Peter Schnohr

A 15-Year Follow-up Study of Ventilatory Function in Adults with Asthma

BACKGROUND Although the prevalence of asthma and morbidity related to asthma are increasing, little is known about the natural history of lung function in adults with this disease. METHODS We used data from a longitudinal epidemiologic study of the general population in a Danish city, the Copenhagen City Heart Study, to analyze changes over time in the forced expiratory volume in one second (FEV1) in adults with self-reported asthma and adults without asthma. The study was conducted between 1976 and 1994; for each patient, three measurements of lung function were obtained over a 15-year period. The final data set consisted of measurements from 17,506 subjects (8136 men and 9370 women), of whom 1095 had asthma. RESULTS Among subjects who participated in all three evaluations, the unadjusted decline in FEV1 among subjects with asthma was 38 ml per year, as compared with 22 ml per year in those without asthma. The decline in FEV1 normalized for height (FEV1 divided by the square of the height in meters) was greater among the subjects with asthma than among those without the disease (P<0.001). Among both men and women, and among both smokers and nonsmokers, subjects with asthma had greater declines in FEV1 over time than those without asthma (P<0.001). At the age of 60 years, a 175-cm-tall nonsmoking man without asthma had an average FEV1 of 3.05 liters, as compared with 1.99 liters for a man of similar age and height who smoked and had asthma. CONCLUSIONS In a sample of the general population, people who identified themselves as having asthma had substantially greater declines in FEV1 over time than those who did not.

Regular physical activity reduces hospital admission and mortality in chronic obstructive pulmonary disease: a population based cohort study

Background: Information about the influence of regular physical activity on the course of chronic obstructive pulmonary disease (COPD) is scarce. A study was undertaken to examine the association between regular physical activity and both hospital admissions for COPD and all-cause and specific mortality in COPD subjects. Methods: From a population-based sample recruited in Copenhagen in 1981–3 and 1991–4, 2386 individuals with COPD (according to lung function tests) were identified and followed until 2000. Self-reported regular physical activity at baseline was classified into four categories (very low, low, moderate, and high). Dates and causes of hospital admissions and mortality were obtained from Danish registers. Adjusted associations between physical activity and hospital admissions for COPD and mortality were obtained using negative binomial and Cox regression models, respectively. Results: After adjustment for relevant confounders, subjects reporting low, moderate or high physical activity had a lower risk of hospital admission for COPD during the follow up period than those who reported very low physical activity (incidence rate ratio 0.72, 95% confidence interval (CI) 0.53 to 0.97). Low, moderate and high levels of regular physical activity were associated with an adjusted lower risk of all-cause mortality (hazard ratio (HR) 0.76, 95% CI 0.65 to 0.90) and respiratory mortality (HR 0.70, 95% CI 0.48 to 1.02). No effect modification was found for sex, age group, COPD severity, or a background of ischaemic heart disease. Conclusions: Subjects with COPD who perform some level of regular physical activity have a lower risk of both COPD admissions and mortality. The recommendation that COPD patients be encouraged to maintain or increase their levels of regular physical activity should be considered in future COPD guidelines, since it is likely to result in a relevant public health benefit.

Type of Alcohol Consumed and Mortality from All Causes, Coronary Heart Disease, and Cancer

