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1.  Serum Lipids and the Risk of Gastrointestinal Malignancies in the Swedish AMORIS Study 
Journal of Cancer Epidemiology  2012;2012:792034.
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.
doi:10.1155/2012/792034
PMCID: PMC3437288  PMID: 22969802
2.  Inorganic phosphate and the risk of cancer in the Swedish AMORIS study 
BMC Cancer  2013;13:257.
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.
doi:10.1186/1471-2407-13-257
PMCID: PMC3664604  PMID: 23706176
Cancer; Inorganic phosphate; Prospective cohort study
3.  Iron metabolism and risk of cancer in the Swedish AMORIS study 
Cancer Causes & Control  2013;24(7):1393-1402.
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.
doi:10.1007/s10552-013-0219-8
PMCID: PMC3675271  PMID: 23649231
Cancer; C-reactive protein; Iron; Iron-binding capacity; Sweden
4.  Serum calcium and risk of gastrointestinal cancer in the Swedish AMORIS study 
BMC Public Health  2013;13:663.
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.
doi:10.1186/1471-2458-13-663
PMCID: PMC3729677  PMID: 23866097
Gastrointestinal cancer; Calcium; Albumin
5.  Biomarker-based score to predict mortality in persons aged 50 years and older: a new approach in the Swedish AMORIS study 
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.
PMCID: PMC3316450  PMID: 22493753
Frailty; mortality; albumin; HDL-cholesterol; C-reactive protein; gamma-glutamyltransferase
6.  Association between levels of C-reactive protein and leukocytes and cancer: Three repeated measurements in the Swedish AMORIS study 
Objective
To study levels of C-reactive protein (CRP) and leukocytes, as inflammatory markers, in the context of cancer risk.
Methods
From the Apolipoprotein MOrtality RISk (AMORIS) study, we selected 102,749 persons with one measurement and 9,273 persons with three repeated measurements of CRP and leukocytes. Multivariate Cox proportional hazards regression was applied to categories of CRP (<10, 10-15, 15-25, 25-50, >50 g/L) and quartiles of leukocytes. An Inflammation-based Predictive Score (IPS) indicated whether someone had CRP levels >10mg/L combined with leukocytes >10×109/L. Reverse causality was assessed by excluding those with <3, 5, or 7 years of follow-up. To analyze repeated measurements of CRP and leukocytes the repeated IPS (IPSr) was calculated by adding the IPS of each measurement.
Results
In the cohort with one measurement, there was a positive trend between CRP and cancer, with the lowest category being the reference: 0.99 (0.92-1.06), 1.28 (1.11-1.47), 1.27 (1.09-1.49), 1.22 (1.01-1.48) for the 2nd to 5th categories, respectively. This association disappeared when excluding those with follow-up <3, 5 or 7 years. The association between leukocytes and cancer was slightly stronger. In the cohort with repeated measurements the IPSr was strongly associated with cancer risk: 1.87 (1.33-2.63), 1.51 (0.56-4.06), 4.46 (1.43-13.87) for IPSr =1, 2, and 3, compared to IPSr =0. The association remained after excluding those with follow-up <1 year.
Conclusions and impact
Our large prospective cohort study adds evidence for a link between inflammatory markers and cancer risk by using repeated measurements and ascertaining reverse causality.
doi:10.1158/1055-9965.EPI-10-1190
PMCID: PMC3078551  PMID: 21297038
cancer; C-reactive protein; leukocytes; Sweden
7.  Associations between smoking, components of metabolic syndrome and lipoprotein particle size 
BMC Medicine  2013;11:195.
Background
The clustering of metabolic and cardiovascular risk factors is known as metabolic syndrome (MetS). The risk of having MetS is strongly associated with increased adiposity and can be further modified by smoking behavior. Apolipoproteins (apo) associated with low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C) may be altered in MetS. This study aimed to examine the association between smoking and the following parameters: MetS and its components, levels of apolipoproteins and estimated lipoprotein particle size, separately for men and women, and in different body mass index (BMI) classes.
