Adherence to dietary guidelines and risk of dementia: a prospective cohort study of 94 184 individuals.

AIMS: Recent estimates suggest that 40% of dementia cases could be avoided by treating recognised cardiovascular risk factors such as hypertension, diabetes, smoking and physical inactivity. Whether diet is associated with dementia remains largely unknown. We tested if low adherence to established dietary guidelines is associated with elevated lipids and lipoproteins and with increased risk of Alzheimer's disease and non-Alzheimer's dementia ­ a dementia subtype with a high frequency of cardiovascular risk factors. METHODS: We used the prospective Copenhagen General Population Study including 94 184 individuals with dietary information and free of dementia at baseline. Mean age at study entry was 58 years, and 55% (N = 51 720) were women and 45% (N = 42 464) were men. Adherence to dietary guidelines was grouped into low, intermediate and high adherence based on food frequency questionnaires. Main outcomes were non-Alzheimer's dementia and Alzheimer's disease. RESULTS: Low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol and plasma triglyceride levels were higher in individuals with intermediate and low adherence to dietary guidelines compared with individuals with high adherence (all p for trends <0.001). Age and sex-adjusted hazard ratios (HRs) for non-Alzheimer's dementia v. individuals with high adherence were 1.19 (95% confidence interval 0.97­1.46) for intermediate adherence, and 1.54 (1.18­2.00) for low adherence. Corresponding HRs in multivariable-adjusted models including APOE genotype were 1.14 (0.92­1.40) and 1.35 (1.03­1.79). These relationships were not observed in individuals on lipid-lowering therapy. CONCLUSIONS: Low adherence to national dietary guidelines is associated with an atherogenic lipid profile and with increased risk of non-Alzheimer's dementia ­ the subtype of dementia with a high frequency of vascular risk factors. This study suggests that implementation of dietary guidelines associated with an anti-atherogenic lipid profile could be important for prevention of non-Alzheimer's dementia.

Cardiac chamber volumes and left ventricular mass in people living with HIV and matched uninfected controls.

OBJECTIVES: People living with HIV (PLWH) have increased risk of cardiovascular diseases compared with uninfected populations. We assessed structural cardiac abnormalities and their associated risk factors in well-treated PLWH and uninfected controls using multidetector computed tomography (MDCT). METHODS: People living with HIV and age- and sex-matched uninfected controls underwent MDCT to determine left atrial volume (LAV), left ventricular diastolic volume (LVDV), right ventricular diastolic volume (RVDV) and left ventricular mass (LVM). All outcomes were indexed to body surface area (BSA) (LAVi, LVDVi, RVDVi and LVMi). RESULTS: A total of 592 PLWH and 1184 uninfected controls were included in the study. PLWH had smaller mean (SD) LAVi [40 (8) vs. 41 (9) mL/m2 ; P = 0.002] and LVDVi [61 (13) vs. 65 (14) mL/m2 ; P < 0.001] but larger RVDVi [89 (18) vs. 86 (17) mL/m2 ; P < 0.001] than uninfected controls. HIV was independently associated with 7 mL (95% CI: -10 to -3) smaller LVDV, and with 12 mL (95% CI: 8-16) larger RVDV, and 4 g (95% CI: 1-6) larger LVM after adjustment for cardiovascular risk factors and BSA. Large RVDV in PLWH was not associated with obstructive lung function. CONCLUSIONS: HIV was independently associated with smaller LVDV and larger RVDV and LVM. Alterations in cardiac chamber volumes in PLWH were mainly minor. The clinical impact of these findings is uncertain, but it seems unlikely that alterations in cardiac chamber volumes explain the increased burden of cardiovascular disease previously observed in PLWH.

Prevalence of impaired renal function in virologically suppressed people living with HIV compared with controls: the Copenhagen Comorbidity in HIV Infection (COCOMO) study.