Several population studies from different countries have shown a J-shaped relation between intake of alcohol and mortality from all causes (1-6). Studies comparing different countries have found a strong inverse relation between incidence rates of coronary heart disease and wine consumption but a weak or nonexistent relation for consumption of beer or spirits (7-9). The findings that different types of alcoholic beverages have different effects on mortality are indirectly supported by several clinical and experimental studies (10-12). In contrast, prospective studies have shown that beer (13), spirits (14), and wine (15) may have protective effects. However, most of these investigations were based on populations with one predominant type of alcohol consumption; this precluded valid comparison of the effects of the three different types of alcohol. We sought to analyze the effect of intake of different types of alcohol on mortality from all causes, coronary heart disease, and cancer in several large Danish cohort studies. Methods The Copenhagen Centre for Prospective Population Studies is based on three study samples: that of the Copenhagen City Heart Study; that of the Copenhagen County Centre of Preventive Medicine (the former Glostrup Population Studies), which includes six cohorts; and that of the Copenhagen Male Study (16-18). The study samples of the Copenhagen City Heart Study, initiated in 1976, and the Copenhagen County Centre of Preventive Medicine, initiated in 1964, were randomly selected within age strata from the populations residing in defined areas in greater Copenhagen. For the Copenhagen Male Study, initiated in 1971, employees of 14 large companies in Copenhagen were invited to participate. The mean participation rate in all studies was 80% (range, 69% to 88%). The combined study sample comprises 13 064 men and 11 459 women for whom information on alcohol intake and lifestyle-related variables, described below, was complete. Alcohol Intake Participants of the Copenhagen City Heart Study and the studies in the Copenhagen County Centre of Preventive Medicine were asked about their current average weekly intake of beer, wine, and spirits. In the Copenhagen Male Study, participants were asked about their average daily intake of beer, wine, and spirits on weekdays (Monday through Thursday) and weekends (Friday through Sunday); these reports were combined to estimate weekly alcohol consumption. Persons in our study who did not drink alcohol because they were receiving disulfiram or other medication were excluded from the analysis. One bottle of beer contains 11.6 g of alcohol, and 12 g is an approximate average for one serving of wine or spirits. We grouped participants into five categories on the basis of total intake of alcohol: less than 1 drink/wk (nondrinkers), 1 to 7 drinks/wk, 8 to 21 drinks/wk, 22 to 35 drinks/wk, and more than 35 drinks/wk. Intake of beer, wine, and spirits was categorized similarly; however, because of the frequency of end point data, more than 21 drinks/wk is the highest intake category for the individual types of beverages. Smoking Status Participants reported whether they were never-smokers, former smokers, or current smokers. Current smokers reported grams of tobacco smoked per day in the form of cigarettes (1 g/d), small cigars (3 g/d), cigars (5 g/d), and pipe tobacco (50 g/package). Five groups were defined: never-smokers, former smokers, smokers of 1 to 14 g of tobacco daily, smokers of 15 to 24 g of tobacco daily, and smokers of more than 24 g of tobacco daily. Education Participants reported the number of years that they attended school. Three groups were defined: fewer than 8 years, 8 to 11 years, and 12 or more years of school education. Physical Activity Participants reported whether they were physically active during leisure time. Four groups were defined: sedentary (<2 h/wk), light activity (2 to 4 h/wk), moderate activity (>4 h/wk, noncompetitive) and heavy activity (>4 h/wk, competitive). Body Mass Index Body weight and height were measured while the participant was wearing light clothes and no shoes. Body mass index was calculated as weight in kg divided by height in meters squared. Five categories of body mass index were defined: less than 20.0 kg/m2, 20.0 to 24.9 kg/m2, 25.0 to 29.9 kg/m2, 30.0 to 34.9 kg/m2, and 35.0 kg/m2 or more. Changes in Lifestyle-Related Variables When participants were re-examined during follow-up, the newly obtained values for alcohol intake, smoking status, physical activity, and body mass index were used to replace the old values in the statistical analyses. Observation time and vital status were included in the modeling accordingly. Follow-up Participants were followed from date of entry into the study to date of death, loss to follow-up, emigration, or end of follow-up, whichever came first. The vital status of populations was followed by using each participants unique identification number in the national Central Person Register until 9 January 1995. Fewer than 1% of the participants were lost to follow-up. Causes of death were obtained from the National Board of Health and were defined by using codes from International Classifications of Diseases, Eighth Revision (codes 410.0 to 414.0 for coronary heart disease and codes 140.0 to 209.0 for cancer). According to a previous study, the reported diagnoses for these grouped codes have proven to be sufficiently valid (20). Statistical Analysis We performed Poisson regression (21) by using SAS/STAT software (22) to estimate the effect of alcohol intake on the risk for death. These models generate estimates of relative risk that are adjusted for confounders. Each model included the following potential confounders as categorical variables: age, cohort study, sex, education, body mass index, physical activity, and smoking status. Owing to collinearity, it was impossible to include both the amount by type of beverage (beer, wine, or spirits) consumed and total alcohol intake in the same regression. We therefore estimated the influence of alcohol according to number of drinks consumed per week [0, 1 to 7, 8 to 21, 22 to 35,>35] in three regressions: 1) total alcohol consumption in drinks per week, without considering beverage type; 2) alcohol consumption in drinks of each beverage per week, without considering the total intake; and 3) percentage of total alcohol intake consumed as wine (0%, 1% to 30%,>30%). Effects that were insignificant according to the likelihood ratio test (5% level) were removed by backward elimination. A term indicating interaction between total alcohol intake and percentage alcohol consumed as beer, wine, or spirits was included in the analyses to assess whether the effects of beer, wine, and spirits differed at different levels of total alcohol intake; no such effects were identified, as judged from the fit of the model. Likewise, no interaction was found between sex and intake of different types of beverage in terms of mortality. Results A total of 4275 women and 1635 men drank less than 1 drink per week; 64 women and 1032 men drank 35 or more drinks per week. Of 13 613 participants who drank alcohol, 12 846 (69%) included wine in their intake (Table 1). During 257 859 person-years of follow-up, 4833 participants died; of these, 1075 died of coronary heart disease and 1552 died of cancer. Table 1. Baseline Characteristics of the Study Participants Baseline Characteristics Compared with participants who drank alcohol but no wine, those for whom wine made up more than 30% of their total alcohol intake were more likely to be women and have a higher educational level but were less likely to be smokers (Table 1). Participants for whom wine made up more than 30% of their alcohol intake were similar to those who drank no alcohol in terms of smoking habits, body mass index, and physical activity. Across categories of total alcohol intake, mean alcohol intake within the different categories of wine drinking was similar; for example, among participants who drank 8 to 21 drinks/wk, those who drank no wine, those who drank 1% to 30% wine, and those who drank more than 30% wine had a mean alcohol intake of 13.3, 13.7, and 12.8 drinks/wk, respectively. However, among light drinkers (1 to 7 drinks/wk), those who drank 1% to 30% of their alcohol as wine had a slightly higher mean intake than did those who avoided wine and those who drank more than 30% of their alcohol intake as wine. Thus, assessment of the effects of wine intake may not be subject to residual confounding by total alcohol intake when controlled for as specified. Total Alcohol Intake and Mortality We found J-shaped relations between total alcohol intake and all-cause mortality in the three substudies. Pooled analyses also revealed J-shaped relations (Table 2). When nondrinkers were used as the reference group (relative risk, 1.00), intake of 1 to 7 drinks per week carried a relative risk of 0.82 (95% CI, 0.76 to 0.88) and intake of more than 35 drinks per week carried a relative risk of 1.10 (CI, 0.95 to 1.26). Alcohol intake was negatively related to death from coronary heart disease and positively related to death from cancer (Table 2). Table 2. Relative Risk for Death with Regard to Total Alcohol Intake and Intake of Beer, Wine, and Spirits Intake of Beer, Wine, and Spirits and Mortality Light to moderate intake of beer or spirits had a small effect on death from all causes (Table 2). This finding contrasted with the effect of wine intake on mortality: Participants who drank 8 to 21 glasses of wine per week had a relative risk for death from all causes of 0.76 (CI, 0.67 to 0.86). Intake of fewer than 22 drinks of beer, wine, and spirits per week all carried lower risk for death from coronary heart disease; the reduction in risk was of the same magnitude for beer and wine drinking but was smaller and not statistically significant for spirits drinking. Furthermore, light to moderate drinkers of wine had