Methods
We included 24,389 men and 35,078 women aged between 18 and 80 years who participated in the LifeLines Cohort Study between December 2006 and January 2012; 5,685 men and 6,989 women were current smokers. Participants were categorized into three different body mass index (BMI) classes (BMI <25; BMI 25 to 30; BMI ≥30 kg/m2). MetS was defined according to the National Cholesterol Education Program’s Adult Treatment Panel III (NCEP:ATPIII) criteria. Blood pressure, anthropometric and lipid measurements were rigorously standardized, and the large sample size enabled a powerful estimate of quantitative changes. The association between smoking and the individual MetS components, and apoA1 and apoB, was tested with linear regression. Logistic regression was used to examine the effect of smoking and daily tobacco smoked on risk of having MetS. All models were age adjusted and stratified by sex and BMI class.
Results
Prevalence of MetS increased with higher BMI levels. A total of 64% of obese men and 42% of obese women had MetS. Current smoking was associated with a higher risk of MetS in both sexes and all BMI classes (odds ratio 1.7 to 2.4 for men, 1.8 to 2.3 for women, all P values <0.001). Current smokers had lower levels of HDL cholesterol and apoA1, higher levels of triglycerides and apoB, and higher waist circumference than non-smokers (all P <0.001). Smoking had no consistent association with blood pressure or fasting blood glucose. In all BMI classes, we found a dose-dependent association of daily tobacco consumption with MetS prevalence as well as with lower levels of HDL cholesterol, higher triglyceride levels and lower ratios of HDL cholesterol/apoA1 and, only in those with BMI <30, LDL cholesterol/apoB (all P <0.001).
Conclusions
Smoking is associated with an increased prevalence of MetS, independent of sex and BMI class. This increased risk is mainly related to lower HDL cholesterol, and higher triglycerides and waist circumference. In addition, smoking was associated with unfavorable changes in apoA1 and apoB, and in lipoprotein particle size.
Please see related commentary: http://www.biomedcentral.com/1741-7015/11/196.
doi:10.1186/1741-7015-11-195
PMCID: PMC3766075  PMID: 24228807
Metabolic syndrome; Smoking; HDL; Cholesterol; Apolipoproteins; Triglycerides; Obesity; Cross-sectional; BMI classes
8.  A Prospective Study of Inflammation Markers and Endometrial Cancer Risk in Postmenopausal Hormone Non-Users 
BACKGROUND
It is hypothesized that inflammation may mediate the relationship between obesity and endometrial cancer risk. We examined the associations of three inflammation markers, C-reactive protein (CRP), interleukin (IL)-6, and tumor necrosis factor (TNF)-α, with risk of endometrial cancer.
METHODS
A case-cohort study was nested within the Women’s Health Initiative, a cohort of postmenopausal women. Baseline plasma samples of 151 incident endometrial cancer cases and 301 subcohort subjects not using hormones were assayed.
RESULTS
CRP, but not IL-6 or TNF-α, was positively associated with endometrial cancer risk after adjusting for age and BMI [hazard ratio comparing extreme quartiles (HRq4-q1) = 2.29; 95% confidence interval (CI) = 1.13–4.65; ptrend = 0.012). After additional adjustment for estradiol and insulin, this association was attenuated (HRq4-q1 = 1.70;95% CI= 0.78–3.68; ptrend = 0.127). Obesity (BMI ≥ 30 kg/m2) was associated with endometrial cancer risk in an age-adjusted model. The obesity effect was reduced by 48%, 67%, and 77% when either estradiol, CRP, or insulin, respectively, was included in the model, and it became null when all three factors were adjusted for simultaneously.
CONCLUSIONS
The association between inflammation, as indicated by a relatively high level of CRP, and endometrial cancer risk may partially be explained by hyperinsulinemia and elevated estradiol. Nevertheless, all three factors contribute to and mediate the link between obesity and endometrial cancer in postmenopausal women not using hormones.
IMPACT
The association between obesity and endometrial cancer risk in postmenopausal women may be attributed to inflammation, insulin resistance, and elevated estrogen.
doi:10.1158/1055-9965.EPI-10-1222
PMCID: PMC3096873  PMID: 21415362
9.  White Blood Cell Counts as Risk Markers of Developing Metabolic Syndrome and Its Components in the Predimed Study 
PLoS ONE  2013;8(3):e58354.