OBJECTIVES: While renal impairment is reported more frequently in people living with HIV (PLWH) than in the general population, the PLWH samples in previous studies have generally been dominated by those at high renal risk. METHODS: Caucasian PLWH who were virologically suppressed on antiretroviral treatment and did not have injecting drug use or hepatitis C were recruited from the Copenhagen Comorbidity in HIV Infection (COCOMO) study. Sex- and age-matched controls were recruited 1:4 from the Copenhagen General Population Study up to November 2016. We defined renal impairment as one measurement of estimated glomerular filtration rate ≤ 60 mL/min/1.73 m2 , and assessed associated factors using adjusted logistic regression models. The impact of HIV-related factors was explored in a subanalysis. RESULTS: Among 598 PLWH and 2598 controls, the prevalence of renal impairment was 3.7% [95% confidence interval (CI) 2.3-5.5%] and 1.7% (95% CI 1.2-2.2%; P = 0.0014), respectively. After adjustment, HIV status was independently associated with renal impairment [odds ratio (OR) 3.4; 95% CI 1.8-6.3]. In addition, older age [OR 5.4 (95% CI 3.9-7.5) per 10 years], female sex [OR 5.0 (95% CI 2.6-9.8)] and diabetes [OR 2.9 (95% CI 1.3-6.7)] were strongly associated with renal impairment. The association between HIV status and renal impairment became stronger with older age (P = 0.02 for interaction). Current and nadir CD4 counts, duration of HIV infection and previous AIDS-defining diagnosis were not associated with renal impairment among virologically suppressed PLWH. CONCLUSIONS: The prevalence of renal impairment is low among low-risk virologically suppressed Caucasian PLWH, but remains significantly higher than in controls. Renal impairment therefore remains a concern in all PLWH and requires ongoing attention.

Diagnostic performance of clinical characteristics to detect airflow limitation in people living with HIV and in uninfected controls.

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is underdiagnosed in the general population and possibly also in people living with HIV (PLWH). We evaluated the diagnostic performance of symptoms and risk factors for assessment of airflow limitation in PLWH and in uninfected controls. METHODS: Spirometry was performed in the Copenhagen Comorbidity in HIV Infection (COCOMO) study and Copenhagen General Population Study (CGPS), and airflow limitation was defined by forced expiratory volume in 1 s/forced vital capacity < lower limit of normal. We calculated the sensitivity, specificity, predictive values and area under the curve (AUC) of symptoms and risk factors for assessment of airflow limitation in PLWH and uninfected controls. RESULTS: A total of 1083 PLWH and 12 074 uninfected controls were included in the study. The sensitivity for sputum, chronic cough, breathlessness, wheezing, current and cumulative smoking and self-reported COPD was higher, but the specificity lower, in PLWH than in uninfected controls. The negative and positive predictive values were largely similar between the groups. The AUCs were similar or slightly higher in PLWH and highest for > 20 pack-years smoked [0.65; 95% confidence interval (CI) 0.58-0.72] and wheezing (0.64; 95% CI 0.57-0.71). A summed score for five variables was associated with slightly higher AUC in PLWH compared with uninfected controls [0.71 (95% CI 0.63-0.79) versus 0.65 (95% CI 0.63-0.68), respectively; P = 0.06]. CONCLUSIONS: Clinical variables were relatively poor discriminators of airflow limitation in PLWH and uninfected controls. Active COPD case finding by screening for symptoms and relevant exposures, as recommended in the general population, is likely to yield similar diagnostic power in PLWH.

High plasma 25-hydroxyvitamin D and high risk of nonmelanoma skin cancer: a Mendelian randomization study of 97 849 individuals.