Smoking and risk of myocardial infarction in women and men : longitudinal population study

Abstract Objective: To compare risk of myocardial infarction associated with smoking in men and women, taking into consideration differences in smoking behaviour and a number of potential confounding variables. Design: Prospective cohort study with follow up of myocardial infarction. Setting: Pooled data from three population studies conducted in Copenhagen. Subjects: 11 472 women and 13 191 men followed for a mean of 12.3 years. Main outcome measures: First admission to hospital or death caused by myocardial infarction. Results: 1251 men and 512 women had a myocardial infarction during follow up. Compared with non-smokers, female current smokers had a relative risk of myocardial infarction of 2.24 (range 1.85-2.71) and male smokers 1.43 (1.26-1.62); ratio 1.57 (1.25-1.97). Relative risk of myocardial infarction increased with tobacco consumption in both men and women and was higher in inhalers than in non-inhalers. The risks associated with smoking, measured by both current and accumulated tobacco exposure, were consistently higher in women than in men and did not depend on age. This sex difference was not affected by adjustment for arterial blood pressure, total and high density lipoprotein cholesterol concentrations, triglyceride concentrations, diabetes, body mass index, height, alcohol intake, physical activity, and level of education. Conclusion: Women may be more sensitive than men to some of the harmful effects of smoking. Interactions between components of smoke and hormonal factors that may be involved in development of ischaemic heart disease should be examined further.