Background
The Metabolic Syndrome (MetS) is a cluster of metabolic abnormalities that includes hyperglucemia, hypertension, dyslipidemia and central obesity, conferring an increased risk of cardiovascular disease. The white blood cell (WBC) count has been proposed as a marker for predicting cardiovascular risk. However, few prospective studies have evaluated the relationship between WBC subtypes and risk of MetS.
Methods
Participants were recruited from seven PREDIMED study centers. Both a baseline cross-sectional (n = 4,377) and a prospective assessment (n = 1,637) were performed. Participants with MetS at baseline were excluded from the longitudinal analysis. The median follow-up was 3.9 years. Anthropometric measurements, blood pressure, fasting glucose, lipid profile and WBC counts were assessed at baseline and yearly during the follow-up. Participants were categorized by baseline WBC and its subtype count quartiles. Adjusted logistic regression models were fitted to assess the risk of MetS and its components.
Results
Of the 4,377 participants, 62.6% had MetS at baseline. Compared to the participants in the lowest baseline sex-adjusted quartile of WBC counts, those in the upper quartile showed an increased risk of having MetS (OR, 2.47; 95%CI, 2.03–2.99; P-trend<0.001). This association was also observed for all WBC subtypes, except for basophils. Compared to participants in the lowest quartile, those in the top quartile of leukocyte, neutrophil and lymphocyte count had an increased risk of MetS incidence. Leukocyte and neutrophil count were found to be strongly associated with the MetS components hypertriglyceridemia and low HDL-cholesterol. Likewise, lymphocyte counts were found to be associated with the incidence of the MetS components low HDL-cholesterol and high fasting glucose. An increase in the total WBC during the follow-up was also associated with an increased risk of MetS.
Conclusions
Total WBC counts, and some subtypes, were positively associated with MetS as well as hypertriglyceridemia, low HDL-cholesterol and high fasting glucose, all components of MetS.
Trial registration
Controlled-Trials.comISRCTN35739639.
doi:10.1371/journal.pone.0058354
PMCID: PMC3602299  PMID: 23526980
10.  Clinical Usefulness of Different Lipid Measures for Prediction of Coronary Heart Disease in Type 2 Diabetes 
Diabetes Care  2011;34(9):2095-2100.
OBJECTIVE
We assessed the association between different blood lipid measures and risk of fatal/nonfatal coronary heart disease (CHD).
RESEARCH DESIGN AND METHODS
We conducted an observational study of patients with type 2 diabetes from the Swedish National Diabetes Register. Baseline LDL cholesterol, non-HDL cholesterol, ratio of non-HDL to HDL cholesterol (non-HDL:HDL), and ratio of triacylglycerol to HDL cholesterol (TG:HDL) was measured in 18,673 patients aged 30–70 years, followed for a mean of 4.8 years from 2003 to 2007.
RESULTS
Hazard ratios (HRs) for CHD per 1-SD increment in lipid measures were 1.23 with non-HDL:HDL, 1.20 with non-HDL cholesterol, 1.17 with LDL cholesterol, and 1.15 with TG:HDL (all P < 0.001 when adjusted for clinical characteristics and nonlipid risk factors). The best global model fit was found with non-HDL:HDL. When patients within the lowest tertile of a lipid measure were compared with those with all lipid measures within the highest tertile, the adjusted HR for CHD was 0.62 with non-HDL:HDL <3.5 mmol/L, 0.65 with non-HDL cholesterol <3.3 mmol/L, and 0.70 with LDL cholesterol <2.5 mmol/L (all P < 0.001). The lowest tertile of LDL and non-HDL cholesterol corresponded with treatment targets according to U.S. and European guidelines. HRs for CHD were 0.52, 0.62, and 0.66 with the lowest deciles of non-HDL:HDL, non-HDL cholesterol, and LDL cholesterol ≤1.8 mmol/L (all P < 0.001). Mean TG:HDL was considerably lower in patients within the lowest tertile of non-HDL:HDL, 0.82 ± 0.47, than in those within the lowest tertile of LDL cholesterol (<2.5 mmol/L), 1.49 ± 1.03.