BACKGROUND: High plasma 25-hydroxyvitamin D [25(OH)D] concentration has been associated observationally with a high risk of nonmelanoma skin cancer (NMSC), whereas many studies suggest that vitamin D could have a protective effect against cancer. The true association between vitamin D and risk of skin cancer remains unclear. OBJECTIVES: To test the hypothesis that genetically high plasma 25(OH)D protects against NMSC. METHODS: We included 103 084 individuals from the Danish general population, of whom 35 298 had plasma 25(OH)D measured and 97 849 were genotyped for four genetic variants near DHCR7 and CYP2R1 associated with 25(OH)D concentrations. We tested the association between plasma 25(OH)D levels and NMSC observationally and between genetically determined 25(OH)D levels and NMSC, using an instrumental variable approach. RESULTS: Multivariate-adjusted hazard ratios of NMSC were 3·27 [95% confidence interval (CI) 2·22-4·84] for plasma 25(OH)D ≥ 50 nmol L-1 vs. < 25 nmol L-1 . Genetic variants around DHCR7 and CYP2R1 were associated with up to 8·2 nmol L-1 higher 25(OH)D concentrations (F = 314). The odds ratio (OR) for a genetically determined 20 nmol L-1 higher plasma 25(OH)D was 1·11 (95% CI 0·91-1·35) for NMSC, with a corresponding observational multivariable adjusted OR of 1·13 (95% CI 1·10-1·17). CONCLUSIONS: Genetically determined high 25(OH)D levels did not appear to protect against NMSC, whereas high plasma 25(OH)D concentrations were associated with an observational high risk of NMSC. Thus, the observational association likely reflects confounding by sun exposure rather than causality.

Association between the antioxidant uric acid and depression and antidepressant medication use in 96 989 individuals.

OBJECTIVE: In the last decade, several studies have suggested that depression is accompanied by increased oxidative stress and decreased antioxidant defenses. We tested the hypothesis that high levels of the antioxidant uric acid are associated with lower risk of hospitalization with depression and use of prescription antidepressant medication. METHOD: We examined plasma levels of the antioxidant uric acid in 96 989 individuals from two independent cohort studies. Logistic regression and Cox proportional hazards regression models were multivariable adjusted for age, gender, alcohol, smoking, income, body mass index, C-reactive protein, hemoglobin, triglycerides, cardiovascular disease, diabetes, and intake of meat and vegetables. Results were performed separately in each study and combined in a meta-analysis. RESULTS: In both studies, high uric acid was associated with lower risk of hospitalization as in-patient or out-patient with depression and antidepressant medication use. A doubling in uric acid was associated with an effect estimate of 0.57 (95% CI 0.49-0.65) and 0.77 (0.73-0.81) for hospitalization with depression and antidepressant medication use. The association was consistent across strata of all covariates. Results were attenuated in Cox regression analyses with less statistical power. CONCLUSION: High plasma levels of uric acid were associated with low risk of depression hospitalization and antidepressant medication use.

Asthma, other atopic conditions and risk of infections in 105 519 general population never and ever smokers.

BACKGROUND: Individuals with atopic conditions may have increased susceptibility to infections outside the organs directly affected by their atopic condition. OBJECTIVE: We tested the hypothesis that atopic conditions overall, and stratified by smoking history, are associated with increased risk of hospitalization for infections. METHODS: We collected information on smoking history and self-reported atopic conditions from 105 519 individuals from the general population and followed them for up to 23 years for infectious disease hospitalizations and deaths. For asthma, we focused on never smokers with asthma diagnosed before age 50 (early asthma) to minimize confounding by chronic obstructive pulmonary disease. RESULTS: During follow-up, 11 160 individuals had infections. Never smokers with early asthma versus no atopic conditions had significantly increased risks of any infection (hazard ratio 1.65; 95% confidence interval 1.40-1.94), pneumonia (2.44; 1.92-3.11) and any non-respiratory tract infection (1.36; 1.11-1.67); results were similar in ever smokers. Never smokers with any asthma had significantly increased risks of any infection (1.44; 1.24-1.66) and pneumonia (1.99; 1.62-2.44). Neither atopic dermatitis (1.00; 0.91-1.10) nor hay fever (1.00; 0.93-1.07) was associated with risk of any infection. In never smokers, risk estimates for any infection were comparable between asthma and diabetes, as were the population attributable fractions of 2.2% for any asthma and 2.9% for diabetes. CONCLUSION: Early asthma was associated with significantly increased risks of any infection, pneumonia and any non-respiratory tract infection in never and ever smokers. In never smokers, risk estimates as well as population attributable fractions for any infection were comparable between asthma and diabetes, suggesting that asthma may be a substantial risk factor for infections in the general population.

