Single nucleotide polymorphism in the low-density lipoprotein receptor is associated with a threefold risk of stroke. A case-control and prospective study.

BACKGROUND: More than 600 different, but rare, mutations in the low-density lipoprotein (LDL) receptor have been identified as the cause of familial hypercholesterolaemia. In contrast, only a single common amino acid-changing polymorphism (A370T) has been reported in this gene. The association of this polymorphism with variations in lipid levels is at present unclear. METHODS: We obtained genotypes for 9238 individuals from The Copenhagen City Heart Study, of which 465 had stroke and 1019 had ischaemic heart disease. RESULTS: In this cohort from the Danish general population, 90.2% (n = 8,332), 9.5% (n = 875), and 0.3% (n = 31) were 370A homozygotes, A370T heterozygotes, and 370T homozygotes, respectively. The incidences of stroke in 370A homozygotes, A370T heterozygotes, and 370T homozygotes were 28, 26, and 100 per 10,000 person-years, respectively (370T homozygotes vs. 370A homozygotes: log-rank, P = 0.002). The relative risk and odds ratio for stroke in 370T homozygotes vs. 370A homozygotes were 3.6 (95% confidence interval, 1.5-8.8) and 3.6 (95% confidence interval, 1.3-9.8) in prospective and cross-sectional studies, respectively. Furthermore, average age at onset of stroke in 370T homozygotes tended to be lower than in heterozygotes and 370A homozygotes combined (59 vs. 66 years, P = 0.08). In contrast, neither levels of cholesterol, LDL cholesterol, apolipoprotein B, or triglycerides, nor risk of ischaemic heart disease was associated with genotype. CONCLUSION: This is the first prospective study to suggest an association between a polymorphism in the LDL receptor and stroke. Because this association is independent of lipid levels, our results point toward a hitherto unknown function of this receptor in the brain.     

Angiotensinogen mutations and risk for ischemic heart disease, myocardial infarction, and ischemic cerebrovascular disease. Six case-control studies from the Copenhagen City Heart Study

BACKGROUND: The M235T and T174M angiotensinogen mutations have been linked to increased risk for ischemic heart and cerebrovascular disease. OBJECTIVE: To determine whether angiotensinogen mutations are associated with ischemic heart disease, myocardial infarction, and ischemic cerebrovascular disease. DESIGN: Six case-control studies from the Copenhagen City Heart Study. SETTING: Copenhagen, Denmark. PARTICIPANTS: Participants in the Copenhagen City Heart Study and patients from the same hospital with ischemic heart disease (n = 866 and n = 943, respectively), myocardial infarction (n = 519 and n = 493, respectively), or ischemic cerebrovascular disease (n = 489 and n = 434, respectively) and 7975 controls without these conditions. MEASUREMENTS: Genotypes for the M235T and T174M angiotensinogen mutations were compared between controls and Copenhagen City Heart Study participants with ischemic heart disease, myocardial infarction, and cerebrovascular disease (studies 1a, 1b, and 1c) and patients from Copenhagen University Hospital with the same conditions (studies 2a, 2b, and 2c). RESULTS: Relative allele frequencies of 235T and 174M in the general population were 0.41 and 0.12, respectively. Genotype was not associated with increased risk for ischemic heart or ischemic cerebrovascular disease in studies of either mutation alone or combined in women or men. Among compound heterozygotes (235MT /174TM ), women in case-control study 2a had decreased risk for ischemic heart disease in age-adjusted analysis; however, this decreased risk was not seen in multifactorial-adjusted or matched analyses, in men, or in case-control study 1a. Among double homozygotes (235TT /174MM ), women in case-control study 2b had increased risk for myocardial infarction in matched analysis; however, this increased risk was not seen in age- or multifactorial-adjusted analyses, in men, or in case-control study 1b. Among single homozygotes (235TT /174TT ), men in case-control study 2b had increased risk for myocardial infarction in multifactorial-adjusted and matched analyses. This risk was not present in age-adjusted analysis, in women, or in case-control study 1b. In addition, male single homozygotes had decreased risk for ischemic cerebrovascular disease in case-control study 2c in age- and multifactorial-adjusted analyses, but this finding was not seen in matched analysis, in women, or in case-control study 1c. CONCLUSIONS: In six large case-control studies, the M235T and T174M angiotensinogen mutations were not consistently associated with increased (or decreased) risk for ischemic heart disease, myocardial infarction, or ischemic cerebrovascular disease. Statistically significant associations may represent chance findings rather than real phenomena.     

Coronary heart disease risk factors ranked by importance for the individual and community. A 21 year follow-up of 12 000 men and women from The Copenhagen City Heart Study.

AIMS: The importance of coronary heart disease risk factors may differ between individuals and community and by sex and age. METHODS AND RESULTS The Copenhagen City Heart Study followed for 21 years a random sample of 5599 men and 6478 women aged 30 to 79 years at baseline. The importance of risk factors in individuals and the community were evaluated as relative- and population-attributable risks. We traced 2180 coronary events. In Cox regression analysis with ten risk factors entered simultaneously, relative risks for coronary heart disease in men ranged from 1.69 to 1.20 with the highest risks for diabetes, hypertension, smoking, and physical inactivity. In women, relative risks ranged from 2.74 to 1.19 with the highest risks for diabetes, smoking, hypertension, and physical inactivity. Population-attributable risks in men ranged from 22% to 3% with the highest risks for smoking, hypertension, and no daily alcohol intake. In women, attributable risks ranged from 37% to 3% with the highest risks for smoking, hypertension, and hypercholesterolaemia. Several of these rankings differed by age. CONCLUSIONS: The importance of coronary heart disease risk factors may differ for individuals, the community, and by sex and age. Consequently, prevention strategies should be tailored accordingly.     