CONCLUSIONS
Non-HDL:HDL had a stronger effect on CHD risk than LDL cholesterol, and low TG:HDL values were more often seen within the lowest non-HDL:HDL tertile than within the lowest LDL cholesterol tertile. LDL cholesterol was not the best predictor of CHD risk in type 2 diabetes.
doi:10.2337/dc11-0209
PMCID: PMC3161275  PMID: 21775750
11.  Association of apolipoprotein A1 and B with kidney function and chronic kidney disease in two multiethnic population samples 
Nephrology Dialysis Transplantation  2012;27(7):2839-2847.
lipoprotein risk factors for atherosclerosis, i.e., increased LDL cholesterol, increased triglycerides and decreased HDL cholesterol, also are associated with progression of loss of kidney function...Goek and coworkers describe the association of the apoliproteins A1 and B and eGFR in two large cohorts derived from the general polulation [the NHANES III (N=7,023) and the ARIC study (n=10,292)]. The results were similar in both cohorts...
Background
Circulating lipoproteins and their protein constituents, apolipoproteins, are risk factors for chronic kidney disease (CKD). The associations between apolipoprotein A1, apolipoprotein B and their ratio with glomerular filtration rate estimated from the new CKD Epidemiology Collaboration (CKD-EPI) equation (eGFR) are not well studied in the general population.
Methods
Associations between apolipoprotein A1, B and their ratio with the outcomes of eGFR, CKD (eGFR <60 mL/min/1.73m2) and albuminuria were examined in the Atherosclerosis Risk in Communities study (ARIC, n = 10 292, 1996–98) and the Third National Health and Nutrition Examination Survey (NHANES III, n = 7023, 1988–91). Cross-sectional multivariable-adjusted analyses were performed using linear and logistic regression. Prospective analyses related baseline apolipoprotein levels to subsequent CKD incidence over 10 years using the ARIC Carotid MRI follow-up cohort (n = 1659).
Results
Higher apolipoprotein A1 quartiles were associated with a lower prevalence of CKD [Q4 versus Q1: odds ratio (OR) 0.73, P-trend = 0.02 in ARIC; Q4 versus Q1: OR 0.53, P-trend <0.01 in NHANES III] as well as with higher eGFR (P-trend <0.01 in ARIC and NHANES III). No consistent significant associations were found for apolipoprotein B in either study. The apolipoprotein B/A1 ratio was significantly associated with eGFR across quartiles in both studies (P-trend <0.01) and with CKD in ARIC (Q4 versus Q1: OR 1.23, P-trend = 0.01). Prospectively, there were trends for the association of apolipoproteins with incident CKD [Q4 versus Q1: incidence rate ratio (IRR) = 0.68 for apolipoprotein A1, P-trend = 0.1; Q4 versus Q1: IRR = 1.35 for apolipoprotein B, P-trend = 0.2]. Associations were not systematically stronger when comparing traditional lipids (total cholesterol, low-density lipoprotein or high-density lipoprotein) to apolipoproteins.
Conclusions
Higher serum apolipoprotein A1 was associated with lower prevalence of CKD and higher eGFR estimated by the CKD-EPI equation in two large multiethnic population-based samples. While apolipoprotein B showed no consistent associations, a higher apolipoprotein B/A1 ratio was significantly associated with lower eGFR in both studies. The direction and magnitude of the longitudinal associations between apolipoproteins and CKD incidence were overall similar to those observed cross-sectionally. No consistent differences became apparent between traditional lipids and apolipoproteins.
doi:10.1093/ndt/gfr795
PMCID: PMC3471548  PMID: 22287661
apolipoprotein; ARIC; chronic kidney disease; epidemiology; NHANES
12.  Effect of Excessive Weight Gain With Intensive Therapy of Type 1 Diabetes on Lipid Levels and Blood Pressure 
Context
Intensive treatment of type 1 diabetes results in greater weight gain than conventional treatment.
Objective
To determine the effect of this weight gain on lipid levels and blood pressure.
Design
Randomized controlled trial; ancillary study of the Diabetes Control and Complications Trial (DCCT).
Setting
Twenty-one clinical centers.
Participants
The 1168 subjects enrolled in DCCT with type 1 diabetes who were aged 18 years or older at baseline.
Intervention
Randomized to receive either intensive (n = 586) or conventional (n = 582) diabetes treatment with a mean follow-up of 6.1 years.