Filaggrin loss-of-function mutations as risk factors for ischemic stroke in the general population.

Essentials FLG mutations cause atopic dermatitis, previously found to be associated with ischemic stroke. Association between FLG mutations and ischemic stroke was examined in 97 174 Danish individuals. FLG mutations were associated with increased ischemic stroke risk in the general population. The association was most pronounced in younger individuals, and in current and former smokers. SUMMARY: Background Heritability studies have shown a considerable genetic component to ischemic stroke risk; however, much is unknown as to which genes are responsible. Also, previous studies have found an association between atopic dermatitis and increased ischemic stroke risk. Objective To test the hypothesis that FLG loss-of-function mutations, known to be associated with atopic dermatitis, were also associated with ischemic stroke. Methods A total of 97 174 individuals, with 3597 cases of ischemic stroke, from the Copenhagen General Population Study, the Copenhagen City Heart Study and the Copenhagen Carotid Stroke Study were genotyped for the two most common filaggrin mutations, FLG R501X and FLG 2282del4. Results FLG mutation carriers had an odds ratio for ischemic stroke of 1.15 (95% confidence interval [CI], 1.02-1.30) compared with non-carriers. Risk of ischemic stroke for FLG mutation carriers was higher among individuals aged < 50 years, with an odds ratio of 1.72 (1.11-2.67), compared with non-carriers. When stratified for smoking, ischemic stroke risk was primarily seen in current and former smokers, with an odds ratio of 1.25 (1.08-1.44). FLG mutations were not associated with conventional cardiovascular risk factors except for slightly more pack-years smoked among mutation carriers, but were associated with increased risk of self-reported eczema, with an odds ratio of 1.42 (1.32-1.52). Finally, self-reported eczema was associated with increased ischemic stroke risk, with an age and sex adjusted hazard ratio of 1.24 (1.01-1.52); however, the association was not statistically significant after multifactorial adjustment. Conclusion In this study of 97 174 individuals from the Danish general population, FLG loss-of-function mutations were associated with increased ischemic stroke risk; however, residual confounding is a possibility.

Common breast cancer risk alleles and risk assessment: a study on 35 441 individuals from the Danish general population.

Background: We hypothesized that common breast cancer risk alleles are associated with incidences of breast cancer and other cancers in the general population, and identify low risk women among those invited for screening mammography. Participants and Methods: About 35 441 individuals from the Danish general population were followed in Danish health registries for up to 21 years after blood sampling. After genotyping 72 breast cancer risk loci, each with 0­2 alleles, the sum for each individual was calculated. We used the simple allele sum instead of the conventional polygenic risk score, as it is likely more sensitive in detecting associations with risks of other endpoints than breast cancer. Results: Breast cancer incidence in the 19 010 women was increased across allele sum quintiles (log-rank trend test; P = 1×10 − 12), but not incidence of other cancers (P = 0.41). Age- and study-adjusted hazard ratio for the fifth versus the first allele sum quintile was 1.82 (95% confidence interval; 1.53­2.18). Corresponding hazard ratios per allele were 1.04 (1.03­1.05) and 1.05 (1.02­1.08) for breast cancer incidence and mortality, similar across risk factors. In 50-year-old women, the starting age for screening mammography in Denmark, the average 5-year breast cancer risk was 1.5%, overall and 1.1%, 1.4%, 1.6%, 1.7%, 2.1%, for the first through fifth quintile, respectively. Based on age, nulliparity, familial history, and allele sum, 25% of women aged 50­69 years, and 94% of women aged 40­49 years, had absolute 5-year breast cancer risks ≤ 1.5%. Using polygenic risk score led to similar results. Conclusion: Common breast cancer risk alleles are associated with incidence and mortality of breast cancer in the general population, but not with other cancers. After including breast cancer allele sum in risk assessment, 25% of women currently being offered screening mammography had an absolute 5-year risk below the cutoff of average risk for a 50-year-old woman.

