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Background: Emerging evidence points to potential roles of the humoral immune responses in the development of pancreatic cancer. Epidemiological studies have suggested involvement of viral and bacterial infections in pancreatic carcinogenesis. Experimental studies have reported high expression levels of antigens in pancreatic cancer cells. Therefore, we aimed to investigate the role of different components of humoral immunity in the context of pancreatic cancer. We evaluated associations between pre-diagnostic serum markers of the overall humoral immune system [immunoglobulin A (IgA), immunoglobulin G (IgG) and immunoglobulin M (IgM)], and the risk of pancreatic cancer in the Swedish Apolipoprotein-related MORtality RISk (AMORIS) study. Methods: We selected all participants (≥20 years old) with baseline measurements of IgA, IgG or IgM ( n = 41,900, 136,221, and 29,919, respectively). Participants were excluded if they had a history of chronic pancreatitis and individuals were free from pancreatic cancer at baseline. Multivariate Cox proportional hazards regression was used to estimate risk of pancreatic cancer for medical cut-offs of IgA, IgG, and IgM. Results: Compared to the reference level of 6.10-14.99 g/L, risk of pancreatic cancer was elevated among those with IgG levels <6.10 g/L [HR: 1.69 (95% CI 0.99-2.87)], and an inverse association was observed among those with IgG levels ≥15.00 g/L [0.82 (95% CI 0.64-1.05); P trend = 0.027]. The association appeared to be stronger for women than men [HR: 0.64 (95% CI 0.43-0.97) and 0.95 (95% CI 0.69-1.29), respectively]. No associations were observed with IgA or IgM. Conclusion: An inverse association was observed between pre-diagnostic serum levels of IgG and risk of pancreatic cancer. Our findings highlight the need to further investigate the role of immune response in pancreatic cancer etiology., (Copyright © 2020 Sollie, Santaolalla, Michaud, Sarker, Karagiannis, Josephs, Hammar, Walldius, Garmo, Holmberg, Jungner and Van Hemelrijck.)

Background: Nested case-control studies examining the association between serum markers of chronic inflammation, focused on three specific biomarkers (CRP, IL-8 and TNF-α), and risk of pancreatic cancer have reported no associations. In this study, we evaluated associations between standard pre-diagnostic serum markers of chronic inflammation (CRP, albumin, haptoglobin and leukocytes) and pancreatic cancer risk in the Swedish Apolipoprotein-related MORtality RISk (AMORIS) prospective cohort study., Methods: We selected all participants (≥20 years old) with baseline measurements of CRP, albumin, haptoglobin and leukocytes between 1985 and 1996 (n = 61,597). Participants were excluded if they had a history of chronic pancreatitis and all individuals were free from pancreatic cancer at baseline. Cox proportional multivariable hazards regression analysis was carried out for medical cut-offs of CRP, albumin, haptoglobin and leukocytes., Results: We observed an increased risk of pancreatic cancer for those individuals with higher levels of serum haptoglobin (≥1.4 g/L), CRP (≥10 mg/L) and leukocytes (≥10 × 10 9 cells/L) compared to those with haptoglobin levels < 1.4 g/L, CRP levels < 10 mg/L and Leukocyte levels < 10 × 10 9 cells/L [haptoglobin HR: 2.23 (95% CI 1.72-2.88), CRP HR: 1.32 (95% CI 1.00-1.74), leukocytes HR: 2.20 (95% CI 1.52-3.18)]. No associations were noted for serum albumin., Conclusions: We found an increased risk of pancreatic cancer associated with pre-diagnostic serum levels of haptoglobin, CRP and leukocytes. Our finding suggests a possible role of chronic inflammation in the aetiology of pancreatic cancer and highlight the need to further investigate this association.

Background: Metabolites are genetically and environmentally determined. Consequently, they can be used to characterize environmental exposures and reveal biochemical mechanisms that link exposure to disease. To explore disease susceptibility and improve population risk stratification, we aimed to identify metabolic profiles linked to carcinogenesis and mortality and their intrinsic associations by characterizing subgroups of individuals based on serum biomarker measurements. We included 13,615 participants from the Swedish Apolipoprotein MOrtality RISk Study who had measurements for 19 biomarkers representative of central metabolic pathways. Latent Class Analysis (LCA) was applied to characterise individuals based on their biomarker values (according to medical cut-offs), which were then examined as predictors of cancer and death using multivariable Cox proportional hazards models., Results: LCA identified four metabolic profiles within the population: (1) normal values for all markers (63% of population); (2) abnormal values for lipids (22%); (3) abnormal values for liver functioning (9%); (4) abnormal values for iron and inflammation metabolism (6%). All metabolic profiles (classes 2-4) increased risk of cancer and mortality, compared to class 1 (e.g. HR for overall death was 1.26 (95% CI: 1.16-1.37), 1.67 (95% CI: 1.47-1.90), and 1.21 (95% CI: 1.05-1.41) for class 2, 3, and 4, respectively)., Conclusion: We present an innovative approach to risk stratify a well-defined population based on LCA metabolic-defined subgroups for cancer and mortality. Our results indicate that standard of care baseline serum markers, when assembled into meaningful metabolic profiles, could help assess long term risk of disease and provide insight in disease susceptibility and etiology.

Purpose: The roles of folate and vitamin B12 in prostate cancer (PCa) or breast cancer (BC) development are unclear. We investigated their roles using the prospective Swedish Apolipoprotein MOrtality RISk (AMORIS) study., Methods: 8,783 men and 19,775 women with vitamin B12 and folate serum measurements were included. Their associations with PCa and BC risk categories were evaluated using Cox proportional hazards regression., Results: During mean follow-up of 13 years, 703 men developed PCa. There was an inverse association between folate > 32 nmol/L and high-risk PCa [hazard ratio (HR) 0.12, 95% confidence interval (CI) 0.02-0.90], and a positive association between folate < 5 nmol/L and metastatic PCa (HR 5.25, 95% CI 1.29-21.41), compared with folate 5-32 nmol/L. No associations with vitamin B12 were found. 795 women developed BC during mean follow-up of 14 years. When restricting to the fasting population, there was a positive association between folate > 32 nmol/L and BC (HR 1.47, 95% CI 1.06-2.04)., Conclusion: High folate levels may protect against PCa and low folate levels may increase risk of metastatic PCa. High fasting folate levels may be associated with an increased BC risk. Vitamin B12 was not found to be linked with risk of PCa or BC. Longitudinal studies with serum and dietary information could help define new prevention targets and add information on the role of folate fortification.

Purpose: Lifestyle-related conditions such as obesity are associated with prostate cancer progression, but the associations with hyperglycemia and dyslipidemia are unclear. This study, therefore, aims to examine the association of glucose, triglycerides, and total cholesterol with prostate cancer death., Methods: From the Swedish AMORIS cohort, we selected 14,150 men diagnosed with prostate cancer between 1996 and 2011 who had prediagnostic measurements of serum glucose, triglycerides, and total cholesterol. Multivariable Cox proportional hazards regression models were used to determine the hazard ratios for death in relation to the aforementioned metabolic markers., Results: Using clinical cut-off points, a non-significant positive association was observed between glucose and prostate cancer death. When compared to those with glucose in the lowest quartile, those in the highest quartile had greater risk of prostate cancer death (HR 1.19; 95% CI 1.02-1.39). However, neither total cholesterol nor triglycerides were associated with prostate cancer death. Glucose and triglycerides were positively associated with overall, cardiovascular, and other deaths. Hypercholesterolemia was only associated with risk of CVD death., Conclusion: Our results suggest that glucose levels may influence prostate cancer survival, but further studies using repeated measurements are needed to further elucidate how glucose levels may influence prostate cancer progression.

There is evidence that derangement in serum electrolytes like sodium and potassium is associated with increased morbidity and mortality among hospitalized critically ill patients, but their role in the context of cancer survival remains poorly understood. We sought to investigate the association of pre-diagnostic serum sodium and potassium with risk of overall, cancer-specific, and cardiovascular (CV) death among 11,492 men diagnosed with prostate cancer (PCa) from the Swedish AMORIS study. Multivariable Cox proportional hazards regression was used to assess the risk of death by clinical categories of pre-diagnostic serum sodium and potassium. During a mean follow-up of 5.7 years, 1649 men died of PCa. Serum levels of sodium were not indicative of PCa-specific or CV death. A weak positive association was found between pre-diagnostic higher serum potassium (> 5 mEq/L) and overall death [HR: 1.26 (95% CI: 1.01-1.59)] as compared to low/normal levels of clinical cut-offs. The current study did not find strong evidence for a role of electrolytes in PCa mortality. To further disentangle the potential role of electrolytes in cancer development, future studies should use repeated measurement of serum electrolytes.This research project was reviewed and approved by the Stockholm Ethical Committee (Dnr 2010/1:7).

