Co-regulatory networks of human serum proteins link genetics to disease.

Proteins circulating in the blood are critical for age-related disease processes; however, the serum proteome has remained largely unexplored. To this end, 4137 proteins covering most predicted extracellular proteins were measured in the serum of 5457 Icelanders over 65 years of age. Pairwise correlation between proteins as they varied across individuals revealed 27 different network modules of serum proteins, many of which were associated with cardiovascular and metabolic disease states, as well as overall survival. The protein modules were controlled by cis- and trans-acting genetic variants, which in many cases were also associated with complex disease. This revealed co-regulated groups of circulating proteins that incorporated regulatory control between tissues and demonstrated close relationships to past, current, and future disease states.

[Heart failure among elderly Icelanders: Incidence, prevalence, underlying diseases and long-term survival].

INTRODUCTION: Heart failure (HF) is a common and a serious condition that predominantly affects elderly people. On the basis of the left ventricular ejection fraction (EF) it can be divided into HF with reduced or preserved ejection fraction (HFrEF and HFpEF, respectively). The goal of this study was to investigate the prevalence and incidence of HF among elderly Icelanders, explore underlying diseases and estimate the effect of HF on overall survival. MATERIAL AND METHODS: Included were 5706 participants of the AGES study. The hospital records of those diagnosed with HF before entry into AGES were used to calculate prevalence and the records of those diagnosed from entry into AGES until 28.2.2010 were used to calculate incidence. All cases of HF were verified according to predetermined criteria for diagnosis. Information on underlying diseases and EF of HF patients were obtained from hospital records. Survival was estimated using Kaplan-Meier survival curves. RESULTS: Lifetime prevalence of HF was 3.6% as of 2004, higher among men than women (p<0,001). The incidence was 16.2 cases per 1000 person-years, higher among men than among women (p<0,001). The incidence of HFrEF was 6.1 per 1000 person-years also higher among men than women (p<0,001). The incidence of HFpEF was 6.8 per 1000 person-years and there was no statistical difference between the sexes (p=0.62). The age adjusted 5-year survival rate of HF-patients was 32.5%, there was no statistical difference in relative survival between men and women (p=0.46). There was no statistical difference between the survival of patients with HFrEF and those with HFpEF (p=0.52). CONCLUSION: Both prevalence and incidence of HF are high among elderly Icelanders, increasing sharply with age and 5-year survival rate is only around 30%. While men are more likely to develop HF, especially HFrEF, women are more likely to be diagnosed with HFpEF.

Prevalence of heart failure in the elderly and future projections: the AGES-Reykjavík study.

OBJECTIVES: To assess the prevalence of heart failure (HF) in a randomly selected study population of elderly individuals representing the general population of Iceland. Furthermore, to project the number of individuals likely to have HF in the future. DESIGN: Baseline characteristics and clinical data from 5706 individuals who participated in the population based AGES-Reykjavik Study and gave their informed consent were used. Their age range was 66-98 years (mean age 77.0 ± 5.9 years), 57.6% were females. HF-diagnoses were established by review of hospital records and adjudicated according to prespecified criteria. Data from the 'Statistics Iceland' institution on the current size, age and sex distribution of the population and its prediction into the sixth decade were also used. RESULTS: The prevalence of HF was 3.6% in the sexes combined, but higher in men (5.1%) than women (2.7%) (p < .001). The prevalence of HF per age groups ≤69, 70-74, 75-79, 80-84 and ≥85 years was 1.7%, 1.5%, 3.7%, 5.2% and 7.2%, respectively. The number of individuals ≥70 years with HF will increase considerably in the future. Thus, a calculation based on the projected age distribution and increase in the number of elderly ≥70 years in the coming decades, demonstrated that the number of patients with HF will have increased 2.3-fold by the year 2040 and tripled by the year 2060. CONCLUSIONS: This study, in a cohort of elderly participants representative of the general population in a Nordic country, predicts that HF will be a major and increasing health problem in the coming decades.

Airflow obstruction, atherosclerosis and cardiovascular risk factors in the AGES Reykjavik study.