Association of Loss-of-Function Mutations in the ABCA1 Gene With High-Density Lipoprotein Cholesterol Levels and Risk of Ischemic Heart Disease

CONTEXT Low levels of high-density lipoprotein (HDL) cholesterol are inversely related to cardiovascular risk. Whether this is a causal effect is unclear. OBJECTIVE To determine whether genetically reduced HDL cholesterol due to heterozygosity for 4 loss-of-function mutations in ABCA1 cause increased risk of ischemic heart disease (IHD). DESIGN, SETTING, AND PARTICIPANTS Three studies of white individuals from Copenhagen, Denmark, were used: the Copenhagen City Heart Study (CCHS), a 31-year prospective general population study (n = 9022; 28 heterozygotes); the Copenhagen General Population Study (CGPS), a cross-sectional general population study (n = 31,241; 76 heterozygotes); and the Copenhagen Ischemic Heart Disease Study (CIHDS), a case-control study (n = 16,623; 44 heterozygotes). End points in all 3 studies were recorded during the period of January 1, 1976, through July 9, 2007. MAIN OUTCOME MEASURES Levels of HDL cholesterol in the general population, cellular cholesterol efflux, and the association between IHD and HDL cholesterol and genotype. RESULTS Heterozygotes vs noncarriers for 4 ABCA1 mutations (P1065S, G1216V, N1800H, R2144X) had HDL cholesterol levels of 41 mg/dL (interquartile range, 31-50 mg/dL) vs 58 mg/dL (interquartile range, 46-73 mg/dL), corresponding to a reduction in HDL cholesterol of 17 mg/dL (P < .001). A 17-mg/dL lower HDL cholesterol level in the CCHS was associated with a multifactorially adjusted hazard ratio for IHD of 1.70 (95% confidence interval [CI], 1.57-1.85). However, for IHD in heterozygotes vs noncarriers, the multifactorially adjusted hazard ratio was 0.67 (95% CI, 0.28-1.61; 1741 IHD events) in the CCHS, the multifactorially adjusted odds ratio was 0.82 (95% CI, 0.34-1.96; 2427 IHD events) in the CGPS, and the multifactorially adjusted odds ratio was 0.86 (95% CI, 0.32-2.32; 2498 IHD cases) in the CIHDS. The corresponding odds ratio for IHD in heterozygotes vs noncarriers for the combined studies (n = 41,961; 6666 cases; 109 heterozygotes) was 0.93 (95% CI, 0.53-1.62). CONCLUSION Lower plasma levels of HDL cholesterol due to heterozygosity for loss-of-function mutations in ABCA1 were not associated with an increased risk of IHD.

Lung-Function Trajectories Leading to Chronic Obstructive Pulmonary Disease.

BACKGROUND Chronic obstructive pulmonary disease (COPD) is thought to result from an accelerated decline in forced expiratory volume in 1 second (FEV1) over time. Yet it is possible that a normal decline in FEV1 could also lead to COPD in persons whose maximally attained FEV1 is less than population norms. METHODS We stratified participants in three independent cohorts (the Framingham Offspring Cohort, the Copenhagen City Heart Study, and the Lovelace Smokers Cohort) according to lung function (FEV1 ≥80% or <80% of the predicted value) at cohort inception (mean age of patients, approximately 40 years) and the presence or absence of COPD at the last study visit. We then determined the rate of decline in FEV1 over time among the participants according to their FEV1 at cohort inception and COPD status at study end. RESULTS Among 657 persons who had an FEV1 of less than 80% of the predicted value before 40 years of age, 174 (26%) had COPD after 22 years of observation, whereas among 2207 persons who had a baseline FEV1 of at least 80% of the predicted value before 40 years of age, 158 (7%) had COPD after 22 years of observation (P<0.001). Approximately half the 332 persons with COPD at the end of the observation period had had a normal FEV1 before 40 years of age and had a rapid decline in FEV1 thereafter, with a mean (±SD) decline of 53±21 ml per year. The remaining half had had a low FEV1 in early adulthood and a subsequent mean decline in FEV1 of 27±18 ml per year (P<0.001), despite similar smoking exposure. CONCLUSIONS Our study suggests that low FEV1 in early adulthood is important in the genesis of COPD and that accelerated decline in FEV1 is not an obligate feature of COPD. (Funded by an unrestricted grant from GlaxoSmithKline and others.).