Background: The long-term trajectories of lipid and glucose levels in subjects who experience a major cardiovascular (CV) event at a young age has not been well studied. Our objective was to investigate lipid, lipoprotein, apolipoprotein (apo), and glucose levels in individuals experiencing a CV event before 50 years of age., Methods and Findings: A first CV event [non-fatal myocardial infarction (MI), coronary revascularisation, or CV related death] before age 50 was recorded in 2,939 (cumulative incidence 1.2% in males and 0.3% in females) of 361,353 individuals included in the prospective Swedish AMORIS (Apolipoprotein-related MOrtality RISk) study with health examinations 1985-1996 and follow-up through 2011. In a nested case-control analysis, cases with a CV event were matched to randomly selected controls. Population risk factor trajectories were calculated up to 20 years prior to an event. Total cholesterol (TC), triglyceride (TG), and glucose levels were higher in cases than in controls as early as 20 years prior to the event with differences increasing over time. Low density lipoprotein, apoB, and the apoB/apoA-1 ratio were higher and increased over time, while HDL and apoA-1 were lower in cases compared to controls. The odds ratio was 2.5 (95% confidence interval 1.6-3.7) for TC ≥5 mmol/L and TG ≥1.7 mmol/L in cases versus controls. The adjusted population-attributable fractions including lipids, glucose, diabetes, smoking, hypertension, and obesity indicated that about 50% of CV events before age 50 may be associated with elevated lipid and glucose levels., Conclusions: Elevated TC, TG, LDL, apoB, and glucose levels and high apoB/apo A-1 ratio documented two decades before a CV event in subjects younger than 50 years may account for about half of CV events before age 50, which calls for early recognition and possibly treatment of modifiable CV risk factors in young individuals., Competing Interests: Niklas Hammar is adjunct professor of epidemiology at the Institute of Environmental Medicine, Karolinska Institutet (KI) and also employee of AstraZeneca Research & Development, Mölndal, Sweden. The research of the current study has no relation to the drug development or other activities performed by AstraZeneca and AstraZeneca had no influence on the initiation, conduct or interpretation of the study. The CALAB laboratory was overtaken by another company in 1997 but the laboratory database containing data from 1985 to 1996 was still owned and managed by Ingmar Jungner who donated the database to the Institute of Environmental Medicine in 2012. Ingmar Jungner is retired since many years and is not active in any business activities. He still is a member of the AMORIS Steering Committee. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Aims: To describe trajectories for metabolic risk factors for type 2 diabetes (T2D) up to 25 years prior to diagnosis and to estimate the absolute 20-year risk for T2D based on a simple set of commonly measured key risk factors., Methods: From the Swedish AMORIS cohort we included 296 428 individuals with data on fasting glucose obtained in health examinations during 1985-1996 (baseline period). All participants were followed until 2012 for development of incident T2D. The 20-year T2D risk based on age, sex, body mass index (BMI), fasting glucose and triglycerides was estimated. Trajectories for biomedical risk factors of T2D starting from >20 years before diagnosis and including fasting glucose, triglycerides and BMI were evaluated according to yearly means for cases and controls., Results: We identified 28 244 new T2D cases during the study period, with an average 20-year risk of 8.1%. This risk was substantially increased in overweight and obese participants and those with elevated fasting glucose and triglyceride levels, in both men and women. T2D cases had higher mean BMI and fasting glucose and triglyceride levels compared with controls >20 years before diagnosis and the difference in fasting glucose levels increased over time., Conclusions: Development of T2D is associated with subtle elevations in glucose and lipid levels >20 years before diagnosis. This suggests that diabetogenic processes tied to chronic insulin resistance operate for decades prior to the development of T2D. A simple risk classification can help in early identification of individuals who are at increased risk., (© 2018 John Wiley & Sons Ltd.)

Background: Improvements in detection and treatment of prostate cancer (PCa) translate into more men living with PCa, who are therefore potentially at risk of a secondly diagnosed primary tumour (SDPTs). Little is known about potential biochemical mechanisms linking PCa with the occurrence of SDPTs. The current study aims to investigate serum biomarkers of glucose and lipid metabolism and gamma-glutamyl transferase (GGT) measured prior to PCa diagnosis and their association with the occurrence of SDPTS., Methods: From the Swedish AMORIS cohort, we selected all men diagnosed with PCa between 1996 and 2011, with at least one of the five biomarkers of interest (glucose, fructosamine, triglycerides, total cholesterol (TC), GGT) measured on average 16 years before PCa diagnosis (n = 10,791). Multivariate Cox proportional hazards models were used to determine hazard ratios (HR) for risk of SDPTs (overall and subtypes) by levels of the five biomarkers. Effect modification of treatment was assessed., Results: 811 SDPTS were diagnosed during a median follow-up time of 5 years. Elevated levels of triglycerides (HR: 1.37, 95%CI: 1.17-1.60), TC (HR: 1.22, 95%CI: 1.04-1.42) and GGT (HR: 1.32, 95%CI: 1.02-1.71) were associated with an increased risk of SDPTs. Risk of SDPTs subtypes varied by biomarkers., Conclusion: Elevated levels of biomarkers of lipid metabolism and GGT measured prior to PCa diagnosis were associated with an increased risk of SDPTs, suggesting a potential common biochemical background for development of PCa and SDPTs.

Chronic inflammation is one of the underlying risks associated with thyroid cancer. We ascertained the association between commonly measured serum biomarkers of inflammation and the risk of thyroid cancer in Swedish Apolipoprotein-related MORtality RISk (AMORIS) study. 226,212 subjects had baseline measurements of C-reactive protein, albumin and haptoglobin. Leukocytes were measured in a subgroup of 63,845 subjects. Associations between quartiles and dichotomized values of inflammatory markers and risk of thyroid cancer were analysed using multivariate Cox proportional hazard models. 202 individuals were diagnosed with thyroid cancer during a mean follow-up of 19.6 years. There was a positive association between lower albumin levels and risk of developing thyroid cancer [Hazard Ratio for albumin ≤ 40 g/L: 1.50 (95% Confidence Interval = 1.04-2.16)]. When stratified by a metabolic score, we observed similar association for albumin with higher HR among those with metabolic score ≥ 1, as compared to those with metabolic score of 0 [HR 1.98 (95% CI = 1.11-3.54) vs 1.17 (95% CI = 0.72-1.89)] ( P = 0.19). Apart from albumin, none of the serum markers of inflammation studied showed a link with the risk of developing thyroid cancer-suggesting that the role of inflammation may be more complicated and requires assessment of more specialised measurements of inflammation., Competing Interests: CONFLICTS OF INTEREST None to declare.

Metabolic syndrome (MetS) is associated with non-alcoholic fatty liver disease, which may progress to cirrhosis, a significant risk factor of hepatocellular carcinoma (HCC), the commonest malignant primary liver cancer (PLC). We investigated the association between the individual components of MetS (lipids, apolipoproteins, raised glucose, diabetes and obesity), PLC and cirrhosis. A total of 509,436 participants from the Swedish AMORIS cohort, recruited between January 1985 and December 1996 (end-date December 2011), aged ≥20 with baseline triglycerides (TG), total cholesterol (TC), glucose and liver enzymes were included. Those with baseline benign liver tumours, PLC or cirrhosis were excluded. Multivariate Cox regression, adjusted for age, gender, socio-economic status, liver disease (excluding cirrhosis) and MetS factors were used to estimate the association with PLC and cirrhosis. There were 766 PLC and 2,775 cirrhosis cases over 13 years. Raised TG, low TC, raised glucose, diabetes and low HDL were associated with an increased risk of developing PLC and cirrhosis. ApoB/ApoA-I ratio were also associated with PLC, whilst low LDL, raised TG/HDL, low ApoA-I and low ApoB were associated with cirrhosis. Obesity was significantly associated with PLC but not cirrhosis. Raised TG, low TC, raised glucose and diabetes showed stronger associations with PLC in participants with cirrhosis but many participants developed PLC without cirrhosis. Individual components of MetS (lipids, apolipoproteins, raised glucose, diabetes and obesity) were associated with an increased risk of developing PLC or cirrhosis. MetS components were more strongly associated with PLC with preceding cirrhosis history but many participants developed PLC without cirrhosis., (© 2017 UICC.)

