The aim was to identify genetic determinants for the development of hyperlipidemia and/or atherosclerosis. The present set of studies demonstrates for the first time the clinical expression (phenotype) of a newly discovered monogenic disorder named Familial Defective Apolipoprotein B-100 (FDB). FDB is caused by a G to A mutation in the binding protein (apolipoprotein B-100) for the cholesterol-rich low density lipoprotein (LDL), such that the affinity of LDL to the LDL receptor is severely reduced. In all 135 individuals with FDB from 56 families and 8 different countries, including Denmark, are described. On average, the effect of the FDB mutation was to increase plasma and LDL cholesterol in both men and women by about 3 mmol/l; at age 55 the average plasma cholesterol of men and women with FDB was 9.4 mmol/l and 8.9 mmol/l, respectively. A sharp rise in frequency of coronary artery disease as a function of age in both FDB males and females was comparable to that found in Familial Hypercholesterolemia (FH). At the age of 60, about 70% of both men and women with FDB had coronary artery disease; at the same age approximately 40% had tendon xanthomas, and 35% had arcus corneae, irrespective of gender. Surprisingly, the frequencies of arcus corneae were not strikingly higher than those found in the general population sample from the Copenhagen City Heart Study. Only few patients with FDB had xanthelasmas. Finally, the frequency of this mutation was estimated at 1/500-1/700 in the general population, which is equivalent to that of clinical FH. All in all the results suggest FDB to be a severe genetic disorder with early penetrance, associated with substantial elevations in plasma and LDL cholesterol and with an increased frequency of premature coronary artery disease and of tendon xanthomas. For comparison, a number of common polymorphisms in the 5'-flanking region of the insulin gene, in the apoB gene and in the apoAI-CIII-AIV gene cluster, associated with minor effects on hyperlipidemia and/or cardiovascular disease are also examined.
Atherosclerosis is an inflammatory condition where cysteinyl leukotrienes have been identified to play an important role. Furthermore, cysteinyl leukotrienes may also affect thrombus formation. Using prospective, cross-sectional and case-control designs, we tested the hypothesis that hitherto unknown genetic variation, likely to affect the function of leukotriene C(4) synthase, is associated with risk of venous thromboembolism, ischemic stroke and myocardial infarction.
Resequencing the gene coding for leukotriene C(4) synthase in an extreme risk population with more than 1500 individuals revealed 17 new mutations, of which four are likely to change protein function (211G>A (minor allele frequency, 0.0001), IVS3 + 1G>A (0.002), 374G>A (0.0006) and 451_453+10del (0.0007)). Based on genotyping 50,000 individuals, age and sex adjusted odds ratios for venous thromboembolism were 2.0 (95% CI, 1.3-3.5) for IVS3+1G>A heterozygotes vs. wild type, and 1.9 (1.5-2.7) for any mutation heterozygote vs. wild type. Corresponding values were 2.0 (1.3-3.2) and 1.5 (1.1-2.1) for ischemic stroke, and 1.0 (0.8-1.3) and 1.2 (1.0-1.4) for myocardial infarction.
Four novel mutations that are likely to change the function of leukotriene C(4) synthase were associated with increased risk of venous thromboembolism and ischemic stroke. These findings need confirmation in other independent studies. In addition, the mechanism behind these findings deserves further investigation.
BACKGROUND: Cystic fibrosis is a recessive disorder mainly characterised by lung disease. We tested the hypothesis that individuals heterozygous for the common cystic fibrosis deltaF508 mutation are at risk of obstructive pulmonary disease. METHODS: We studied a cross-sectional sample from the general population of Copenhagen, Denmark, aged 20 years and older. We did spirometry to measure forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), and did genotyping on blood samples of 9141 individuals. We asked all participants whether they had asthma, and asked for information on smoking and other factors that could have contributed to obstructive pulmonary disease. FINDINGS: We identified 250 carriers of the deltaF508 mutation (2.7% [95% CI 2.5-3.1]). 9% of carriers reported having asthma compared with 6% of non-carriers (p=0.04). The odds ratio for asthma in participants heterozygous for deltaF508 mutation was 2.0 (1.2-3.5, p=0.02). Furthermore, among individuals with airway obstruction, the percentage predicted FEV1 and FVC were significantly lower in participants heterozygous for deltaF508 than in non-carriers (49 vs 58%, p=0.004; and 70 vs 82%, p
The ß(2) -adrenergic receptor (ADRB2) is located on smooth muscle cells and is an important regulator of smooth muscle tone. The Thr164Ile polymorphism (rs1800888) in the ADRB2 gene is rare but has profound functional consequences on receptor function and could cause lifelong elevated smooth muscle tone. We tested the hypothesis that Thr164Ile is associated with increased blood pressure, increased frequency of hypertension and increased risk of cardiovascular disease (CVD).
A total of 66 750 individuals from two large Danish general population studies were genotyped, and 1943 Thr164Ile heterozygotes and 16 homozygotes were identified.
