OBJECTIVE: A common polymorphism (-1C to T) in the translation initiation sequence of annexin A5 (ANV) gene has recently been associated with a decreased risk of acute myocardial infarction (AMI). The aim of the present study was to analyze the association between the ANV genepolymorphism and the risk of AMI and ischemic sudden cardiac death (SCD) in middle-aged Finnish males. MATERIAL AND METHODS: A case-control study involving three distinct groups of subjects was carried out: (1) victims of SCD (n=98), (2) survivors of AMI (n=212), and (3) randomly selected control subjects without any history of coronary heart disease (n=243). The ANV polymorphism was genotyped in each study group. RESULTS: Among the control group of healthy Finnish males the prevalence rates of the CC, CT, and TT genotypes were 83.1%, 15.2%, and 1.6%, respectively. Among the survivors of AMI, the prevalence rates of CC, CT, and TT were 79.7%, 20.3%, and 0%, respectively, and among the victims of SCD 83.7%, 16.3%, and 0%, respectively. No significant differences in the genotype or allele distributions were observed between the study groups. CONCLUSION: The -1C to T polymorphism in the ANV gene is not associated with the risk of AMI or SCD in middle-aged Finnish males.
The -250G>A promoter variant in hepatic lipase associates with elevated fasting serum high-density lipoprotein cholesterol modulated by interaction with physical activity in a study of 16,156 Danish subjects.
CONTEXT: Hepatic lipase plays a pivotal role in the metabolism of high-density lipoprotein (HDL) and low-density lipoprotein by involvement in reverse cholesterol transport and the formation of atherogenic small dense low-density lipoprotein. OBJECTIVES: The objective was to investigate the impact of variants in LIPC on metabolic traits and type 2 diabetes in a large sample of Danes. Because behavioral factors influence hepatic lipase activity, we furthermore examined possible gene-environment interactions in the population-based Inter99 study. DESIGN: The LIPC -250G>A (rs2070895) variant was genotyped in the Inter99 study (n = 6070), the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care Denmark screening cohort of individuals with risk factors for undiagnosed type 2 diabetes (n = 8662), and in additional type 2 diabetic patients (n = 1,064) and glucose-tolerant control subjects (n = 360). RESULTS: In the Inter99 study, the A allele of rs2070895 associated with a 0.057 mmol/liter [95% confidence interval (CI) 0.039-0.075] increase in fasting serum HDL-cholesterol (HDL-c) (P = 8 x 10(-10)) supported by association in the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care study [0.038 mmol/liter per allele (95% CI 0.024-0.053); P = 2 x 10(-7)). The allelic effect on HDL-c was modulated by interaction with self-reported physical activity (P(interaction) = 0.002) because vigorous physically active homozygous A-allele carriers had a 0.30 mmol/liter (95% CI 0.22-0.37) increase in HDL-c compared with homozygous G-allele carriers. CONCLUSIONS: We validate the association of LIPC promoter variation with fasting serum HDL-c and present data supporting an interaction with physical activity implying an increased effect on HDL-c in vigorous physically active subjects carrying the -250 A allele. This interaction may have potential implications for public health and disease prevention.
The A1555G mutation of the mtDNA is associated with both aminoglycoside-induced and non-syndromic hearing loss. The A1555G is relatively frequent in the Spanish and some Asian populations, but has only been reported rarely in other populations, possibly because of ascertainment bias. We studied 85 Danish patients with varying degrees of hearing impairment and found two patients with the A1555G mutation (2.4%). Neither had received aminoglycosides. Our study indicates that the mutation might not be uncommon in Danish patients with hearing impairment.
Acute intermittent porphyria (AIP) is an autosomal dominant disorder caused by a partial deficit of porphobilinogen deaminase (PBGD), the third of eight enzymes in the haem biosynthetic pathway. The overt disease is characterized by neuropsychiatric symptoms that are often triggered by exogenous factors such as certain drugs, stress, and alcohol. The aim of this work has been to identify the underlying genetic defect in each AIP-affected family in order to provide early counselling to assist in the avoidance of precipitating factors. The prevalence of AIP in Sweden is in the order of 1:10 000. The major mutation in Sweden, W198X, is due to a founder effect in the northern part of the country. This mutation, together with a further 11 mutations, have been reported previously. The present communication encompasses the great majority of AIP kindreds in Sweden and includes a further 27 mutations within the PBGD gene. This includes 14 completely new mutations, as well as 11 known mutations detected for the first time in Sweden. The majority of the mutations are located in exons 10 and 12 with fewer in exon 7. The clinical and biochemical outcomes in some patients are described. We also use the three-dimensional structure of the porphobilinogen deaminase enzyme to predict the possible molecular and functional consequences of the new Swedish missense and nonsense mutations.