Purpose: To evaluate the association between commonly measured serum biomarkers of inflammation and penile and testicular cancer risk in the Swedish Apolipoprotein-related MORtality RISk (AMORIS) study., Materials and Methods: A total of 205,717 subjects had baseline measurements of C-reactive protein, albumin, and haptoglobin. The association between quartiles and dichotomised values of inflammatory markers and penile and testicular cancer risk were analysed by using multivariate Cox proportional hazard models., Results: A total of 125 men were diagnosed with testicular cancer and 50 with penile cancer during a mean follow-up of 20.3 years. No statistically significant trends were seen between serum inflammatory markers and risk of penile cancer, but higher albumin levels increased the risk of testicular cancer [HR for albumin (g/L): 1.10 (95% CI: 1.03-1.18)]. However, this trend was not observed when using medical cut-offs of albumin., Conclusions: In the present study, we did not find support for an association between commonly used markers of inflammation and risk of testicular or penile cancer. The role of inflammation may be more complicated and require assessment of more specialised measurements of inflammation in future studies.

Objectives: Serum uric acid has been suggested to be associated with cancer risk. We aimed to study the association between serum uric acid and cancer incidence in a large Swedish cohort., Results: A positive association was found between uric acid levels and overall cancer risk, and results were similar with adjustment for glucose, triglycerides and BMI. Hazard ratio (HR) for overall cancer for the 4th quartile of uric acid compared to the 1st was 1.08 (95% CI: 1.05-1.11) in men and 1.12 (1.09 - 1.16) in women. Site-specific analysis showed a positive association between uric acid and risk of colorectal, hepatobiliary, kidney, non-melanoma skin, and other cancers in men and of head and neck and other cancers in women. An inverse association was observed for pulmonary and central nervous system (CNS) cancers in men and breast, lymphatic and haematological, and CNS malignancies in women., Materials and Methods: We included 493,281 persons aged 20 years and older who had a measurement of serum uric acid and were cancer-free at baseline in the AMORIS study. Multivariable Cox proportional hazards regression was used to investigate sex-specific quartiles of serum uric acid in relation to cancer risk in men and women. Analysis was further adjusted for serum glucose, triglycerides and, where available, BMI. Site-specific analysis was performed for major cancers., Conclusions: Altered uric acid levels were associated with risk of overall and some specific cancers, further indicating the potential role of uric acid metabolism in carcinogenesis.

Background: Inflammation has been linked with development of some cancers. We investigated systemic inflammation in relation to colorectal cancer incidence and subsequent survival using common serum inflammatory markersDesign:A cohort of men and women aged 20 years and older in greater Stockholm area with serum C-reactive protein (CRP) and albumin measured between 1986 and 1999 were included (n=325 599). A subset of these had baseline measurements of haptoglobin and leukocytes. Multivariable Cox regression was performed to assess risk of colorectal cancer by levels of inflammatory markers, adjusting for potential confounders. Analyses were stratified by circulating glucose, total cholesterol and triglycerides. Overall and CRC-specific death following diagnosis were assessed as secondary outcomes., Results: A total of 4764 individuals were diagnosed with colorectal cancer. A positive association between haptoglobin and colorectal cancer incidence was found (hazard ratio (HR): 1.17; 95% CI: 1.06-1.28). A positive association was also observed with leukocytes (HR: 1.21; 95% CI: 1.03-1.42). No evidence of association was noted between CRP and colorectal cancer risk. Higher risks of all-cause death were seen with haptoglobin and leukocytes levels. Higher haptoglobin levels were linked with an increased risk of colorectal cancer death (HR: 1.19; 95% CI: 1.01-1.41)., Conclusions: Prediagnostic systemic inflammation may impact colorectal cancer incidence and survival; therefore, prompting investigations linking inflammatory pathways preceding colorectal cancer with disease severity and progression.

Objective: To assess the associations of blood biomarkers of carbohydrate, lipid, and apolipoprotein metabolisms with the future risk of amyotrophic lateral sclerosis (ALS)., Methods: In the Apolipoprotein-related MOrtality RISk study, we enrolled 636,132 men and women during 1985-1996 in Stockholm, Sweden, with measurements of serum glucose, total cholesterol, triglycerides, apolipoprotein B (apoB), and apolipoprotein A-I (apoA-I). Serum low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were either directly measured or calculated from total cholesterol, triglycerides, and apoA-I. The cohort was followed until the end of 2011. We used Cox models and mixed-effects models to, first, estimate the associations between these biomarkers and ALS incidence and, second, to assess the changes of these biomarkers during the 20 years before ALS diagnosis., Results: One-unit increase of LDL-C (hazard ratio [HR] = 1.14; 95% confidence interval [CI] = 1.02-1.27), apoB (HR = 1.68; 95% CI = 1.17-2.42), and apoB/apoA-I ratio (HR = 1.90; 95% CI = 1.29-2.78) was associated with a higher incidence of ALS. High glucose level (≥6.11mmol/L) was associated with a lower incidence (HR = 0.62; 95% CI = 0.42-0.93), whereas high LDL-C/HDL-C (≥3.50; HR = 1.50; 95% CI = 1.15-1.96) and high apoB/apoA-I (≥0.90 for men, ≥0.8 for women; HR = 1.41; 95% CI = 1.04-1.90) ratios were associated with a higher incidence. During the 10 years before diagnosis, ALS patients had increasing levels of LDL-C, HDL-C, apoB, and apoA-I, whereas gradually decreasing levels of LDL-C/HDL-C and apoB/apoA-I ratios., Interpretation: Alterations in the carbohydrate, lipid, and apolipoprotein metabolisms are associated with ALS risk and may serve as prodromal symptoms decades before ALS diagnosis. The imbalance between apoB and apoA-I as well as between LDL-C and HDL-C may be an etiological mechanism for ALS and needs to be further studied. Ann Neurol 2017;81:718-728., (© 2017 American Neurological Association.)

Background: The lipid and glucose metabolisms are postulated as possible intermediary mechanisms in linking obesity and breast cancer (BC). Links between serum lipid and glucose biomarkers and BC risk has been observed in the Swedish Apolipoprotein MORtality RISk (AMORIS) cohort. We conducted a follow-up analysis including information on tumour characteristics., Methods: One thousand eight hundred twenty-four women diagnosed with BC, with serum biomarker levels of glucose, triglycerides, cholesterol (total, HDL, and LDL), and apolipoproteins A-1 and B recorded in a routine health check at baseline were included. BC severity was split into categories (good, moderate, and poor prognosis) based on ER status, TNM stage, and age at diagnosis. Proportional odds models were used to obtain odds ratios (ORs) and 95% confidence intervals (CI), with the interval time between baseline measurement and BC diagnosis accounted for., Results: Serum glucose and the ApoB/ApoA-1 ratio showed a non-statistically significant positive association with BC severity (proportional OR: 1.25 (95%CI: 0.92-1.70) for glucose (

Background: Different etiological pathways may precede development of specific breast cancer subtypes and impact prevention or treatment strategies. We investigated the association between gamma-glutamyl transferase (GGT) and development of specific breast cancer subtypes based on oestrogen receptor (ER), progesterone receptor (PR) and HER2 status., Methods: We included 231,283 cancer-free women in a Swedish cohort. Associations between GGT and breast cancer subtypes were investigated with nested case-control and case-case analyses. We used logistic regression models to assess serum GGT in relation to breast cancer subtype, based on individual and combined receptor status., Results: Positive associations were found between serum GGT and development of ER+, ER- and PR+ breast cancers compared to controls (odds ratio (OR) 1.14 (95% confidence interval (CI) 1.08-1.19), 1.11 (1.01-1.23) and 1.18 (1.12-1.24), respectively) and of ER+/PR+ tumours. We found inverse associations between GGT levels and PR- breast cancers compared to PR+ (OR 0.87 (0.80-0.95)), between ER+/PR- tumours compared to ER+/PR+ tumours and between ER-/PR-/HER+ compared to ER+/HER2 or PR+/HER2 tumours (OR 0.55 (95% CI 0.34-0.90)., Conclusion: The observed associations between pre-diagnostic serum GGT and different breast cancer subtypes may indicate distinct underlying pathways and require further investigations to tease out their clinical implications.

To investigate the association between serum calcium and risk of breast cancer using a large cohort and a systematic review with meta-analysis. From the Swedish Apolipoprotein Mortality Risk (AMORIS) Study we included 229,674 women who had baseline measurements of serum total calcium and albumin. Multivariable Cox regression was used to assess the association between total and albumin-corrected calcium and breast cancer risk. For the systematic review, an electronic search of MEDLINE and EMBASE databases was performed to identify other prospective cohorts assessing the relationship between serum calcium and breast cancer risk. We pooled the results of our AMORIS cohort with other eligible studies in a meta-analysis using a random effects model. I² test was used to assess heterogeneity. In the AMORIS study, 10,863 women were diagnosed with breast cancer (mean follow-up: 19 years). We found an inverse association between total serum calcium and breast cancer when comparing the fourth quartile to the first quartile (HR: 0.94, 95% CI: 0.88-0.99, p value for trend 0.04) and similar results using albumin-corrected calcium. In the systematic review, we identified another two prospective cohorts evaluating pre-diagnostic serum total calcium and breast cancer. Combining these studies and our findings in AMORIS in a meta-analysis showed a protective effect of serum calcium against breast cancer, with a summary RR of 0.80 (95% CI: 0.66-0.97). No substantial heterogeneity was observed. Our findings in AMORIS and the meta-analysis support an inverse association between serum calcium and breast cancer risk, which warrants mechanistic investigations., Competing Interests: Niklas Hammar is employed by AstraZeneca. However, the views expressed in this study are his own and not those of AstraZeneca’s. No medical writer was involved in the study or manuscript preparation.