Thr164Ile genotype was associated with increased systolic and diastolic blood pressure in women (trend: P = 0.04 and 0.02): systolic and diastolic blood pressure increased by 5% and 2%, respectively, in female homozygotes compared with female noncarriers. All female Thr164Ile homozygotes had hypertension compared with 58% of female heterozygotes and 54% of female noncarriers (chi-square: P = 0.001). Female Thr164Ile homozygotes and heterozygotes had odds ratios for ischaemic heart disease (IHD) of 2.93 (0.56-15.5) and 1.28 (1.03-1.61), respectively, compared with female noncarriers (trend: P = 0.007). These differences were not observed in men. Furthermore, Gly16Arg (rs1042713) and Gln27Glu (rs1042714) in the ADRB2 gene were not associated with blood pressure, hypertension or CVD either in the population overall or in women and men separately.
ADRB2 Thr164Ile is associated with increased blood pressure, increased frequency of hypertension and increased risk of IHD amongst women in the general population. These findings, particularly for homozygotes, are novel.
From the 1Department of Clinical Biochemistry The Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital The Copenhagen City Heart Study, Bispebjerg Hospital, Copenhagen University Hospital Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
Abstract. Thomsen M, Nordestgaard BG, Tybjaerg-Hansen A, Dahl M (Department of Clinical and The Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital; The Copenhagen City Heart Study, Bispebjerg Hospital, Copenhagen University Hospital; Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark) Scavenger receptor AI/II truncation, lung function and COPD: a large population-based study. J Intern Med 2010; doi: 10.1111/j.1365-2796.2010.02308.x. Objectives. The scavenger receptor A-I/II (SRA-I/II) on alveolar macrophages is involved in recognition and clearance of modified lipids and inhaled particulates. A rare variant of the SRA-I/II gene, Arg293X, truncates the distal collagen-like domain, which is essential for ligand recognition. We tested whether the Arg293X variant is associated with reduced lung function and risk of chronic obstructive pulmonary disease (COPD) in the general population. Methods. We genotyped 48 741 individuals from the adult Danish general population for Arg293X, and recorded lung function and spirometry-defined COPD. Results. Arg293X homozygotes (n = 5) and heterozygotes (n = 587), compared with noncarriers (n = 48 149), had a 6% and 1% reduction in predicted percentage of forced vital capacity (FVC % predicted) (P = 0.05) and a nonsignificant 7% and 1% reduction in predicted percentage of forced expiratory volume in one second (FEV(1) % predicted) (P = 0.06), respectively. The Arg293X genotype interacted with gender (P = 0.004) and a(1) -antitrypsin MZ heterozygosity (P = 0.049), but not with superoxide dismutase-3 E1I1 heterozygosity (P = 0.11) in determining FEV(1) % predicted. Amongst men, FEV(1) % predicted and FVC % predicted were both reduced by 4% (P = 0.0004 and P = 0.0003, respectively) in Arg293X heterozygotes compared with noncarriers. Corresponding values were 14% (P = 0.03) and 11% (P = 0.04) amongst MZ heterozygotes, and 9% (P = 0.03) and 8% (P = 0.04) amongst E1I1 heterozygotes, compared with noncarriers. Lung function did not differ between Arg293X heterozygotes and noncarriers amongst females or individuals without MZ and E1I1. Arg293X heterozygosity was associated with spirometry-defined COPD amongst men [odds ratio (95% confidence interval): 1.7 (1.1-2.4)], but not with COPD in the whole cohort or in any other subgroup. Conclusions. SRAI/II Arg293X heterozygotes have reduced lung function and increased COPD risk amongst men. They also have reduced lung function amongst individuals heterozygous for the a(1) -antitrypsin MZ and superoxide dismutase-3 E1I1 genotypes.
BACKGROUND: In a cross-sectional study, we previously showed that cystic fibrosis phenylalanine-508 deletion (DeltaF508) heterozygosity may be overrepresented among individuals with asthma. OBJECTIVE: Using 15-year follow-up data from the Copenhagen City Heart Study, we now further explore this relationship. METHODS: As part of 3 surveys in 1976 to 1978, 1981 to 1983, and 1991 to 1994, we measured pulmonary function and asked all participants about asthma and pulmonary risk factors. RESULTS: There was no difference in annual decline in lung function between DeltaF508 heterozygotes and noncarriers overall; however, among individuals with familial asthma, the annual declines in FEV(1) and forced vital capacity (FVC) were 49 and 36 mL in DeltaF508 heterozygotes versus 24 and 17 mL in noncarriers (P =.01 and P =.12, respectively). Cross-sectionally based on triple measurements, FEV(1) and FVC in individuals aged 20 to 70 years were lower in heterozygous participants versus noncarriers (P =.02 and P =.004, respectively). The average reduction of FEV(1) and FVC in DeltaF508 heterozygotes versus noncarriers was 70 mL (P =.06) and 136 mL (P =.008). Finally, 10% of carriers reported asthma versus 7% of noncarriers (P =.02), resulting in an odds ratio of 2.0 (1.3-3.2) for asthma in DeltaF508 heterozygotes. CONCLUSION: Cystic fibrosis DeltaF508 heterozygotes may be overrepresented among individuals with asthma and may have poorer lung function than noncarriers. Furthermore, DeltaF508 heterozygosity in context with familial predisposition to asthma may be associated with a greater annual FEV(1) decline.