Intake of Beer, Wine, and Spirits and Risk of Stroke The Copenhagen City Heart Study

BACKGROUND AND PURPOSE Alcohol consumption has been associated with a protective effect on risk of ischemic stroke. There may, however, be differences in the effect of beer, wine, and spirits due to properties other than ethanol, a topic that has gained only little attention in stroke research. METHODS Our analysis was a prospective cohort study of 13 329 eligible men and women, aged 45 to 84 years, participating in the Copenhagen City Heart Study. Information on alcohol habits and a number of socioeconomic and health-related factors was obtained at baseline. During 16 years of follow-up, 833 first-ever strokes occurred. Data were analyzed by means of multiple Poisson regression. RESULTS We found indications of a U-shaped relation between intake of alcohol and risk of stroke. In analyses adjusted for age, sex, and smoking, intake of wine on a monthly, weekly, or daily basis was associated with a lower risk of stroke compared with no wine intake (monthly: relative risk [RR], 0. 83; 95% CI, 0.69 to 0.98; weekly: RR, 0.59; 95% CI, 0.45 to 0.77; daily: RR, 0.70; 95% CI, 0.46 to 1.00). This effect of wine intake remained after complete adjustment for confounding variables (monthly: RR, 0.84; 95% CI, 0.70 to 1.02; weekly: RR, 0.66; 95% CI, 0.50 to 0.88; daily: RR, 0.68; 95% CI, 0.45 to 1.02). There was no association between intake of beer or spirits on risk of stroke. CONCLUSIONS The differences in the effects of beer, wine, and spirits on the risk of stroke suggest that compounds in the wine in addition to ethanol are responsible for the protective effect on risk of stroke.

PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses.

OBJECTIVES The aim of this study was to examine the effect of PCSK9 R46L on low-density lipoprotein cholesterol (LDL-C), risk of ischemic heart disease (IHD), and mortality. BACKGROUND The 46L allele has been associated with reductions in LDL-C and risk of IHD, but results vary between studies. METHODS We determined the association of R46L genotype with LDL-C, risk of IHD, myocardial infarction (MI), and mortality in the prospective CCHS (Copenhagen City Heart Study) (n = 10,032) and validated the results in: 1) the cross-sectional CGPS (Copenhagen General Population Study) (n = 26,013); and 2) the case-control CIHDS (Copenhagen Ischemic Heart Disease Study) (n = 9,654). We also performed meta-analyses of present and previous studies (n = 66,698). RESULTS In carriers (2.6%) versus noncarriers, the 46L allele was associated with reductions in LDL-C of 0.35 to 0.55 mmol/l (11% to 16%) from 20 to 80+ years in the general population (CCHS and CGPS; p values <0.0001). Observed risk reductions for IHD in 46L allele carriers were: 6% in the CCHS study (hazard ratio [HR]: 0.94; 95% confidence interval [CI]: 0.68 to 1.31), 46% in the CGPS study (odds ratio [OR]: 0.54; 95% CI: 0.39 to 0.77), 18% in the CIHDS study (OR: 0.82; 95% CI: 0.55 to 1.21), and 30% in the studies combined (OR: 0.70; 95% CI: 0.58 to 0.86). In the CCHS study, HR for mortality was 1.18 (95% CI: 0.93 to 1.50). In meta-analyses, 46L allele carriers had a 12% (0.43 mmol/l) reduction in LDL-C and a 28% reduction in risk of IHD (HR: 0.72; 95% CI: 0.62 to 0.84), similar to results in the CCHS, CGPS, and CIHDS studies combined. However, the observed 12% (0.43 mmol/l) reduction in LDL-C theoretically predicted an only 5% reduction in risk of IHD (HR: 0.95; 95% CI: 0.92 to 0.97). CONCLUSIONS The PCSK9 46L allele was associated with reductions in LDL-C from 20 to 80+ years in the general population. The reduction in risk of IHD was larger than predicted by the observed reduction in LDL-C alone. This could be because genotype is a better predictor of lifelong exposure to LDL-C than LDL-C measured in adult life.