Background and Aims: Previous epidemiological studies have shown positive associations between serum calcium concentration and risk of cardiovascular disease (CVD), but results differ by definition of CVD. We examined the association of circulating calcium with incident and fatal CVD, myocardial infarction (MI), and stroke in the Swedish AMORIS cohort., Methods: We included 441,738 participants of the AMORIS database linked for follow-up information on morbidity and mortality. Concentrations of total calcium were fully automated measured using a colorimetric method; concentrations of albumin were measured with a bromocresol green method between 1985 and 1995. The association of albumin-corrected calcium concentration and risk of incident and fatal CVD, MI, and stroke, respectively, was assessed with multivariable adjusted Cox proportional hazards models., Results: Until December 31, 2011, during a median follow-up time of 21 years, 90,866 incident cases of CVD, 21,271 of MI, and 25,810 of stroke were identified. High serum calcium concentrations were associated with increased risk of non-fatal CVD (Hazard ratio [HR] = 1.12, 95% CI 1.10-1.14, top [≥2.40 nmol/L] vs. bottom [≤2-25 nmol/L] quintile), MI (1.19, 1.14-1.25), and stroke (1.11, 1.06-1.15) and fatal disease (CVD: 1.41, 1.35-1.47; MI: 1.41, 1.31-1.51; stroke: 1.30, 1.20-1.41). Effect modification by sex was observed for incident disease such that associations were stronger among women than men. Serum calcium was positively associated with both incident and fatal ischemic stroke and with fatal hemorrhagic stroke, but not with incident hemorrhagic stroke. In a sub-groups analysis, the results remained significant after adjustment for smoking., Conclusions: The results support a modest positive association between serum calcium and risk of CVD, but the underlying mineral metabolism and the exact mechanisms are currently unclear., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: In recent clinical guidelines, individuals with chronic kidney disease are considered to have a similar 10-year absolute risk of cardiovascular death as individuals with diabetes or established cardiovascular disease. There is limited evidence to support this claim., Methods: We investigated the 10-year risk for cardiovascular death in individuals with moderate or severe chronic kidney disease (glomerular filtration rate of 30-60 or <30 mL/min/1.73 m(2), respectively) in a cohort of primary care health check-ups in Stockholm, Sweden (n = 295,191, 46% women, 4290 cardiovascular deaths during 10 years follow-up). We also assessed the risk associated with diabetes or cardiovascular disease. The inclusion criteria, exposure, study outcome and follow-up period adhered strictly to the definitions of the European Society of Cardiology guidelines., Results: The absolute 10-year risk of cardiovascular death was 3.9% and 14.0% in individuals with moderate and severe chronic kidney disease, respectively, but was substantially lower in women and in younger individuals. The risk in individuals with prevalent diabetes and cardiovascular disease was approximately two and three times higher compared to the risk estimate for moderate chronic kidney disease (hazard ratio (HR) 4.1, 95% confidence interval (CI) 3.8-4.5 and HR 6.2, 95% CI 5.7-6.7 vs. HR 2.3 95% CI 2.0-2.6, respectively) while the risk for individuals with severe chronic kidney disease appeared more congruent to that of diabetes and cardiovascular disease (HR 5.5, 95% CI 3.3-8.9)., Conclusions: Although moderate chronic kidney disease is an independent predictor for an increased 10-year risk of cardiovascular death, only those with severe chronic kidney disease had similar risk to those with diabetes or cardiovascular disease., (© The European Society of Cardiology 2015.)

Lifestyle-related risk factors such as hyperglycemia and dyslipidemia have been associated with several cancers. However, studies exploring their link with prostate cancer (PCa) clinicopathological characteristics are sparse and inconclusive. Here, we investigated the associations between serum metabolic markers and PCa clinicopathological characteristics. The study comprised 14,294 men from the Swedish Apolipoprotein MOrtality RISk (AMORIS) cohort who were diagnosed with PCa between 1996 and 2011. Univariate and multivariable logistic regression were used to investigate the relation between glucose, triglycerides and total cholesterol and PCa risk categories, PSA, Gleason score, and T-stage. Mean age at time of PCa diagnosis was 69 years. Men with glucose levels >6.9 mmol/L tend to have PSA<4 μg/L, while those with glucose levels of 5.6-6.9 mmol/L had a greater odds of PSA>20 μg/L compared to PSA 4.0-9.9 μg/L. Hypertriglyceridemia was also positively associated with PSA>20 μg/L. Hyperglycemic men had a greater odds of intermediate- and high-grade PCa and advanced stage or metastatic PCa. Similarly, hypertriglyceridemia was positively associated with high-grade PCa. There was also a trend toward an increased odds of intermediate risk localized PCa and advanced stage PCa among men with hypertriglyceridemia. Total cholesterol did not have any statistically significant association with any of the outcomes studied. Our findings suggest that high serum levels of glucose and triglycerides may influence PCa aggressiveness and severity. Further investigation on the role of markers of glucose and lipid metabolism in influencing PCa aggressiveness and severity is needed as this may help define important targets for intervention., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Prior findings linking allergy and cancer have been inconsistent, which may be driven by diverse assessment methods. We used serum specific immunoglobulin E (IgE) against common inhalant allergens that was assessed prior to cancer diagnosis in studying this association. We selected 8,727 Swedish men and women who had measurements of serum allergen-specific IgE and total IgE between 1992 and 1996. Multivariable Cox regression using age as a timescale was performed to assess the associations of IgE sensitization, defined by any levels of serum specific IgE ≥35 kU/L, with risk of overall and specific cancers. A test for trend was performed by assigning scores derived from allergen-specific IgE levels at baseline as an ordinal scale. Kaplan-Meier curves and log-rank test were used to assess cancer survival by IgE sensitization status. During a mean follow-up of 16 year, 689 persons were diagnosed with cancer. We found an inverse association between IgE sensitization and cancer risk, with a hazard ratio (HR) of 0.83 and 95% confidence intervals (CI) of 0.70-0.99. A similar trend was seen with specific IgE scores overall (Ptrend = 0.007) and in women (Ptrend = 0.01). Although IgE sensitization was not associated with risk of common site-specific cancers, serum specific IgE scores were inversely associated with melanoma risk in men and women combined, and with risk of female breast and gynecological cancers combined. No association with survival was observed. The association between circulating IgE levels and incident cancer may point toward a role of T-helper 2 (TH2)-biased response in development of some cancers.

Background: Abnormal glucose and lipids levels may impact survival after breast cancer (BC) diagnosis, but their association to other causes of mortality such as cardiovascular (CV) disease may result in a competing risk problem., Methods: We assessed serum glucose, triglycerides (TG) and total cholesterol (TC) measured prospectively 3 months to 3 years before diagnosis in 1798 Swedish women diagnosed with any type of BC between 1985 and 1999. In addition to using Cox regression, we employed latent class proportional hazards models to capture any heterogeneity of associations between these markers and BC death. The latter method was extended to include the primary outcome (BC death) and competing outcomes (CV death and death from other causes), allowing latent class-specific hazard estimation for cause-specific deaths., Results: A lack of association between prediagnostic glucose, TG or TC with BC death was observed with Cox regression. With latent class proportional hazards model, two latent classes (Class I and II) were suggested. Class I, comprising the majority (81.5 %) of BC patients, had an increased risk of BC death following higher TG levels (HR: 1.87, 95 % CI: 1.01-3.45 for every log TG increase). Lower overall survival was observed in Class II, but no association for BC death was found. On the other hand, TC positively corresponded to CV death in Class II, and similarly, glucose to death from other causes., Conclusion: Addressing cohort heterogeneity in relation to BC survival is important in understanding the relationship between metabolic markers and cause-specific death in presence of competing outcomes.