Vitamin D has potential antithrombotic effects, suggesting that vitamin D analogs could be used as adjunctive antithrombotic agents. However, epidemiologic evidence of an association between reduced 25-hydroxyvitamin D concentrations and the risk of venous thromboembolism is lacking.
To test the hypothesis that reduced plasma 25-hydroxyvitamin D concentrations are associated with an increased risk of venous thromboembolism in the general population.
We prospectively studied 18 791 participants from the Copenhagen City Heart Study and the Copenhagen General Population Study. During up to 30 years of follow-up, 950 participants were diagnosed with venous thromboembolism. Plasma 25-hydroxyvitamin D concentrations were adjusted for seasonal variation.
The cumulative incidence of venous thromboembolism as a function of age increased with decreasing tertiles of seasonally adjusted plasma 25-hydroxyvitamin D (log-rank trend: P = 4 × 10(-4) ). On comparison of participants in the lowest and the highest tertile of plasma 25-hydroxyvitamin D concentrations, the crude risk estimate in a model adjusted for age and sex was a 37% (95% confidence interval [CI] 15-64%) increased risk of venous thromboembolism. The corresponding risk increase in a model adjusted for age, sex, body mass index, smoking and cancer was 26% (95% CI 5-51%), and in a multivariable-adjusted model also including physical activity, hormone replacement therapy, menopausal status, oral contraception use and lipid-lowering therapy it was 28% (95% CI 6-53%). Furthermore, corresponding risk increases with attempts to correct for regression dilution bias were 103% (95% CI 37-202%), 70% (95% CI 14-155%) and 73% (95% CI 15-160%) in the three models, respectively.
In these large general population studies, we observed a stepwise increasing risk of venous thromboembolism with decreasing tertiles of seasonally adjusted plasma 25-hydroxyvitamin D concentrations.
Abstract. Ellervik C, Tybjaerg-Hansen A, Appleyard M, Ibsen H, Nordestgaard BG (Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Herlev; Naestved Hospital, University of Copenhagen, Naestved; Copenhagen University Hospital, University of Copenhagen, Copenhagen East; Bispebjerg Hospital, Copenhagen University Hospital, University of Copenhagen, Bispebjerg; and Holbaek Hospital, Holbaek; Denmark). Haemochromatosis genotype and iron overload: association with hypertension and left ventricular hypertrophy. J Intern Med 2010; doi: 10.1111/j.1365-2796.2010.02217.x. Objective. We hypothesized that there is an association between haemochromatosis genotype C282Y/C282Y and/or iron overload and risk of hypertension and/or left ventricular hypertrophy (LVH). Methods. We analysed data from a cross-sectional study of the general population including 8992 individuals from the Copenhagen City Heart Study (CCHS), a follow-up study of 36 480 individuals from the Copenhagen General Population Study (CGPS), and a case-only study of 3815 Scandinavians from the Losartan Intervention For End-point Reduction in Hypertension Genetic Substudy (LIFEGEN) with LVH and hypertension. Results. In the CCHS, individuals with C282Y/C282Y versus wild type/wild type had an odds ratio for antihypertensive medication use of 4.8 (1.8-13; P = 0.003). In the CGPS, the corresponding hazard ratio was 1.7 (1.0-2.3; P = 0.003). Also, hazard ratios for antihypertensive medication use in the CGPS were 1.6 (1.0-2.6; P = 0.05) for transferrin saturation >/=80% vs. /=80% vs. wild type/wild type + transferrin saturation
Three DNA polymorphisms (XbaI, EcoRI, MspI) in the 3'-end of the apolipoprotein B gene were studied in relation to atherosclerosis, lipoprotein levels and age in three groups of atherosclerotic individuals and in nonatherosclerotic controls. The atherosclerotic groups comprised a postmyocardial infarction group with a mean age of 48 years, a group of individuals operated on for carotid stenosis with a mean age of 62 years, and a group of 85-year-olds with clinical coronary artery disease, peripheral arterial disease, or both. All 311 individuals were unrelated Caucasians of Danish ancestry. For the XbaI polymorphism, the X- allele was an independent predictor for myocardial infarction on multivariate analysis, but did not distinguish between patients and controls on univariate analysis. Additionally, this polymorphism was associated with variation in lipoprotein levels, but there was no clear evidence of a gene dosage effect. For the EcoRI polymorphism, the E- allele was associated with elevated levels of VLDL cholesterol, plasma triglycerides and VLDL triglycerides. Similar, but weaker associations were found for the MspI polymorphism. There were no significant differences in allele frequencies as a function of age for any of the DNA polymorphisms. In conclusion, while variation associated with the EcoRI polymorphism appears to be involved in the regulation of VLDL metabolism, variation associated with the XbaI polymorphism may determine susceptibility to coronary artery disease independent of other conventional risk factors, but it also appears to affect variation in lipoprotein levels.