Regular physical activity modifies smoking-related lung function decline and reduces risk of chronic obstructive pulmonary disease: a population-based cohort study

RATIONALE: We have previously reported that regular physical activity reduces risk of chronic obstructive pulmonary disease (COPD) exacerbation. We hypothesized that higher levels of regular physical activity could reduce the risk of COPD by modifying smoking-related lung function decline. OBJECTIVE: To estimate the longitudinal association between regular physical activity and FEV(1) and FVC decline and COPD risk. METHODS: A population-based sample (n = 6,790) was recruited and assessed with respect to physical activity, smoking, lung function, and other covariates, in Copenhagen in 1981-1983, and followed until 1991-1994. Mean level of physical activity between baseline and follow-up was classified into "low," "moderate," and "high." FEV(1) and FVC decline rates were expressed as milliliters per year. COPD was defined as FEV(1)/FVC < or = 70%. Adjusted associations between physical activity and FEV(1) and FVC decline, and COPD incidence, were obtained using linear and logistic regression, respectively. RESULTS: Active smokers with moderate and high physical activity had a reduced FEV(1) and FVC decline compared with those with low physical activity (relative change of +2.6 and +4.8 ml/yr of FEV(1), P-for-trend = 0.006, and +2.6 and +7.7 ml/yr of FVC, P-for-trend < 0.0001, for the moderate and high physical activity group, respectively), after adjusting for all potential confounders and risk factors of lung function decline. Active smokers with moderate to high physical activity had a reduced risk of developing COPD as compared with the low physical activity group (odds ratio, 0.77; p = 0.027). CONCLUSIONS: This prospective study shows that moderate to high levels of regular physical activity are associated with reduced lung function decline and COPD risk among smokers.     

Perceived stress and risk of colorectal cancer in men and women: a prospective cohort study

Objective. We aim to assess the relationship between stress and risk of primary colorectal cancer in men and women. Design. A prospective cohort study Setting. The Copenhagen City Heart Study, Denmark Subjects. A total of 6488 women and 5426 men were included in the study. The participants were asked about intensity and frequency of stress at baseline in 1981–1983 and were followed until the end of 2000 in the Danish Cancer Registry. Less than 0.1% was lost to follow‐up. Main outcome measures. First time incidence of primary colorectal cancer. Results. During follow‐up 162 women and 166 men were diagnosed with colorectal cancer. Women with moderate and high stress intensity had a hazard ratio of 0.60 (95% CI: 0.37–0.98) and 0.52 (0.23–1.14) for colorectal cancer, respectively, compared to women with no stress. For colon cancer, a one‐unit increase on a seven‐point stress‐score was associated with an 11% lower incidence of the disease (HR = 0.89, 95% CI: 0.81–0.99) amongst women. There was no consistent evidence of an association between stress and colorectal cancer in men. Conclusion. Perceived stress was associated with lower risk of particularly colon cancer in women, whilst there was no clear relationship between stress and colorectal cancer in men.     

Intensity versus duration of walking, impact on mortality: the Copenhagen City Heart Study.

BACKGROUND: Current recommendations prescribe that every adult should accumulate 30 min or more of moderate-intensity physical activity in leisure time, preferably all days of the week. To further support these recommendations we examined the impact of walking intensity and walking duration on all-cause mortality. DESIGN: Relative intensity and duration of walking were recorded in 7308 healthy women and men aged 20-93 at the third examination (1991-1994) of the Copenhagen City Heart Study. During an average of 12 years of follow-up 1391 deaths were recorded. RESULTS: For both sexes we found a significant inverse association between walking intensity and risk of death, but only a weak inverse association to walking duration. For women walking with average intensity, the adjusted hazard ratio (HR) of death was 0.75 [95% confidence interval (CI) 0.61-0.92; P<0.01] and walking with fast intensity 0.48 (95% CI 0.35-0.66; P<0.001) compared to women walking with slow intensity. For men the relative risks were 0.54 (95% CI 0.45-0.67; P<0.001) and 0.43 (95% CI 0.32-0.59; P<0.001), respectively. CONCLUSION: Our findings indicate that the relative intensity and not the duration of walking is of most importance in relation to all-cause mortality. Thus our general recommendation to all adults would be that brisk walking is preferable to slow.     

Perceived stress as a risk factor for changes in health behaviour and cardiac risk profile: a longitudinal study

Objective. The aim of this study was to evaluate the long‐term effects of stress on changes in health behaviour and cardiac risk profile in men and women. Design. A prospective cohort study. Setting. The Copenhagen City Heart Study, Denmark. Subjects. The analyses were based on 7066 women and men from the second (1981–1983) and third (1991–1993) wave of the Copenhagen City Heart Study. All participants were asked questions on stress and health behaviour and they had their weight, height, blood pressure and level of blood lipids measured by trained personnel. Main outcome measures. Changes in health behaviour (smoking, physical activity, alcohol consumption, overweight) and cardiac risk profile (cholesterol, HDL cholesterol, blood pressure, diabetes). Results. Individuals with high levels of stress compared to those with low levels of stress were less likely to quit smoking (OR = 0.58; 95% CI: 0.41–0.83), more likely to become physically inactive (1.90; 1.41–2.55), less likely to stop drinking above the sensible drinking limits (0.43; 0.24–0.79), and stressed women were more likely to become overweight (1.55; 1.12–2.15) during follow‐up. Men and women with high stress were more likely to use antihypertensive medication (1.94; 1.63–2.30), and stressed men were more than two times as likely to develop diabetes during follow‐up (2.36; 1.22–4.59). Conclusion. This longitudinal study supports a causal relation between stress and cardiovascular diseases mediated through unfavourable changes in health behaviour and cardiac risk profile.