Background: There is evidence that high level of serum lactate dehydrogenase (LDH) is associated with poorer overall survival in several malignancies, but its link to cancer-specific survival is unclear., Methods: A total of 7895 individuals diagnosed with cancer between 1986 and 1999 were selected for this study. Multivariable Cox proportional hazards regression was used to assess overall and cancer-specific death by the z-score and clinical categories of serum LDH prospectively collected within 3 years before diagnosis. Site-specific analysis was performed for major cancers. Analysis was repeated by different lag times between LDH measurements and diagnosis., Results: At the end of follow-up, 5799 participants were deceased. Hazard ratios (HRs) and 95% confidence intervals (CIs) for overall and cancer-specific death in the multivariable model were 1.43 (1.31-1.56) and 1.46 (1.32-1.61), respectively, for high compared with low prediagnostic LDH. Site-specific analysis showed high LDH to correlate with an increased risk of death from prostate, pulmonary, colorectal, gastro-oesophageal, gynaecological and haematological cancers. Serum LDH assessed within intervals closer to diagnosis was more strongly associated with overall and cancer-specific death., Conclusions: Our findings demonstrated an inverse association of baseline serum LDH with cancer-specific survival, corroborating its role in cancer progression.

Inflammation has been linked to cancer but its role in breast cancer is unclear. We investigated common serum markers of inflammation: C-reactive protein (CRP), albumin, haptoglobin and white blood cells (WBC) in relation to breast cancer incidence, severity and survival. A total of 155179 women aged 20 and older without any history of cancer were selected from a large Swedish cohort. Hazard ratios (HRs) for breast cancer were estimated with Cox regression, adjusting for potential confounders. Ordered and binomial logistic regression models were used to assess the associations of serum inflammatory markers with breast cancer severity and oestrogen receptor (ER) positivity at diagnosis, on the other. Cumulative incidence functions by levels of inflammatory markers were assessed for early death from breast cancer and all causes. During a mean follow-up of 18.3 years, 6606 women were diagnosed with breast cancer, of whom 1474 died. A positive association with incident breast cancer was seen for haptoglobin ≥ 1.4g/l [HR 1.09; 95% confidence interval (CI): 1.00-1.18] compared to lower levels. No association was observed between inflammatory markers and breast cancer severity or ER positivity. Higher haptoglobin was linked to risk of early death from breast cancer (HR: 1.27, 95% CI: 1.02-1.59), whereas higher risk of early death from all causes was additionally found with CRP ≥ 10mg/l (HR: 1.19, 95% CI: 1.04-1.36) and WBC ≥ 10×10(9)/l (HR: 1.57, 1.14-2.16). Our findings indicate that prediagnostic serum inflammatory markers were weakly linked to incident breast cancer but corresponded to worse survival after diagnosis., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Aim: To examine the association of sialic acid (SA) with first recorded diabetes mellitus-related hospitalization., Methods: From a population-based study in Värmland, Sweden, between 1962 and 1965, 87,035 men and women were selected and followed for first recorded diabetes-related hospitalization until 2005. The association of SA was calculated and stratified for gender by Cox's proportional hazards models. Adjustments were made for conventional risk factors and socioeconomic status. Association analyses were made for comparisons between SA-levels above and below median., Results: The mean age was 47.2 (SD 13.0) years and the total numbers of incident diabetes-related hospitalizations in men and women were 3445 and 3273, respectively. Hazard ratios per one standard deviation of SA were 1.12 (95% CI: 1.08-1.17, p<0.0001) in men and 1.17 (95% CI: 1.13-1.22, p<0.0001) in women. Interaction analyses indicated a relatively higher SA-associated risk in women than in men with above median SA levels., Conclusions: In this large population-based cohort followed for more than 40 years, elevated SA, as a marker of systemic inflammation, was independently associated with risk of diabetes and diabetes-related hospitalizations., (Copyright © 2014 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

Context: Fructosamine is a glycemic biomarker which may be useful for indication and control of diabetes respectively., Objective: The objective of the study was to evaluate fructosamine as an indicator of hyperglycaemia and glucose control in subjects with diabetes., Design, Setting & Patients: From the AMORIS cohort, subjects with serum glucose, fructosamine and HbA1c from the same examination were studied cross-sectionally and longitudinally (n = 10,987; 5,590 overnight-fasting). The guidelines of the American Diabetes Association were followed for classification of prediabetes and diabetes. Separate analyses were performed in patients with a newly detected or a known diagnosis of type 1 or type 2 diabetes respectively., Results: All three biomarkers were strongly correlated. With regard to the association between fructosamine and HbA1c Pearson linear correlation coefficients in the range of 0.67-0.75 were observed in fasting and non-fasting subjects with type 1 or type 2 diabetes. Analyses of glucose control in fasting patients with type 2 diabetes having all three biomarkers measured at three separate occasions within on average 290 days of the index examination showed similar trends over time for glucose, fructosamine and HbA1c. Discrimination of subjects with and without diabetes across the range of fructosamine levels was good (area under curve (AUC) 0.91-0.95) and a fructosamine level of 2.5 mmol/L classified subjects to diabetes with a sensitivity of 61% and a specificity of 97%., Conclusions: Fructosamine is closely associated with HbA1c and glucose respectively and may be a useful biomarker of hyperglycaemia and glucose control in clinical and epidemiological studies.

Background: Observational studies have indicated that high calcium intake may prevent colorectal cancer, but as for randomized trials the results are inconclusive. Meanwhile, limited data on the link between serum calcium and cancer risk is available. We investigated the relation between serum calcium and risk of different gastrointestinal cancers in a prospective study., Methods: A cohort based on 492,044 subjects with baseline information on calcium (mmol/L) and albumin (g/L) was selected from the Swedish Apolipoprotein MOrtality RISk (AMORIS) study. Multivariable Cox proportional hazard models were used to analyse associations between standardised levels, quartiles and age/sex-specific categories of serum calcium and risk of oesophageal, stomach, colon, rectal cancer and also colorectal cancer combined, while taking into account serum albumin and other comorbidities., Results: During 12 years of follow-up, we identified 323 incident oesophageal cancers, 782 stomach cancers, 2519 colon cancers, and 1495 rectal cancers. A positive association was found between albumin-adjusted serum calcium and risk of oesophageal [HR: 4.82 (95% CI: 2.07 - 11.19) for high compared to normal age-specific calcium levels] and colon cancer [e.g. HR: 1.07 (95% CI: 1.00 - 1.14) for every SD increase of calcium] as well as colorectal cancer [e.g. HR: 1.06 (95% CI: 1.02-1.11) for every SD increase of calcium] in women. In men there were similar but weaker non-statistically significant trends., Conclusion: The positive relation between serum calcium, oesophageal cancer and colorectal cancer calls for further studies including calcium regulators to evaluate whether there is a true link between calcium metabolism and development of gastrointestinal cancer.

Objectives: Pre-clinical studies have shown that iron can be carcinogenic, but few population-based studies investigated the association between markers of the iron metabolism and risk of cancer while taking into account inflammation. We assessed the link between serum iron (SI), total-iron binding capacity (TIBC), and risk of cancer by levels of C-reactive protein (CRP) in a large population-based study (n = 220,642)., Methods: From the Swedish Apolipoprotein Mortality Risk (AMORIS) study, we selected all participants (>20 years old) with baseline measurements of serum SI, TIBC, and CRP. Multivariate Cox proportional hazards regression was carried out for standardized and quartile values of SI and TIBC. Similar analyses were performed for specific cancers (pancreatic, colon, liver, respiratory, kidney, prostate, stomach, and breast cancer). To avoid reverse causation, we excluded those with follow-up <3 years., Results: We found a positive association between standardized TIBC and overall cancer [HR 1.03 (95% CI 1.01-1.05)]. No statistically significant association was found between SI and cancer risk except for postmenopausal breast cancer [HR for standardized SI 1.09 (95% CI 1.02-1.15)]. The association between TIBC and specific cancer was only statistically significant for colon cancer [i.e., HR for standardized TIBC: 1.17 (95% CI 1.08-1.28)]. A borderline interaction between SI and levels of CRP was observed only in stomach cancer., Conclusions: As opposed to pre-clinical findings for serum iron and cancer, this population-based epidemiological study showed an inverse relation between iron metabolism and cancer risk. Minimal role of inflammatory markers observed warrants further study focusing on developments of specific cancers.