BACKGROUND AND AIMS: Airflow limitation, i.e. reduced forced expiratory volume in 1-s (FEV1), is associated with increased prevalence of atherosclerosis, however, causal mechanisms remain elusive. The objective of the study was to determine if the association between airflow obstruction and markers of atherosclerosis is mediated by systemic inflammation. METHODS: 1154 subjects from the longitudinal AGES Reykjavik study were included. Population characteristics, systemic inflammation markers from blood (white blood cell counts (WBC) and level of C-reactive protein (CRP)) were compared between patients with and without airflow limitation defined by reduced FEV1 on spirometry. Atherosclerosis burden was quantified by measurements of coronary artery calcium, aortic arch and distal aortic calcification in addition to carotid intimal media thickness (CIMT). RESULTS: Subjects were split into four groups according to smoking status and whether airflow limitation was present. There was a higher overall burden of atherosclerosis in ever-smokers compared to never-smokers, and in individuals with airflow obstruction compared to individuals without airflow obstruction. After adjusting for population characteristics, Framingham cardiovascular risk factors and markers of systemic inflammation (WBC and CRP), there was a significantly increased aortic arch and distal aorta calcification and higher CIMT measurement in individuals with airflow obstruction compared to individuals without airflow obstruction. After adjusting for population characteristics, Framingham cardiovascular risk factors and markers of systemic inflammation (WBC and CRP), there was a significantly increased aortic arch and distal aorta calcification and higher CIMT measurement in individuals with airflow obstruction compared to individuals without airflow obstruction. CONCLUSIONS: Systemic inflammation (WBC and CRP) does not appear to mediate the association between airflow limitation and atherosclerosis. Only airflow limitation and not systemic inflammation (WBC and CRP) appears to be an independent predictor of atherosclerosis.

Oral contraceptives, hormone replacement therapy and breast cancer risk: a cohort study of 16 928 women 48 years and older.

BACKGROUND: Findings on potential interactive effects of oral contraceptives (OCs) and hormone replacement therapy (HRT) on breast cancer risk have been inconsistent. We aimed to use population-based cohort data to determine whether former use of OCs affects breast cancer risk among HRT users, taking into account regimens of HRT, duration and currency of use. METHODS: The cohort consisted of 16 928 Icelandic women who visited the Icelandic Cancer Detection Clinic in 1979-2006 and provided information on use of OCs and HRT when they were 48 years or older. By record linkage to the Icelandic Cancer Registry, all breast cancer diagnosed during follow-up was identified. Using Cox regression, hazard ratios (HRs) for breast cancer according to hormone use were estimated, adjusting for menstrual and reproductive risk factors. Also, interaction analyses were carried out. RESULTS: Breast cancer risk was significantly increased among ever users of combined estrogen and progestin (EP-HRT) preparations (HR=2.61; 95% CI 2.00-3.41) and not among users of estrogen-only regimens (E-only HRT) (HR=1.13; 95% CI 0.85-1.49). Ever users of both OCs and HRT had higher breast cancer risk than users of only one of the two (HR=2.19; 95% CI 1.67-2.87). After restricting the analysis to EP-HRT and focusing on long-term and current use, there was an indication of a negative interaction with ever OC use (p=0.06); HR=2.87; 95% CI 1.79-4.60 for never OC users and HR=2.24; 95% CI 1.51-3.34 for former OC users. CONCLUSION: After taking HRT regimen, duration and currency of use into account, the results of our population-based cohort study do not support the notion that former OC use increases breast cancer risk among HRT users, on the contrary there was an indication of a slightly lower risk in former OC users, restricted to current, long-term EP-HRT users.

Association of air pollution and use of glyceryl trinitrate against angina pectoris: a population-based case-crossover study.