Relation of ventilatory impairment and of chronic mucus hypersecretion to mortality from obstructive lung disease and from all causes.

The relation of ventilatory impairment and chronic mucus hypersecretion to death from all causes and death from obstructive lung disease (chronic bronchitis, emphysema and asthma) was studied in 13,756 men and women randomly selected from the general population of the City of Copenhagen. During the 10 year follow up 2288 subjects died. In 164 subjects obstructive lung disease was considered to be an underlying or a contributory cause of death (obstructive lung disease related death); in 73 subjects it was considered to be the underlying cause of death (obstructive lung disease death). Forced expiratory volume in one second, expressed as a percentage of the predicted value (FEV1% pred), and the presence of chronic phlegm were used to characterise ventilatory function and chronic mucus hypersecretion respectively. For mortality analysis the proportional hazards regression model of Cox was used; it included age, sex, pack years, inhalation habit, body mass index, alcohol consumption, and the presence or absence of asthma, heart disease, and diabetes mellitus as confounding factors. By comparison with subjects with an FEV1 of 80% pred or more, subjects with an FEV1 below 40% pred had increased risk of dying from all causes (relative risk (RR) = 5.0 for women, 2.7 for men), a higher risk of obstructive lung disease related death (RR = 57 for women, 34 for men), and a higher risk of obstructive lung disease death (RR = 101 for women, 77 for men). Chronic mucus hypersecretion was associated with only a slightly higher risk of death from all causes (RR = 1.1 for women, 1.3 for men). The association between chronic mucus hypersecretion and obstructive lung disease death varied with the level of ventilatory function, being weak in subjects with normal ventilatory function (for an FEV1 of 80% pred the RR was 1.2), but more pronounced in subjects with reduced ventilatory function (for an FEV1 of 40% pred the RR was 4.2). A similar though statistically non-significant trend was observed with regard to obstructive lung disease related death. This study shows that impaired lung function is very strongly related to total mortality, obstructive lung disease related mortality, and obstructive lung disease mortality and suggests that chronic mucus hypersecretion, in those with impaired ventilatory function, is also a significant risk factor for death from obstructive lung disease.

Association of mutations in the apolipoprotein B gene with hypercholesterolemia and the risk of ischemic heart disease

BACKGROUND Familial hypercholesterolemia leads to premature ischemic heart disease and is often caused by mutations in the gene for the low-density lipoprotein receptor. Mutations in the apolipoprotein B gene, which encodes a ligand for this receptor, may also result in this phenotype. METHODS We studied the genotypes of 9255 women and men from the general population, 948 patients with ischemic heart disease, and 36 patients with familial hypercholesterolemia, all from Denmark, for three mutations in the apolipoprotein B gene: Arg3500Gln, Arg3531Cys, and Arg3500Trp. RESULTS The prevalence of heterozygotes in the general population was 0.08 percent (95 percent confidence interval, 0.03 to 0.16 percent) for both the Arg3500Gln and the Arg3531Cys mutations, and 0.00 percent (95 percent confidence interval, 0.00 to 0.18 percent) for the Arg3500Trp mutation. Among carriers of the Arg3500Gln mutation, cholesterol levels were significantly higher than among noncarriers in the general population - by 100 mg per deciliter (2.6 mmol per liter) among carriers in the general population, 154 mg per deciliter (4.0 mmol per liter) among patients with ischemic heart disease, and 172 mg per deciliter (4.5 mmol per liter) among patients with familial hypercholesterolemia. Heterozygous carriers of the Arg3500Gln mutation were significantly more common among patients with ischemic heart disease (odds ratio, 7.0; 95 percent confidence interval, 2.2 to 22; P=0.003) and patients with familial hypercholesterolemia (odds ratio, 78; 95 percent confidence interval, 16 to 388; P=0.001) than in the general population. Heterzygous carriers of the Arg3531Cys mutation in the general population did not have higher-than-normal plasma cholesterol levels or an increased risk of ischemic heart disease (odds ratio; 1.4; 95 percent confidence interval, 0.2 to 11; P=0.54). CONCLUSIONS The Arg3500Gln mutation in the apolipoprotein B gene, which is responsible for familial defective apolipoprotein B-100 and is present in approximately 1 in 1000 persons in Denmark, causes severe hypercholesterolemia and increases the risk of ischemic heart disease.