Objective: The aim was to investigate country or region of birth-specific prevalence and gender differences of diabetes in residents in Sweden, using Swedish-born men and women as referent., Methods: The Apolipoprotein MOrtality RISk (AMORIS) cohort was used (184,000 men and 151,453 women) aged between 20 and 80 years, with data from the CALAB laboratory, Stockholm, 1985-1996. Diabetes was defined as fasting glucose ≥ 7.0 mmol/L or a hospital diagnosis of diabetes. Country of birth was obtained by linkage to Swedish Censuses 1970-1990. Standardized prevalence rate ratios (SPRR) with 95% confidence intervals (95% CI) were estimated., Results: Five groups of women and one group of men had a significantly higher prevalence than Swedish-born (based on SPRR): women born in Iraq (6.0 (95% CI 1.3-28.9)), North Africa (6.9 (95% CI 3.1-15.3)), South Asia (3.1 (95% CI 1.0-10.0)), Syria (5.3 (95% CI 1.8-16.0)), Turkey (3.7 (95% CI 1.2-10.9)) and men born in other Middle Eastern countries (2.3 (95% CI 1.0-5.5)). Swedish-born men had a higher age-standardized prevalence of diabetes (3.9%) than Swedish born women (2.5%). A higher prevalence among men was also seen in other Western countries. In contrast, a higher age-standardized prevalence among women was observed in immigrants from Turkey (8.9% vs. 3.1%, p<0.001), Syria (13.1% vs. 4.0%, p=0.002), and North Africa (16.8% vs. 6.6%, p<0.001)., Conclusion: Female immigrants to Sweden from Iraq, North Africa, South Asia, Syria, and Turkey have an increased prevalence of diabetes of substantial public health concern., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Both dietary and serum levels of inorganic phosphate (Pi) have been linked to development of cancer in experimental studies. This is the first population-based study investigating the relation between serum Pi and risk of cancer in humans., Methods: From the Swedish Apolipoprotein Mortality Risk (AMORIS) study, we selected all participants (> 20 years old) with baseline measurements of serum Pi, calcium, alkaline phosphatase, glucose, and creatinine (n = 397,292). Multivariable Cox proportional hazards regression analyses were used to assess serum Pi in relation to overall cancer risk. Similar analyses were performed for specific cancer sites., Results: We found a higher overall cancer risk with increasing Pi levels in men ( HR: 1.02 (95% CI: 1.00-1.04) for every SD increase in Pi), and a negative association in women (HR: 0.97 (95% CI: 0.96-0.99) for every SD increase in Pi). Further analyses for specific cancer sites showed a positive link between Pi quartiles and the risk of cancer of the pancreas, lung, thyroid gland and bone in men, and cancer of the oesophagus, lung, and nonmelanoma skin cancer in women. Conversely, the risks for developing breast and endometrial cancer as well as other endocrine cancer in both men and women were lower in those with higher Pi levels., Conclusions: Abnormal Pi levels are related to development of cancer. Furthermore, the in verse association between Pi levels and risk of breast, endometrial and other endocrine cancers may indicate the role of hormonal factors in the relation between Pi metabolism and cancer.

Background: Impaired glucose metabolism has been linked with increased cancer risk, but the association between serum glucose and cancer risk remains unclear. We used repeated measurements of glucose and fructosamine to get more insight into the association between the glucose metabolism and risk of cancer., Methods: We selected 11,998 persons (>20 years old) with four prospectively collected serum glucose and fructosamine measurements from the Apolipoprotein Mortality Risk (AMORIS) study. Multivariate Cox proportional hazards regression was used to assess standardized log of overall mean glucose and fructosamine in relation to cancer risk. Similar analyses were performed for tertiles of glucose and fructosamine and for different types of cancer., Results: A positive trend was observed between standardized log overall mean glucose and overall cancer risk (HR= 1.08; 95% CI: 1.02-1.14). Including standardized log fructosamine in the model resulted in a stronger association between glucose and cancer risk and aninverse association between fructosamine and cancer risk (HR = 1.17; 95% CI: 1.08-1.26 and HR: 0.89; 95% CI: 0.82-0.96, respectively). Cancer risks were highest among those in the highest tertile of glucose and lowest tertile of fructosamine. Similar findings were observed for prostate, lung, and colorectal cancer while none observed for breast cancer., Conclusion: The contrasting effect between glucose, fructosamine, and cancer risk suggests the existence of distinct groups among those with impaired glucose metabolism, resulting in different cancer risks based on individual metabolic profiles. Further studies are needed to clarify whether glucose is a proxy of other lifestyle-related or metabolic factors.

Aims: The association between chronic kidney disease (CKD) and different subtypes of stroke is unclear, and previous studies have yielded conflicting results. We aimed to assess the impact of CKD on the risk of fatal or non-fatal ischemic and hemorrhagic stroke in both men and women., Methods: In 539,287 Swedish men and women, mainly undergoing health controls, with mean age 45 years, and no previous stroke or myocardial infarction, hazard ratios for stroke were calculated to assess the association between renal dysfunction and incidence of stroke. We estimated glomerular filtration rates (GFR) using the Mayo (GFR-Mayo) formula. Glomerular filtration rate 60-90, 30-60, and 15-30 mL per minute per 1.73 m(2) was defined as mildly, moderately, and severely decreased GFR, respectively., Results: There were 17,678 strokes, of which 72% were ischemic, 15% hemorrhagic, and 12% unspecified, during 12 years of follow-up. Hazard ratios (95% confidence intervals) for ischemic stroke were 1.09 (1.04-1.14) for mildly, 1.24 (1.10-1.39) for moderately, and 2.27 (1.63-3.17) for severely decreased GFR-Mayo. The corresponding figures for hemorrhagic stroke were 1.04 (0.93-1.15), 1.26 (0.96-1.64), and 2.31 (1.10-4.87). Ischemic stroke was related to all levels of decreased GFR-Mayo in both genders (P < 0.0003). Hemorrhagic stroke was only related to renal dysfunction among women; hazard ratios (95% confidence intervals) 1.38 (1.14-1.66) for mildly, 1.70 (1.13-2.57) for moderately, and 3.46 (1.09-10.9) for severely decreased GFR-Mayo., Conclusions: Already mildly decreased GFR-Mayo increases the risk of ischemic fatal or non-fatal stroke and severely decreased GFR-Mayo the risk of hemorrhagic stroke in the general population. In gender-specific analyses ischemic stroke was related to a decreased GFR-Mayo in both genders. Hemorrhagic stroke was only related to renal dysfunction among women.

Objective: Pulse pressure (PP) is a risk marker for cardiovascular disease (CVD) in individuals 50 years and older. Inflammation is suggested to influence atherosclerosis, but could also increase PP. We aimed to examine the combined effects of PP and the inflammatory marker sialic acid, and their independent roles on CVD risk., Methods: From a population-based study in Sweden between 1962 and 1965, 18,429 men and 19,414 women at the age of 50 or older were selected and followed for first CVD event until 2005. We investigated the biological interactions between sialic acid and PP. The associations of PP and sialic acid with risk of CVD were calculated by using Cox proportional hazards model. Adjustments were made for conventional risk factors, mean arterial pressure (MAP) and socioeconomic status., Results: The mean age was 59.5 (SD 6.5) years and the number of incident CVD events in men and women were 3641 and 3227, respectively. No biological interaction was seen between PP and sialic acid. In men, the adjusted hazard ratio for PP was 0.92 [95% confidence interval (CI) 0.88-0.96, P < 0.0001) for 1 SD of PP, and 1.09 (95% CI 1.05-1.13, P < 0.0001) for 1 SD of sialic acid. In women, the corresponding figures were 1.02 (95% CI 0.97-1.07, P = 0.48) and 1.09 (95% CI 1.05-1.13, P < 0.0001)., Conclusions: Sialic acid but not PP was an independent risk factor for CVD. The risk induced by PP is highly affected by MAP. This suggests that both estimated arterial stiffness and inflammation contribute through different pathways to risk of CVD.

Background: Few studies have tested differences in relationships between hemoglobin (Hb) and long-term risk of major cardiovascular diseases according to age and gender in healthy subjects as opposed to anemia., Aims: Such relationships were examined and risk-tested in relation to Hb values in the Apolipoprotein MOrtality RISk (AMORIS) Study., Methods: Using data from AMORIS and the Swedish hospital discharge and mortality registers, a prospective cohort study of 114,159 subjects with mean follow-up of 11.8 years, the association between Hb and risk of acute myocardial infarction (AMI), ischemic stroke (IS), and congestive heart failure (CHF) by Cox regression analysis according to age and gender was studied., Results: Elevated Hb levels were associated to acute myocardial infarction (AMI) (HR 1.10 (1.06-1.13) per SD change), mostly confined to men and younger subjects but with greater sex similarity trends for CHF. Slightly increased risks were seen for the lowest Hb levels in the elderly and in females. IS risk was positively and more linearly associated to Hb., Interpretation: In AMORIS the highest AMI and CHF risks were found in the upper region of the distribution, but different shapes of relationships according to age and gender were found. IS associated positively with Hb. Key words:

Background: Obesity is a risk factor for breast and ovarian cancer; the mechanisms of action are not completely understood. Perturbed lipid metabolism often accompanies obesity; we therefore ascertained the associations between lipid components and breast and ovarian cancer risk in a prospective cohort study., Methods: A total of 234,494 women with baseline measurements of triglycerides and total cholesterol and glucose were selected from the AMORIS database.A total of 27,394 had measurements of high-density lipoprotein, low-density lipoprotein, apolipoprotein (Apo) B, and A-I. Associations between quartiles and dichotomized values of lipid components and breast and ovarian cancer risk were analyzed using Cox proportional hazard models., Results: We identified 6,105 women diagnosed with breast cancer and 808 women diagnosed with ovarian cancer. A weak trend was observed between triglycerides and breast cancer (HR, 1.01, 95% Confidence Interval, 0.94-1.09; 0.93 (0.86-1.00) 0.91 (0.84-0.99), second, third, and fourth quartiles; P = 0.01). No other associations between lipid components and risk of breast cancer or ovarian cancer showed statistical significance., Conclusions: A weak protective association was found between levels of triglycerides and risk of breast cancer., Impact: An analysis including information on tumour characteristics of ovarian cancer and breast cancer may provide more insight in possible links between lipid metabolism and the risk of these cancers., (©2012 AACR.)