Main Outcome Measures
Plasma lipid levels and blood pressure in each treatment group categorized by quartile of weight gain.
Results
With intensive treatment, subjects in the fourth quartile of weight gain had the highest body mass index (BMI) (a measure of weight adjusted for height), blood pressure, and levels of triglyceride, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B compared with the other weight gain quartiles with the greatest difference seen when compared with the first quartile (mean values for the highest and lowest quartiles: BMI, 31 vs 24 kg/m2; blood pressure, 120/77 mm Hg vs 113/73 mm Hg; triglyceride, 0.99 mmol/L vs 0.79 mmol/L [88 mg/dL vs 70 mg/dL]; LDL-C, 3.15 mmol/L vs 2.74 mmol/L [122 mg/dL vs 106 mg/dL]; and apolipoprotein B, 0.89 g/L vs 0.78 g/L; all P<.001). In addition, the fourth quartile group had a higher waist-to-hip ratio; more cholesterol in the very low density lipoprotein, intermediate dense lipoprotein, and dense LDL fractions; and lower high-density lipoprotein cholesterol and apolipoprotein A-I levels compared with the first quartile. Baseline characteristics were not different between the first and fourth quartiles of weight gain with intensive therapy except for a higher hemoglobin A1c in the fourth quartile. Weight gain with conventional therapy resulted in smaller increases in BMI, lipids, and systolic blood pressure.
Conclusions
The changes in lipid levels and blood pressure that occur with excessive weight gain with intensive therapy are similar to those seen in the insulin resistance syndrome and may increase the risk of coronary artery disease in this subset of subjects with time.
PMCID: PMC2622729  PMID: 9669786
13.  Obesity, inflammatory markers, and endometrial cancer risk: a prospective case–control study 
Endocrine-Related Cancer  2010;17(4):1007-1019.
Obesity, a major risk factor for endometrial cancer, is a low-grade inflammatory state characterized by elevated concentrations of cytokines and acute phase reactants. The current study had two aims: first to investigate the associations of C-reactive protein (CRP), interleukin 6 (IL6), and IL1 receptor antagonist (IL1Ra) with endometrial cancer risk and second to examine to which extent these markers can influence the association between obesity and endometrial cancer. We conducted a case–control study, nested within the European Prospective Investigation into Cancer and Nutrition, which comprised 305 incident cases of endometrial cancer and 574 matched controls. CRP, IL6, and IL1Ra were measured in prospectively collected blood specimens by immunoassays. Data were analyzed using conditional logistic regression. All statistical tests were two-sided, and P values <0.05 were considered statistically significant. We observed a significant increase in risk of endometrial cancer with elevated levels of CRP (odds ratio (OR) for top versus bottom quartile: 1.58, 95% confidence interval (CI): 1.03–2.41, Ptrend=0.02), IL6 (OR for top versus bottom quartile: 1.66, 95% CI: 1.08–2.54, Ptrend=0.008), and IL1Ra (OR for top versus bottom quartile: 1.82, 95% CI: 1.22–2.73, Ptrend=0.004). After adjustment for body mass index (BMI), the estimates were strongly reduced and became non-significant. The association between BMI and endometrial cancer was also substantially attenuated (∼10–20%) after adjustment for inflammatory markers, even when the effects of C-peptide or estrone had already been taken into account. We provided epidemiological evidence that chronic inflammation might mediate the association between obesity and endometrial cancer and that endometrial carcinogenesis could be promoted by an inflammatory milieu.
doi:10.1677/ERC-10-0053
PMCID: PMC2966326  PMID: 20843938
14.  Risk Prediction for Breast, Endometrial, and Ovarian Cancer in White Women Aged 50 y or Older: Derivation and Validation from Population-Based Cohort Studies 
PLoS Medicine  2013;10(7):e1001492.
Ruth Pfeiffer and colleagues describe models to calculate absolute risks for breast, endometrial, and ovarian cancers for white, non-Hispanic women over 50 years old using easily obtainable risk factors.
Please see later in the article for the Editors' Summary
Background
Breast, endometrial, and ovarian cancers share some hormonal and epidemiologic risk factors. While several models predict absolute risk of breast cancer, there are few models for ovarian cancer in the general population, and none for endometrial cancer.