BACKGROUND: Ambient air pollution has been associated with increased cardiovascular morbidity and mortality. In Reykjavik, Iceland, air pollutant concentrations exceed official health limits several times every year. The aim was to study the association of concentrations of NO2, O3, PM10, and H2S in the Reykjavik capital area with the dispensing of anti-angina pectoris medication, glyceryl trinitrate to the inhabitants. METHODS: Data on daily dispensing of glyceryl trinitrate, were retrieved from the Icelandic Medicines Registry. Data on hourly concentrations of NO2, O3, PM10, and H2S were obtained from the Environment Agency of Iceland. A case-crossover design was used, based on the dispensing of glyceryl trinitrate to 5,246 individuals (≥18 years) between 2005 and 2009. RESULTS: For every 10 µg/m3 increase of NO2 and O3 3-day mean concentrations, the odds ratio (OR) for daily dispensing of glyceryl trinitrates was 1.136 (95% confidence intervals (CI) 1.069-1.207) and 1.094 (95% CI 1.029-1.163) at lag 0, and OR was 1.096 (95% CI 1.029-1.168) and 1.094 (95% CI 1.028-1.166) at lag 1, respectively. CONCLUSIONS: These findings suggest that NO2 and O3 ambient air concentrations may adversely affect cardiovascular health, as measured by the dispensing of glyceryl trinitrates for angina pectoris. Further, the findings suggest that data on the dispensing of medication may be a valuable health indicator when studying the effect of air pollution on cardiovascular morbidity.

Consumption of fish products across the lifespan and prostate cancer risk.

OBJECTIVE: To examine whether fish and fish oil consumption across the lifespan is associated with a lower risk of prostate cancer. DESIGN: The study was nested among 2268 men aged 67-96 years in the AGES-Reykjavik cohort study. In 2002 to 2006, dietary habits were assessed, for early life, midlife and later life using a validated food frequency questionnaire. Participants were followed for prostate cancer diagnosis and mortality through 2009 via linkage to nationwide cancer- and mortality registers. Adjusting for potential confounders, we used regression models to estimate odds ratios (ORs) and hazard ratios (HRs) for prostate cancer according to fish and fish oil consumption. RESULTS: Among the 2268 men, we ascertained 214 prevalent and 133 incident prostate cancer cases, of which 63 had advanced disease. High fish consumption in early- and midlife was not associated with overall or advanced prostate cancer. High intake of salted or smoked fish was associated with a 2-fold increased risk of advanced prostate cancer both in early life (95% CI: 1.08, 3.62) and in later life (95% CI: 1.04, 5.00). Men consuming fish oil in later life had a lower risk of advanced prostate cancer [HR (95%CI): 0.43 (0.19, 0.95)], no association was found for early life or midlife consumption. CONCLUSIONS: Salted or smoked fish may increase risk of advanced prostate cancer, whereas fish oil consumption may be protective against progression of prostate cancer in elderly men. In a setting with very high fish consumption, no association was found between overall fish consumption in early or midlife and prostate cancer risk.

Increased stress among women following an economic collapse--a prospective cohort study.

There is a scarcity of data on mental health effects of the global economic recession. In this study, we investigated potential change in self-reported levels of psychological stress in the Icelandic population as a result of the major national economic collapse that occurred in 2008. We used a national cohort of 3,755 persons who responded to a survey administered in 2007 and 2009, including demographic questions and a stress measure (the 4-item Perceived Stress Scale). We used repeated-measures analysis of variance and logistic regression models to assess change in mean stress levels and risk of high stress levels (>90th percentile) in 2009 as compared with 2007. Age-adjusted mean stress levels increased between 2007 and 2009 (P = 0.004), though the increase was observed only for women (P = 0.003), not for men (P = 0.34). Similarly, the odds ratios for experiencing high stress levels were increased only among women (odds ratio (OR) = 1.37), especially among women who were unemployed (OR = 3.38), students (OR = 2.01), had middle levels of education (OR = 1.65), or were in the middle income bracket (OR = 1.59). The findings indicate that psychological stress may have increased following the economic collapse in Iceland, particularly among females in economically vulnerable groups.

A population-based study of stimulant drug treatment of ADHD and academic progress in children.