Background: Observational studies have shown a positive association between intake of dairy products as well as serum levels of calcium and prostate cancer (PCa) risk. We studied the association between serum calcium and PCa while also accounting for levels of albumin, a protein to which calcium is bound., Methods: A cohort based on 196,022 men with baseline information on calcium (mmol/L) and albumin (g/L) was selected from the Swedish Apolipoprotein MOrtality RISk study. Age-stratified multivariable Cox proportional hazard models were used to analyze associations between calcium and incident and fatal PCa risk., Results: A total of 6,353 men were diagnosed with PCa and 731 died of PCa during mean follow-up of 12 years. A weak negative association was found between levels of calcium or albumin-corrected calcium and PCa risk (HR for quartiles of albumin-corrected calcium: 0.95 (0.89-1.02), 0.93 (0.86-1.00), and 0.91 (0.85-0.98) for the 2nd, 3rd, and 4th quartile compared to the 1st; p for trend: 0.012). BMI did not affect these findings. No association was found between calcium levels and fatal PCa. A positive association between Ca and death was observed when censoring for PCa [HR per SD: 1.14 (1.13-1.16)]., Conclusion: The weak negative association between Ca and PCa risk is likely explained by the relation between Ca and death. This illustrates the need to handle competing risks when defining whether Ca is involved in PCa etiology or whether it acts as a marker of other metabolic events in the causal pathway.

Aim: To evaluate dyslipidemia as predictor of myocardial infarction (MI) in subjects with or without chronic kidney disease (CKD)., Methods: In 142,394 middle-aged Swedes referred for laboratory evaluation, glomerular filtration rates (GFR) were estimated using the Modification of Diet in Renal Disease study equation. CKD was defined as GFR 15-60 mL/min/1.73 m(2). Subjects were stratified into presence or absence of CKD, and lipid measures were related to MI using Cox's proportional hazards regression., Results: During 12 years of follow-up there were 5,466 MIs. The adjusted hazard ratio for MI for the highest versus the lowest quartile of the apolipoprotein (apo) B/apoA-1 ratio among individuals without CKD was 2.88 (95% confidence interval 2.54-3.26) and for those with CKD 3.35 (2.25-4.91). The corresponding estimates for the total cholesterol/high-density lipoprotein (HDL) cholesterol ratio were 3.13 (2.78-3.52) and 3.54 (2.43-5.17), respectively. Receiver operator characteristics analyses showed an advantage in the prediction of MI for the apoB/apoA-1 ratio as compared to conventional lipids (P < 0.0001)., Conclusions: The ratio of apoB/apoA-1, the ratio of total cholesterol/HDL cholesterol, and non-HDL cholesterol were all strong predictors of myocardial infarction, both among subjects with and without renal dysfunction, with a possible advantage for the apoB/apoA-1 ratio.

With exception of cholesterol and total fat intake, associations between lipid biomarkers and kidney cancer have not often been researched. We aimed to assess possible links between lipid profiles and kidney cancer risk in a large prospective cohort study, while also taking into account glucose levels and BMI. A cohort based on 542,924 persons with baseline information on glucose, triglycerides (TGs), total cholesterol (TC) and creatinine was selected from the Swedish Apolipoprotein Mortality Risk study. A subgroup of 85,621 also had baseline measurements of HDL, LDL, apolipoprotein A-I and apoB. Multivariate Cox proportional hazard models were used to analyze associations between quartiles and dichotomized values of these lipid components and kidney cancer risk. During a mean follow-up of 13 years, 958 persons developed kidney cancer. TGs were the only lipid component for which a statistically significant association was found with kidney cancer risk when using both quartiles and a clinical cutoff (hazard ratio: 1.25 (95% CI: 0.99-1.60), 1.29 (1.01-1.66) and 1.66 (1.30-2.13) for the 2nd, 3rd and 4th quartile, compared to the 1st, with p-value for trend: <0.001). The association remained after exclusion of the 95% percentile of TG. Quartiles of glucose were also positively associated with kidney cancer risk, whereas quartiles of TC were negatively associated with kidney cancer risk. This detailed analysis of lipid components only showed a consistent relation between TG levels and kidney cancer risk. Further mechanistic studies are required to assess links between lipid abnormalities and kidney cancer., (Copyright © 2011 UICC.)

Background: Recent studies suggested that gamma-glutamyl transferase (GGT) and C-reactive protein (CRP) are good markers of metabolic abnormalities. We assessed the link between GGT, CRP and common metabolic abnormalities, as well their link to related diseases, such as cancer and cardiovascular disease (CVD)., Methods: We selected 333,313 subjects with baseline measurements of triglycerides (TG), total cholesterol (TC), glucose, GGT and CRP in the Swedish AMORIS study. Baseline measurement of BMI was available for 63,900 persons and 77,944 had baseline measurements of HDL. Pearson correlation coefficients between CRP, GGT, and metabolic components (TG, HDL, BMI and TC) were calculated. To investigate the combined effect of GGT and CRP we created a score ranging from 0 to 6 and used Cox proportional hazard models to evaluate its association with CVD and cancer., Results: 21,216 individuals developed cancer and 47,939 CVD. GGT and TG had the strongest correlation (r=0.22). An increased risk of cancer was identified with elevated levels of GGT or CRP or both markers (GGT-CRP score ≥3); the greatest risk of cancer was found when GGT-CRP score = 6 (HR: 1.40 (95%CI: 1.31-1.48) and 1.60 (1.47-1.76) compared to GGT-CRP score = 0, respectively)., Conclusion: While GGT and CRP have been shown to be associated with metabolic abnormalities previously, their association to the components investigated in this study was limited. Results did demonstrate that these markers were predictive of associated diseases, such as cancer.

Background: Management of frailty is the cornerstone of geriatric medicine, but there remains a need to identify biomarkers that can predict early death, and thereby lead to effective clinical interventions. We aimed to study the combination of C-reactive protein (CRP), albumin, gamma-glutamyl transferase (GGT), and HDL to predict mortality., Methods: A total of 44,457 persons aged 50+ whose levels of CRP, albumin, GGT, and HDL were measured at baseline were selected from the Swedish Apolipoprotein MOrtality RISk (AMORIS) study. A mortality score, ranging from 0 to 4, was created by adding the number of markers with abnormal values according to the clinical cut-off (CRP > 10 mg/L, albumin < 35 mg/L, GGT > 36 kU/L, HDL < 1.04 mmol/L). Mortality was studied with multivariate Cox proportional hazards models., Results: 2,245 persons died from cancer, 3,276 from circulatory disease, and 1,860 from other causes. There was a positive trend between mortality score and all-cause mortality as well as cancer and circulatory disease-specific death (e.g. HR for all-cause mortality: 1.39 (95%CI: 1.32-1.46), 2.04 (1.89-2.21), and 3.36 (2.87-3.93), for score=1, 2, and 3+, compared to score=0). Among cancer patients with no other co-morbidities (n=1,955), there was a positive trend between the score and mortality (HR: 1.24 (95%CI: 1.0.-1.49), 2.38 (95%CI: 1.76-3.22), and 5.47 (95%CI: 2.98-10.03) for score=1, 2, and 3+ compared to score=0)., Conclusions: By combining biomarkers of different mechanisms contributing to patient frailty, we found a strong marker for mortality in persons aged 50+. Elevated risks among cancer patients with no other co-morbidities prior to biomarker assessment call for validation in other cohorts and testing of different combinations and cut-offs than those used here, in order to aid decision-making in treatment of older cancer patients.