IgE and risk of cancer in 37 747 individuals from the general population.

BACKGROUND: Immunoglobulin E (IgE) is produced by plasma cells, often as part of an allergic immune response. It is currently unknown whether plasma IgE levels are associated with risk of cancer in individuals from the general population. We tested the hypothesis that high levels of plasma total IgE are associated with overall risk of cancer and with risk of specific cancers. MATERIALS AND METHODS: Plasma total IgE was measured in 37 747 individuals from the general population, and the participants were followed prospectively for up to 30 years. All statistical tests were two-sided. RESULTS: During a mean follow-up of 7 years, a first cancer was diagnosed in 3454 participants. The multivariable adjusted hazard ratio for a 10-fold higher level of IgE was 1.05 [95% confidence interval (CI) 1.00-1.11; P = 0.04] for any cancer, 0.44 (0.30-0.64; P = 0.00002) for chronic lymphocytic leukemia (CLL), 0.53 (0.33-0.84; P = 0.007) for multiple myeloma, 1.54 (1.04-2.29; P = 0.03) for other non-Hodgkin lymphoma, 1.38 (1.04-1.84; P = 0.03) for cancer of the oral cavity and pharynx, and 1.12 (1.00-1.25; P = 0.05) for lung cancer. The findings for CLL and multiple myeloma were generally robust; however, after correcting for 27 multiple comparisons only the finding for CLL remained significant. CONCLUSION: High levels of plasma total IgE were associated with low risk of CLL and possibly of multiple myeloma, without convincing evidence for high risk of any cancer type.

Plasma testosterone in the general population, cancer prognosis and cancer risk: a prospective cohort study.

BACKGROUND: Testosterone is an important anabolic hormone in humans and in vitro testosterone stimulates growth of lung and colon cancer cells. We tested the hypothesis that plasma testosterone associate with increased risk of cancer and with increased risk of early death after cancer. MATERIALS AND METHODS: Plasma testosterone was measured in 8771 20- to 94-year-old men and women who participated in a prospective study of the general population. Participants were included in 1981-1983 and followed for a median of 22 years (range: 0-30 years). RESULTS: During follow-up, 1140 men and 809 women developed cancer. For risk of early death after cancer, for men, after adjustment for age at diagnosis, tumour stage at diagnosis, and time since blood-sampling, the hazard ratio was 1.30 [95% confidence interval (CI) 1.03-1.65] for the 2nd quintile, 1.31 (1.02-1.67) for the 3rd quintile, 1.52 (1.19-1.93) for the 4th quintile, and 1.52 (1.20-1.91) for the 5th quintile, versus the 1st quintile. For women, corresponding hazard ratios were 1.09 (0.81-1.46), 1.17 (0.86-1.59), 1.03 (0.76-1.39), and 1.80 (1.32-2.46). For risk of cancer, multifactorially adjusted hazard ratios for risk of any cancer were 1.07 (95% CI 0.98-1.18) and 1.06 (0.93-1.22) for men and women, respectively, when testosterone doubled. For both men and women, a doubling of testosterone was not associated with risk of any cancer type. CONCLUSIONS: In this prospective study of 8771 men and women from the general population followed for >30 years, increased levels of testosterone were associated with a 30%-80% increased risk of early death after cancer, but unchanged risk of incident cancer.

Endogenous sex hormones and risk of venous thromboembolism in women and men.