Frequency of promoter endothelial NO-synthase gene allelic polymorphism by using polymerase chain reaction and restriction fragment length polymorphism (RFLP-PCR) was determined in 221 patients with acute coronary syndrome (ACS) and in 83 almost healthy subjects. Data obtained indicate that different promoter allelic variant frequency differs significantly in patients with ACS and in control group. Correlation of normal homozygotes (T/T), heterozygotes (T/C) and pathologic homozygotes (C/C) was 48%, 36% and 16% respectively in patients, and in control it was 48%, 46%, 6% (P
The analysis of the selective excerpt of the children with the inherited disorders has been made on the basis of the Kiev Medical Genetic Center, where the regional anonymous syndromological computer register has been organized. Register's file during 1993-96 has the information about 883 families that has a genetically ill proband. Genetic syndrome has been diagnosed in 78.02% (105 nosological points). The information taken from the register has allowed for the first time to distinguish the inherited pathology from the acquired one, so the new mutation from 30.23% out of all registered inherited disease. The necessity of the creation of the National Genetic Register in the Ukraine and the new conception of the two-stage genetical monitoring of the population has been proved.
Familial hypercholesterolemia (FH) is an autosomal semi-dominant disorder caused by defects in the low density lipoprotein receptor (LDLR) gene and is a well-documented risk factor for developing cardiovascular disease. The LDLR genes of five Swedish children with FH were examined in this study. Initial mutation screening was performed by denaturing gradient gel electrophoresis (DGGE) with enzymatically amplified exon-sized fragments, each containing a tailing GC-rich requence. The GC-clamped fragments had been synthesized with a restriction site adjacent to the intron-corresponding sequence to allow detachment of the clamps, thereby rendering the fragments suitable for subsequent analysis by single-strand conformation polymorphism (SSCP) analysis of samples from patients with no DGGE-detectable mutations. In addition, all the LDLR genes of the patients were screened for large alterations by restriction fragment length polymorphism analysis. Following this strategy, seven different, potentially disease-causing mutations were detected in the five children with FH. Six of the alterations, five single-base substitutions and one dinucleotide deletion, have not previously been described. DGGE detected six of the mutations and SSCP the seventh.
BACKGROUND: The main objective of this study was to investigate the angiotensin converting enzyme (ACE) genotype as a possible risk factor for migraine (both with and without aura) compared to controls. We also wanted to examine whether a clinical response to an ACE inhibitor, lisinopril, or an angiotensin II receptor blocker, candesartan, in migraine prophylaxis was related to ACE genotype. METHODS: 347 migraine patients aged 18-68 (155 migraine without aura (MoA), 187 migraine with aura (MwA) and 5 missing aura subgroup data) and 403 healthy non-migrainous controls > 40 years of age were included in the study. A polymerase chain reaction (PCR) was performed on the genomic DNA samples to obtain the ACE insertion (I)/deletion(D) polymorphisms. RESULTS: No significant differences between migraine patients and controls were found with regard to ACE genotype and allele distributions. Furthermore, there was no significant difference between the controls and the MwA or MoA subgroups. CONCLUSION: In our sample there is no association between ACE genotype or allele frequency and migraine. In addition, ACE genotype in our experience did not predict the clinical response to lisinopril or candesartan used as migraine prophylactics.
Extended MHC haplotypes comprising HLA-A, -B, -DR, C2, BF and GLO1 loci observed in the parents of 497 Danish normal families are presented, with particular regard to the haplotypes that include BF variants or the C2*2 allele. The known association of HLA-B35, -DR1 with both -A3 and -A11 appeared to depend upon the BF type: HLA-B35, BF*S, -DR1 is strongly associated with -A11, whereas -B35,BF*F,-DR1 is strongly associated with -A3. Further, in the present material DZ twins of the same sex shared HLA-haplotypes more often than did twin pairs of different sex.