Background: While the association between obesity and endometrial cancer (EC) is well established, the underlying mechanisms require further study. We assessed possible links between lipid profiles and EC risk, while also taking into account BMI, parity, and menopausal status at baseline., Methods: Using the information available from the Swedish Apolipoprotein MOrtality RISk (AMORIS) study we created a cohort of 225,432 women with baseline values for glucose, triglycerides (TG), and total cholesterol (TC). Two subgroups of 31,792 and 26,317 had, in addition, baseline measurements of HDL, LDL, apolipoprotein A-I and apoB and BMI, respectively. We used Multivariate Cox proportional hazards models to analyze quartiles and dichotomized values of these lipid components for a link to EC risk., Results: During mean follow-up of 12 years (SD: 4.15), 1,144 persons developed endometrial cancer. A statistically significant association was found between TG and EC risk when using both quartiles and a clinical cut-off (Hazard Ratio (HR): 1.10 (95%CI: 0.88-1.37), 1.34 (1.09-1.63), and 1.57 (1.28-1.92)) for the 2(nd), 3(rd), and 4(th) quartile, compared to the 1(st), with P-value for trend: <0.001). The association remained after exclusion of the first three years of follow-up. Also total cholesterol and TG/HDL ratio were positively associated with EC risk, but no link was found for the other lipid components studied., Conclusion: This detailed analysis of lipid components showed a consistent relation between TG levels and EC risk. Future research should continue to analyze the metabolic pathway and its relation to EC risk, as a pathway to further understand the relation of obesity and disease.

Background. Metabolic syndrome has been linked to an increased cancer risk, but the role of dyslipidaemia in gastrointestinal malignancies is unclear. We aimed to assess the risk of oesophageal, stomach, colon, and rectal cancers using serum levels of lipid components. Methods. From the Swedish Apolipoprotein Mortality Risk (AMORIS) study, we selected 540,309 participants (> 20 years old) with baseline measurements of total cholesterol (TC), triglycerides (TG), and glucose of whom 84,774 had baseline LDL cholesterol (LDL), HDL cholesterol (HDL), apolipoprotein B (apoB), and apolipoprotein A-I (apoA-I). Multivariate Cox proportional hazards regression was used to assess glucose and lipid components in relation to oesophageal, stomach, colon, and rectal cancer risk. Results. An increased risk of oesophageal cancer was observed in persons with high TG (e.g. HR: 2.29 (95% CI: 1.42-3.68) for the 4th quartile compared to the 1st) and low LDL, LDL/HDL ratio, TC/HDL ratio, log (TG/HDL), and apoB/apoA-I ratio. High glucose and TG were linked with an increased colon cancer risk, while high TC levels were associated with an increased rectal cancer risk. Conclusion. The persistent link between TC and rectal cancer risk as well as between TG and oesophageal and colon cancer risk in normoglycaemic individuals may imply their substantiality in gastrointestinal carcinogenesis.

Most population-based studies studied the association between inflammation and prostate cancer (PCa) by assessing C-reactive protein (CRP). As these findings have shown inconsistent results, we aimed to also study different markers that have been commonly taken as indications of inflammation. A cohort based on four groups of men (n = 34,891), according to age at cohort entry (45, 55, 65 and 75 years), with measurements of glucose, triglycerides, total cholesterol, haptoglobin, albumin, hemoglobin and leukocytes were selected from the Apolipoprotein Mortality Risk database. A total of 17,937 men had measurements of non-high-sensitive CRP. Multivariate Cox proportional hazard models were used to analyze associations between inflammatory markers and PCa. A total of 49 of 12,063 men developed PCa in the age 45 group, whereas 207 of 9,940, 472 of 8,266 and 276 of 3,618 were diagnosed in the age 55, 65 and 75 groups, respectively. Mean follow-up time was 7.5 years (SD: 3.9). No markers showed an association with PCa risk, nor was there a trend by quartiles or an indication for different PCa risks by strata of hypercholesterolemia, hyperglycemia and hypertriglyceridemia status. The studied markers were not found to be associated with PCa risk. These null findings might be due to methodological issues; however, it is unlikely that strong and long-lasting associations between inflammation and PCa risk were missed as this was a large database with long follow-up. This indicates need for international consensus on appropriate inflammatory markers in the context of cancer that may be practically applied in large studies., (Copyright © 2011 UICC.)

Background: Apart from using gamma-glutamyltransferase (GGT) as a predictor of diabetes, cardiovascular and chronic kidney disease, some evidence suggests GGT as an indicator of cancer risk. We aimed to study the association between GGT and cancer in a large Swedish cohort with 37,809 primary cancers., Methods: In a cohort of 545,460 persons (aged >20 years) who had a measurement of GGT in the Apolipoprotein Mortality Risk (AMORIS) study, multivariate Cox proportional hazards regression was used to investigate categories of GGT (<18, 18-36,36-72, ≥72 U/L) in relation to cancer risk. Stratified analyses were conducted by gender, levels of alanine aminotransferase (ALT) (

Background: Epidemiological evidence indicates that individuals with type 2 diabetes are at an increased risk of cancer. Elevated glucose levels, below the diagnostic threshold for diabetes, have also been suggested to be associated with increased cancer risks., Methods: We investigated possible associations between glucose levels and the risk of breast, endometrial, and ovarian cancer in a cohort of more than 230,000 women, for which information on outcome and potential confounders was obtained by record linkage to population-based registers., Results: Diabetes was associated with an increased risk of postmenopausal breast cancer (HR = 1.22, 95% CI 1.04-1.43). An indication of a slightly elevated breast cancer risk was also found in postmenopausal women with impaired glucose metabolism (HR = 1.11, 95% CI 0.96-1.28). Diabetes (HR = 1.46, 95% CI 1.09-1.96) and impaired glucose metabolism (HR = 1.41, 95% CI 1.08-1.85) were associated with an increased risk of endometrial cancer. No associations were found between glucose levels and ovarian cancer risk. Following adjustment for BMI, estimates were attenuated for endometrial cancer, while point estimates for breast and ovarian cancer remained essentially unchanged., Conclusions: Our results indicate that glucose levels below the diagnostic threshold for diabetes modify the risk not only of endometrial cancer but possibly also of postmenopausal breast cancer.

Background: A detailed analysis of lipid profiles, using apolipoproteins, has not yet been conducted for prostate cancer (PCa). Since several etiological pathways have been proposed for PCa and lipids, we aimed to study this in a large Swedish cohort with 1,469 primary prostate cancers., Methods: A cohort (n = 69,735) of all men aged 35 years or older, whose levels of triglycerides (TG) (mmol/L), total cholesterol (mmol/L), glucose (mmol/L), LDL (mmol/L), HDL (mmol/L), apoB (g/L), and apoA-I (g/L) were measured at baseline, was selected from the Apolipoprotein MOrtality RISk (AMORIS) database. About 2,008 men developed PCa. Multivariate Cox proportional hazard models were used to analyze associations between lipid components and PCa., Results: ApoA-I and HDL were inversely associated with PCa risk (e.g., HR for HDL: 0.93 (95% CI: 0.81-1.07), 0.88 (0.76-1.01), 0.81 (0.70-0.94), for second, third, and fourth quartiles compared with the first quartile; with p for trend: 0.004; HR for apoA-I: 1.00 (0.88-1.13), 0.93 (0.82-1.05), 0.88 (0.77-0.99),), for second, third, and fourth quartiles compared with the first quartile; with p for trend: 0.022). ApoB, LDL, and non-HDL were not associated with PCa risk., Conclusions: Our results show that low HDL and ApoA-I as well as increased lipid ratios are related to increased PCa risk. Experimental studies are required to tease out the underlying biological mechanisms linking these lipid components to PCa.

Background: In a cohort including 5112 prostate cancer (pCa) patients, the authors investigated associations among triglycerides (TG), total cholesterol (TC), and pCa while taking into account glucose., Methods: A cohort (n = 200,660) based on 4 groups of men, according to age at cohort entry, with TG, TC, and glucose measurements was selected from the Apolipoprotein MOrtality RISk (AMORIS) database. Of these, 5112 men developed pCa. Multivariate Cox proportional hazard models were used to analyze associations among TG, TC, and pCa. Competing risks were assessed graphically., Results: Age-stratified analyses for quartiles of TG, TC, and glucose showed a negative association between glucose and pCa risk (HR, 0.93; 95% CI, 0.86-1.01), 0.93 (0.86-1.01), 0.87 (0.81-0.94) for the second, third, and fourth quartiles compared with the first (P(trend) = .001). Stratified analysis by glucose levels (<6.11 or ≥ 6.11 mmol/L) showed a positive association between hypertriglyceridemia (TG ≥ 1.71 mmol/L) and pCa risk, when there were high glucose levels (HR, 1.23; 95% CI, 1.01-1.48). No association was found for hypercholesterolemia (TC ≥ 6.50 mmol/L). Competing risk analysis showed that protective effects of glucose were overestimated in conventional Cox proportional hazard models and strengthened positive findings between TG and pCa risk., Conclusions: The authors'; findings supported the hypothesis that factors of the glucose and lipid metabolism influence pCa risk. Competing risk assessment showed that it is important to take into account the long natural history and age distribution of pCa when interpreting results. The authors'; findings indicate another reason to fight the increasing prevalence of obesity and dyslipidemia., (2010 American Cancer Society.)