OBJECTIVE: We evaluated the hypothesis that later start of stimulant treatment of attention-deficit/hyperactivity disorder adversely affects academic progress in mathematics and language arts among 9- to 12-year-old children. METHODS: We linked nationwide data from the Icelandic Medicines Registry and the Database of National Scholastic Examinations. The study population comprised 11,872 children born in 1994-1996 who took standardized tests in both fourth and seventh grade. We estimated the probability of academic decline (drop of ≥ 5.0 percentile points) according to drug exposure and timing of treatment start between examinations. To limit confounding by indication, we concentrated on children who started treatment either early or later, but at some point between fourth-grade and seventh-grade standardized tests. RESULTS: In contrast with nonmedicated children, children starting stimulant treatment between their fourth- and seventh-grade tests were more likely to decline in test performance. The crude probability of academic decline was 72.9% in mathematics and 42.9% in language arts for children with a treatment start 25 to 36 months after the fourth-grade test. Compared with those starting treatment earlier (≤ 12 months after tests), the multivariable adjusted risk ratio (RR) for decline was 1.7 (95% confidence interval [CI]: 1.2-2.4) in mathematics and 1.1 (95% CI: 0.7-1.8) in language arts. The adjusted RR of mathematics decline with later treatment was higher among girls (RR, 2.7; 95% CI: 1.2-6.0) than boys (RR, 1.4; 95% CI: 0.9-2.0). CONCLUSIONS: Later start of stimulant drug treatment of attention-deficit/hyperactivity disorder is associated with academic decline in mathematics.

Rye bread consumption in early life and reduced risk of advanced prostate cancer.

OBJECTIVE: To determine whether consumption of whole-grain rye bread, oatmeal, and whole-wheat bread, during different periods of life, is associated with risk of prostate cancer (PCa). METHODS: From 2002 to 2006, 2,268 men, aged 67-96 years, reported their dietary habits in the AGES-Reykjavik cohort study. Dietary habits were assessed for early life, midlife, and current life using a validated food frequency questionnaire. Through linkage to cancer and mortality registers, we retrieved information on PCa diagnosis and mortality through 2009. We used regression models to estimate odds ratios (ORs) and hazard ratios (HRs) for PCa according to whole-grain consumption, adjusted for possible confounding factors including fish, fish liver oil, meat, and milk intake. RESULTS: Of the 2,268 men, 347 had or were diagnosed with PCa during follow-up, 63 with advanced disease (stage 3+ or died of PCa). Daily rye bread consumption in adolescence (vs. less than daily) was associated with a decreased risk of PCa diagnosis (OR = 0.76, 95 % confidence interval (CI): 0.59-0.98) and of advanced PCa (OR = 0.47, 95 % CI: 0.27-0.84). High intake of oatmeal in adolescence (≥5 vs. ≤4 times/week) was not significantly associated with risk of PCa diagnosis (OR = 0.99, 95 % CI: 0.77-1.27) nor advanced PCa (OR = 0.67, 95 % CI: 0.37-1.20). Midlife and late life consumption of rye bread, oatmeal, or whole-wheat bread was not associated with PCa risk. CONCLUSION: Our results suggest that rye bread consumption in adolescence may be associated with reduced risk of PCa, particularly advanced disease.

Immediate surge in female visits to the cardiac emergency department following the economic collapse in Iceland: an observational study.

OBJECTIVE: To study potential changes in attendance at emergency departments (ED) in Reykjavík immediately following the swift economic meltdown in Iceland in October 2008. METHODS: Using electronic medical records of the National University Hospital in Reykjavík, a population-based register study was conducted contrasting weekly attendance rates at Reykjavík ED (cardiac and general ED) during 10-week periods in 2006, 2007 and 2008. The weekly number of all ED visits (major track), with discharge diagnoses, per total population at risk were used to estimate RR and 95% CI of ED attendance in weeks 41-46 (after the 2008 economic collapse) with the weekly average number of visits during weeks 37-40 (before the collapse) as reference. RESULTS: Compared with the preceding weeks (37-40), the economic collapse in week 41 2008 was associated with a distinct increase in the total number of visits to the cardiac ED (RR 1.26; 95% CI 1.07 to 1.49), particularly among women (RR 1.41; 95% CI 1.17 to 1.69) and marginally among men (RR 1.15; 95% CI 0.96 to 1.37). A similar increase was not observed in week 41 at the general ED in 2008 or in either ED in 2007 or 2006. In week 41 2008, visits with ischaemic heart disease as discharge diagnoses (ICD-10: I20-25) were increased among women (RR 1.79; 95% CI 1.01 to 3.17) but not among men (RR 1.07; 95% CI 0.71 to 1.62). CONCLUSION: The dramatic economic collapse in Iceland in October 2008 was associated with an immediate short-term increase in female attendance at the cardiac ED.