Methods and Findings
Using data on white, non-Hispanic women aged 50+ y from two large population-based cohorts (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial [PLCO] and the National Institutes of Health–AARP Diet and Health Study [NIH-AARP]), we estimated relative and attributable risks and combined them with age-specific US-population incidence and competing mortality rates. All models included parity. The breast cancer model additionally included estrogen and progestin menopausal hormone therapy (MHT) use, other MHT use, age at first live birth, menopausal status, age at menopause, family history of breast or ovarian cancer, benign breast disease/biopsies, alcohol consumption, and body mass index (BMI); the endometrial model included menopausal status, age at menopause, BMI, smoking, oral contraceptive use, MHT use, and an interaction term between BMI and MHT use; the ovarian model included oral contraceptive use, MHT use, and family history or breast or ovarian cancer. In independent validation data (Nurses' Health Study cohort) the breast and ovarian cancer models were well calibrated; expected to observed cancer ratios were 1.00 (95% confidence interval [CI]: 0.96–1.04) for breast cancer and 1.08 (95% CI: 0.97–1.19) for ovarian cancer. The number of endometrial cancers was significantly overestimated, expected/observed = 1.20 (95% CI: 1.11–1.29). The areas under the receiver operating characteristic curves (AUCs; discriminatory power) were 0.58 (95% CI: 0.57–0.59), 0.59 (95% CI: 0.56–0.63), and 0.68 (95% CI: 0.66–0.70) for the breast, ovarian, and endometrial models, respectively.
Conclusions
These models predict absolute risks for breast, endometrial, and ovarian cancers from easily obtainable risk factors and may assist in clinical decision-making. Limitations are the modest discriminatory ability of the breast and ovarian models and that these models may not generalize to women of other races.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In 2008, just three types of cancer accounted for 10% of global cancer-related deaths. That year, about 460,000 women died from breast cancer (the most frequently diagnosed cancer among women and the fifth most common cause of cancer-related death). Another 140,000 women died from ovarian cancer, and 74,000 died from endometrial (womb) cancer (the 14th and 20th most common causes of cancer-related death, respectively). Although these three cancers originate in different tissues, they nevertheless share many risk factors. For example, current age, age at menarche (first period), and parity (the number of children a woman has had) are all strongly associated with breast, ovarian, and endometrial cancer risk. Because these cancers share many hormonal and epidemiological risk factors, a woman with a high breast cancer risk is also likely to have an above-average risk of developing ovarian or endometrial cancer.
Why Was This Study Done?
Several statistical models (for example, the Breast Cancer Risk Assessment Tool) have been developed that estimate a woman's absolute risk (probability) of developing breast cancer over the next few years or over her lifetime. Absolute risk prediction models are useful in the design of cancer prevention trials and can also help women make informed decisions about cancer prevention and treatment options. For example, a woman at high risk of breast cancer might decide to take tamoxifen for breast cancer prevention, but ideally she needs to know her absolute endometrial cancer risk before doing so because tamoxifen increases the risk of this cancer. Similarly, knowledge of her ovarian cancer risk might influence a woman's decision regarding prophylactic removal of her ovaries to reduce her breast cancer risk. There are few absolute risk prediction models for ovarian cancer, and none for endometrial cancer, so here the researchers develop models to predict the risk of these cancers and of breast cancer.
What Did the Researchers Do and Find?
Absolute risk prediction models are constructed by combining estimates for risk factors from cohorts with population-based incidence rates from cancer registries. Models are validated in an independent cohort by testing their ability to identify people with the disease in an independent cohort and their ability to predict the observed numbers of incident cases. The researchers used data on white, non-Hispanic women aged 50 years or older that were collected during two large prospective US cohort studies of cancer screening and of diet and health, and US cancer incidence and mortality rates provided by the Surveillance, Epidemiology, and End Results Program to build their models. The models all included parity as a risk factor, as well as other factors. The model for endometrial cancer, for example, also included menopausal status, age at menopause, body mass index (an indicator of the amount of body fat), oral contraceptive use, menopausal hormone therapy use, and an interaction term between menopausal hormone therapy use and body mass index. Individual women's risk for endometrial cancer calculated using this model ranged from 1.22% to 17.8% over the next 20 years depending on their exposure to various risk factors. Validation of the models using data from the US Nurses' Health Study indicated that the endometrial cancer model overestimated the risk of endometrial cancer but that the breast and ovarian cancer models were well calibrated—the predicted and observed risks for these cancers in the validation cohort agreed closely. Finally, the discriminatory power of the models (a measure of how well a model separates people who have a disease from people who do not have the disease) was modest for the breast and ovarian cancer models but somewhat better for the endometrial cancer model.
