent or present, respectively) among the centenarians and among the young Finns were not significantly different, whereas the apolipoprotein C-III S2 allele (Sst I restriction site present) occurred more often in the centenarians (frequency, 12.9%) than in the youngest reference population (frequency, 8.8%; P < .05). Centenarians with the apolipoprotein B X2X2 genotype and apolipoprotein E4 phenotype had a higher mean plasma cholesterol level than those with the X1X1 genotype and E2 phenotype (5.24 versus 3.43 mmol/L; P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
[SETTI-Study and antioxidants--more questions than answers].
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Antioxidants↗