BACKGROUND: Use of oral contraceptives with estrogen and hormone replacement therapy with estrogen or testosterone are associated with increased risk of venous thromboembolism (VTE). However, whether endogenous estradiol and testosterone concentrations are also associated with risk of VTE is unknown. OBJECTIVE: We tested the hypothesis that elevated endogenous total estradiol and total testosterone concentrations are associated with increased risk of VTE in the general population. METHODS: We studied 4658 women, not receiving exogenous estrogen, and 4673 men from the 1981-1983 Copenhagen City Heart Study, who had estradiol and testosterone concentrations measured. Of these, 636 developed VTE (deep venous thrombosis [DVT] and/or pulmonary embolism [PE]) during a follow-up of 21 years (range, 0.02-32 years). Associations between endogenous estradiol and testosterone concentrations and risk of VTE were estimated by Cox proportional hazards regression with time-dependent covariates and corrected for regression dilution bias. RESULTS: Multifactorially adjusted hazard ratios of VTE for individuals with estradiol levels >75th vs. ≤25th percentile were 0.84 (95%CI, 0.25-2.85), 1.05 (0.53-2.08) and 1.05 (0.03-35.13) for pre- and post-menopausal women and men, respectively. For testosterone, corresponding risk estimates were 0.64 (0.03-12.32), 1.11 (0.66-1.86) and 1.30 (0.62-2.73). In addition, no associations were observed between extreme hormone percentiles (>95th vs. ≤75th) and risk of DVT, PE or recurrent VTE. CONCLUSION: This prospective study suggests that high endogenous concentrations of estradiol and testosterone in women and men in the general population are not associated with increased risk of VTE, DVT or PE.

25-Hydroxyvitamin D concentrations and risk of venous thromboembolism in the general population with 18,791 participants.

BACKGROUND: 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. OBJECTIVES: To test the hypothesis that reduced plasma 25-hydroxyvitamin D concentrations are associated with an increased risk of venous thromboembolism in the general population. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Risk of cancer by transferrin saturation levels and haemochromatosis genotype: population-based study and meta-analysis.

OBJECTIVE: Increased iron overload, whether or not owing to the presence of the haemochromatosis genotype C282Y/C282Y, may be associated with an increased risk of cancer. The aim of this study was to test the hypothesis that elevated transferrin saturation levels (as a proxy for iron overload) and haemochromatosis genotype C282Y/C282Y are associated with an increased risk of cancer. METHODS: We conducted a population-based study of 8763 individuals, of whom 1417 developed a first cancer during 15years of follow-up, and a meta-analysis. We stratified absolute 10-year risk of cancer by smoking status, an important risk factor. RESULTS: In women, transferrin saturation above 60% versus below 50% was associated with a hazard ratio of 3.6 (95% confidence interval (CI): 2.0-6.5; P<0.001) for any cancer; risk of liver cancer was increased in both women and men. In women, the corresponding absolute 10-year risk of any cancer was 34% and 30% in smokers and nonsmokers, respectively. In men, haemochromatosis genotype C282Y/C282Y versus wild type/wild type was associated with a hazard ratio of 3.7 (95% CI: 1.2-12; P=0.01) for any cancer, with a similar trend in women. In men, the corresponding absolute 10-year risk of cancer was 39% and 27% in smokers and nonsmokers, respectively. Other haemochromatosis genotypes were not associated with increased risk of cancer in women or men. From the meta-analysis, the odds ratio of any cancer for transferrin saturation ≥60% versus a reference group was 1.5 (95% CI: 1.2-1.8) for women and men combined. CONCLUSIONS: We have demonstrated that elevated transferrin saturation levels in women and haemochromatosis genotype C282Y/C282Y in men are associated with increased risk of cancer. Thus, our results support the implementation of cancer screening programmes in patients with iron overload or with C282Y/C282Y.

Cancer risk by combined levels of YKL-40 and C-reactive protein in the general population.