Milk intake in early life and risk of advanced prostate cancer.

The authors investigated whether early-life residency in certain areas of Iceland marked by distinct differences in milk intake was associated with risk of prostate cancer in a population-based cohort of 8,894 men born between 1907 and 1935. Through linkage to cancer and mortality registers, the men were followed for prostate cancer diagnosis and mortality from study entry (in waves from 1967 to 1987) through 2009. In 2002-2006, a subgroup of 2,268 participants reported their milk intake in early, mid-, and current life. During a mean follow-up period of 24.3 years, 1,123 men were diagnosed with prostate cancer, including 371 with advanced disease (stage 3 or higher or prostate cancer death). Compared with early-life residency in the capital area, rural residency in the first 20 years of life was marginally associated with increased risk of advanced prostate cancer (hazard ratio = 1.29, 95% confidence interval (CI): 0.97, 1.73), particularly among men born before 1920 (hazard ratio = 1.64, 95% CI: 1.06, 2.56). Daily milk consumption in adolescence (vs. less than daily), but not in midlife or currently, was associated with a 3.2-fold risk of advanced prostate cancer (95% CI: 1.25, 8.28). These data suggest that frequent milk intake in adolescence increases risk of advanced prostate cancer.

Short hospital stay augmented with education and home-based rehabilitation improves function and quality of life after hip replacement: randomized study of 50 patients with 6 months of follow-up.

BACKGROUND: Because of current cost restrictions, we studied the effect of a shorter hospital stay on function, pain and quality of life (QOL) after total hip replacement (THR). PATIENTS AND METHODS: 50 patients from two hospitals were randomized into a study group (SG) of 27 patients receiving preoperative and postoperative education programs, as well as home visits from an outpatient team, and a control group (CG) of 23 patients receiving "conventional" rehabilitation often augmented by a stay at a rehabilitation center. RESULTS: Mean hospital stay was shorter for the SG than for the CG (6.4 days and 10 days, respectively; p < 0.001). During the 6-month study period, there were 9 non-fatal complications in the SG and 12 in the CG (p = 0.3). The difference in Oxford Hip Score between the groups was not statistically significant before the operation, but was better for the SG at 2 months (p = 0.03) and this difference remained more or less constant throughout the study. The overall score from the Nottingham Health Profile indicated a better QOL in the SG. INTERPRETATION: Our preoperative education program, followed by postoperative home-based rehabilitation, appears to be safer and more effective in improving function and QOL after THR than conventional treatment.

[Trends in overweight and obesity in 45-64 year old men and women in Reykjavík 1975-1994. 2001]. / Thróun ofthyngdar og offitu medal 45-64 ára Reykvíkinga á árunum 1975-1994.

OBJECTIVE: The aim of this study was to assess possible changes in the prevalence of overweight and obesity in Iceland during the last decades. Furthermore, the possible effect of dietary changes on the observed trend in obesity prevalence was evaluated. MATERIAL AND METHODS: Participants came from stages III-V in the Reykjavik Health Study and the Reykjavik part of the MONICA studies from the period 1975-1994. The age groups 45-54 years and 55-64 years were examined. Only the information from the first visit of each person was included. The body mass index (BMI) for the participants was calculated and the percentage of those subjects considered overweight and obese according to WHO standards evaluated, using 25= or >BMI<30 kg/m2 as the cut-off point for overweight and BMI= or >30 kg/m2 as the cut-off point for obesity. Also, the observed trend in obesity prevalence is compared to changes in diet that have occurred in the same period. RESULTS: The results show that the mean weight and height of both men and women have been increasing during the study period. However, weight has increased more than can be accounted for by increased height, resulting in increased BMI. At the same time, the prevalence of overweight and obesity have increased, the relative increase in obesity far exceeding the relative increase in overweight. The prevalence of obesity more than doubled in both age groups of women during the study period, according to trend analyses. At the end of the period, almost 15% (95% confidence interval (CI), 9-22%) in the younger group of women and 25% (95% CI, 17-34%) in the older group were classified as obese. In the younger group of men, the prevalence of obesity almost doubled, while the observed increase in the older group was not statistically significant, according to trend analyses. The prevalence of obesity in the final period was about 19% (95% CI, 13-27%) and 17% (95% CI, 11-25%) in the younger and older groups of men, respectively. According to the food supply statistics there have been insignificant changes in the consumption of energy nutrients during the period. CONCLUSIONS: Overweight and obesity are becoming more common among middle-aged men and women in Reykjavik, during the period 1975-1994 and the rate of increase being comparable to that observed in many Western countries. It is urgent to respond to this problem by promoting a healthier lifestyle, both with respect to diet and physical activity.