BACKGROUND: YKL-40 and C-reactive protein (CRP) are biomarkers that may reflect cancer-related subclinical inflammation. We assessed elevated YKL-40 and CRP levels as combined risk predictors for cancer. METHODS: We measured plasma YKL-40 and CRP at baseline in 8706 individuals from the Danish general population. RESULTS: Hazard ratio (HR) of gastrointestinal cancer for a doubling of YKL-40 levels was 1.37 (95% CI: 1.17-1.61) and indifferent to adjustment for CRP levels. Hazard ratio of lung cancer for a doubling of CRP levels was 1.35 (1.17-1.56) and indifferent to adjustment for YKL-40 levels. Compared to individuals with both low CRP (<1.7 mg l(-1)) and YKL-40 (<154 µg l(-1)), individuals with high YKL-40 but low CRP had an HR of gastrointestinal cancer of 3.36 (1.70-6.64), whereas individuals with high CRP but low YKL-40 had an HR of lung cancer of 2.19 (1.24-3.87). The area under the receiver operating characteristic (ROC) curve was 0.68 for the ability of YKL-40 to predict gastrointestinal cancer and 0.67 for the ability of CRP to predict lung cancer. CONCLUSION: Elevated YKL-40 levels are associated with increased risk of gastrointestinal cancer, independently of CRP levels, whereas elevated CRP levels are associated with increased risk of lung cancer, independently of YKL-40 levels.

Mutation in APOA1 predicts increased risk of ischaemic heart disease and total mortality without low HDL cholesterol levels.

OBJECTIVES: To determine whether mutations in APOA1 affect levels of high-density lipoprotein (HDL) cholesterol and to predict risk of ischaemic heart disease (IHD) and total mortality in the general population. BACKGROUND: Epidemiologically, risk of IHD is inversely related to HDL cholesterol levels. Mutations in apolipoprotein (apo) A-I, the major protein constituent of HDL, might be associated with low HDL cholesterol and predispose to IHD and early death. DESIGN: We resequenced APOA1 in 190 individuals and examined the effect of mutations on HDL cholesterol, risk of IHD, myocardial infarction (MI) and mortality in 10 440 individuals in the prospective Copenhagen City Heart Study followed for 31 years. Results were validated in an independent case-control study (n = 16 035). Additionally, we determined plasma ratios of mutant to wildtype (WT) apoA-I in human heterozygotes and functional effects of mutations in adenovirus-transfected mice. RESULTS: We identified a new mutation, A164S (1 : 500 in the general population), which predicted hazard ratios for IHD, MI and total mortality of 3.2 [95% confidence interval (CI): 1.6-6.5], 5.5 (95% CI: 2.6-11.7) and 2.5 (95% CI: 1.3-4.8), respectively, in heterozygotes compared with noncarriers. Mean reduction in survival time in heterozygotes was 10 years (P < 0.0001). Results for IHD and MI were confirmed in the case-control study. Furthermore, the ratio of mutant S164 to WT A164 apoA-I in plasma of heterozygotes was reduced. In addition, A164S heterozygotes had normal plasma lipid and lipoprotein levels, including HDL cholesterol and apoA-I, and this finding was confirmed in adenovirus-transfected mice. CONCLUSIONS: A164S is the first mutation in APOA1 to be described that predicts an increased risk of IHD, MI and total mortality without low HDL cholesterol levels.

Copy number variation in glutathione-S-transferase T1 and M1 predicts incidence and 5-year survival from prostate and bladder cancer, and incidence of corpus uteri cancer in the general population.

Glutathione-S-transferase T1 (GSTT1) and GSTM1 detoxify carcinogens and thus potentially contribute to inter-individual susceptibility to cancer. We determined the ability of GST copy number variation (CNV) to predict the risk of cancer in the general population. Exact copy numbers of GSTT1 and GSTM1 were measured by real-time PCR in 10 247 individuals, of whom 2090 had cancer. In men, the cumulative incidence of prostate cancer increased and the cumulative 5-year survival decreased with decreasing GSTT1 copy numbers (trends=0.02). The hazard ratios (HRs) (95% CIs) for prostate cancer and for death after prostate cancer diagnosis were, respectively, 1.2 (0.8-1.8) and 1.2 (0.6-2.1) for GSTT1*1/0, and 1.8 (1.1-3.0) and 2.2 (1.1-4.4) for GSTT1*0/0 versus GSTT1*1/1. In women, the cumulative incidence of corpus uteri cancer increased with decreasing GSTT1 copy numbers (trend=0.04). The HRs for corpus uteri cancer were, respectively, 1.8 (1.0-3.2) and 2.2 (1.0-4.6) for GSTT1*1/0 and GSTT1*0/0 versus GSTT1*1/1. Finally, the cumulative incidence of bladder cancer increased, and the cumulative 5-year survival decreased, with decreasing GSTM1 copy numbers (P=0.03-0.05). The HRs for bladder cancer were, respectively, 1.5 (0.7-3.2) and 2.0 (0.9-4.3) for GSTM1*1/0 and GSTM1*0/0 versus GSTM1*1/1. The HR for death after bladder cancer diagnosis was 1.9 (1.0-3.7) for GSTM1*0/0 versus GSTM1*1/0. In conclusion, exact CNV in GSTT1 and GSTM1 predict incidence and 5-year survival from prostate and bladder cancer, and incidence of corpus uteri cancer.