Cardiovascular death in women who had hypertension in pregnancy: a case-control study.

OBJECTIVE: To determine whether an association exists between hypertension in pregnancy and later development of cardiovascular disease. DESIGN: Case-control study of women who delivered with and without hypertensive complications during the same period. SETTING: University Hospital in Reykjavik, Iceland. POPULATION: Three hundred and twenty-five women with hypertension in pregnancy (blood pressure > or =140/90 mmHg after 20 weeks of gestation) in the years 1931-1947, graded by severity. For each case, two normotensive control women, delivering before or after the case and matched for parity and age were selected, giving a total of 629 women. METHODS: Causes of death were evaluated for the presence of ischaemic heart disease, cerebrovascular events and cancer, up until the end of 1996. MAIN OUTCOME MEASURES: Survival curves, median survival times, risk of death by age group and severity of disease. RESULTS: Death with evidence of ischaemic heart disease was more common in cases (24.3%) than in control women (14.6%) (RR 1.66; 95% CI 1.27-2.17). Cerebrovascular event deaths occurred in 9.5% of cases and in 6.5% of controls (RR 1.46; 95% CI 0.94-2.28). Cancer death rates were not different (RR 1.22; 95% CI 0.91-1.63). Survival times were shorter on average by three to nine years as a consequence of cardiovascular disease. This varied by age group in the index pregnancy for women with a history of hypertension in pregnancy. The effect was smaller if the case pregnancy occurred at a young age. There was a linear trend with increasing severity of hypertensive disease in pregnancy in death rates from ischaemic heart disease (chi(2) (1)= 5.8, P= 0.02). CONCLUSIONS: Long term follow up suggests an increased risk of death from ischaemic heart disease and cerebrovascular events among women who suffered hypertension in pregnancy.

Epidemiology of hairy cell leukemia in Iceland.

INTRODUCTION: Hairy cell leukemia (HCL) is a rare B-cell lymphoproliferative disorder. Previous epidemiological studies have mainly focused on cases derived from single institutions or from localized cancer registries. This is the first study in which all cases diagnosed nationwide over a long period of time in a well defined population are analysed. We report the epidemiology of all HCL patients in Iceland, their clinical characteristics, treatment and follow-up. PATIENTS AND METHODS: : All patients diagnosed with HCL in Iceland over a 20 year period, were included in this study. Data was collected retrospectively. RESULTS: Sixteen patients, 13 males and three females were diagnosed with HCL in Iceland from 1981-2000, giving a mean incidence of 4.7/million/year (95% CI: 2.7-7.6) in the population 20 years and older. Eleven patients were treated with a purine analogue, 10 of whom achieved CR. One other patient obtained CR following splenectomy and IFN, giving a total CR rate of 69%. Three other patients (19%) obtained PR, giving a total response rate of 88%. One patient had a variant of HCL and did not respond to any therapy and one patient died of sepsis before any chemotherapy could be given. Six patients with HCL have died, one from complications of HCL. Three patients developed a second malignancy (19%). CONCLUSIONS: The mean incidence of HCL in Iceland is 4.7/million/year. This is slighty higher than the reported incidence in England and Wales, although not significantly higher. The incidence is based on a nationwide information from a well defined stable and racially homogenous island population. Other results are in accordance with previously published studies.