EPHX1 polymorphisms, COPD and asthma in 47,000 individuals and in meta-analysis.

We tested the hypothesis that two well-characterised functional polymorphisms of the microsomal epoxide hydrolase gene (EPHX1), T113C and A139G, may influence susceptibility to chronic obstructive pulmonary disease (COPD) and asthma. We genotyped participants from the Copenhagen City Heart Study (n = 10,038) and the Copenhagen General Population Study (n = 37,022) for the T113C and A139G variants in the EPHX1 gene and measured lung function and recorded COPD hospitalisation and asthma and smoking history. Finally, we meta-analysed results from 19 studies including 7,489 COPD cases and 42,970 controls. The OR for spirometry-defined COPD or COPD hospitalisation did not differ from 1.0 for any of the EPHX1 genotypes or phenotypes overall, or in smokers or nonsmokers separately (p-value for trend 0.18-0.91). Likewise, EPHX1 genotypes or phenotypes did not associate with risk of asthma (p-value for trend 0.46-0.98). In meta-analysis, random effects OR for COPD in T113C heterozygotes and homozygotes versus non-carriers were 1.17 (0.99-1.38) and 1.38 (1.09-1.74), respectively. Corresponding values for A139G were 0.93 (0.83-1.05) and 0.89 (0.78-1.02). Our results indicate that genetically reduced microsomal epoxide hydrolase activity is not a major risk factor for COPD or asthma in the Danish population; however, meta-analysis cannot completely exclude a minor effect on COPD risk.

Surfactant protein B polymorphisms, pulmonary function and COPD in 10,231 individuals.

The surfactant protein (SP)-B gene may influence chronic obstructive pulmonary disease (COPD) and, thus, personalised medicine. We tested whether functional polymorphisms in SP-B (rs1130866 (1580T>C), rs2077079 (-18A>C) and rs3024791 (-384G>A)) associate with reduced lung function and risk of COPD in the general population. We genotyped 10,231 individuals from the general adult Danish population, and recorded spirometry and hospital admissions due to COPD. Because we previously found an association between the rare SP-B 121ins2 mutation and COPD among smokers, we stratified the analyses for smoking status. None of the individual SP-B genotypes or genotype combinations were associated with reduced forced expiratory volume in 1 s (FEV1) % predicted, forced vital capacity (FVC) % pred and FEV1/FVC overall or among smokers (p = 0.25-0.99). The odds ratio for spirometrically defined COPD did not differ from 1.0 for any of the SP-B genotypes or genotype combinations overall or among smokers (p = 0.17-0.78). Similar results were obtained for hospitalisation due to COPD (p = 0.07-0.93); we could exclude overall hazard ratios for heterozygotes of 1.18-1.21 and for homozygotes of 1.25-1.57 or larger for all three polymorphisms. In conclusion, the functional rs1130866, rs2077079 and rs3024791 polymorphisms in the SP-B gene are not associated with reduced lung function or risk of COPD, making it unlikely that these variants will be useful in personalised medicine.

Novel mutations in leukotriene C4 synthase and risk of cardiovascular disease based on genotypes from 50,000 individuals.

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.