What Do These Findings Mean?
These findings show that breast, ovarian, and endometrial cancer can all be predicted using information on known risk factors for these cancers that is easily obtainable. Because these models were constructed and validated using data from white, non-Hispanic women aged 50 years or older, they may not accurately predict absolute risk for these cancers for women of other races or ethnicities. Moreover, the modest discriminatory power of the breast and ovarian cancer models means they cannot be used to decide which women should be routinely screened for these cancers. Importantly, however, these well-calibrated models should provide realistic information about an individual's risk of developing breast, ovarian, or endometrial cancer that can be used in clinical decision-making and that may assist in the identification of potential participants for research studies.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001492.
This study is further discussed in a PLOS Medicine Perspective by Lars Holmberg and Andrew Vickers
The US National Cancer Institute provides comprehensive information about cancer (in English and Spanish), including detailed information about breast cancer, ovarian cancer, and endometrial cancer;
Information on the Breast Cancer Risk Assessment Tool, the Surveillance, Epidemiology, and End Results Program, and on the prospective cohort study of screening and the diet and health study that provided the data used to build the models is also available on the NCI site
Cancer Research UK, a not-for-profit organization, provides information about cancer, including detailed information on breast cancer, ovarian cancer, and endometrial cancer
The UK National Health Service Choices website has information and personal stories about breast cancer, ovarian cancer, and endometrial cancer; the not-for-profit organization Healthtalkonline also provides personal stories about dealing with breast cancer and ovarian cancer
doi:10.1371/journal.pmed.1001492
PMCID: PMC3728034  PMID: 23935463
15.  Gamma-glutamyl transferase and C-reactive protein as alternative markers of metabolic abnormalities and their associated comorbidites: a prospective cohort study 
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.
PMCID: PMC3508539  PMID: 23205179
GGT; CRP; metabolic abnormalities; cardiovascular disease; cancer
16.  Does Waist Indicate Dyslipidemia better than BMI in Korean Adult Population? 
Obesity is an independent and modifiable risk factor for cardiovascular disease, and known as a core of the metabolic syndrome. Obesity has been largely diagnosed based upon anthrompometric measurements like waist circumference (WC) and body mass index (BMI). We sought to determine associations between anthropometric measurements and dyslipidemia in a community adult sample composed of 1,032 community residents (356 men, 676 women) aged 50 yr and over in Namwon, Korea. Blood tests for lipid profiles, including total cholesterol (TC) and HDL cholesterol (HDL) were performed, and dyslipidemia was defined as TC/HDL greater than 4. Anthropometric measurements included WC, waist-to-height ratio (WHtR), waist-to-hip ratio, and BMI. All anthropometric measures were categorized into quartiles and evaluated for associations with dyslipidemia. TC/HDL showed the significant associations with the anthropometric measures, independently of potential confounders. In women, increases of obesity indexes by quartile analyses showed linear increases of odds ratios for dyslipidemia (p values <0.01 by trend test). In men, except BMI, same patterns of association were noted. WC and WHtR were significantly associated with dyslipidemia in Korean adult population. As a simple and non-invasive method for a detection of obesity and dyslipidemia, anthropometric measurements could be efficiently used in clinical and epidemiologic fields.
doi:10.3346/jkms.2005.20.1.7
PMCID: PMC2808579  PMID: 15716594
Anthropometry; Waist Circumference; Body Mass Index; Hyperlipidemia; Population
17.  Major Lipids, Apolipoproteins, and Risk of Vascular Disease 
Context
Associations of major lipids and apolipoproteins with the risk of vascular disease have not been reliably quantified.
Objective
To assess major lipids and apolipoproteins in vascular risk.
Design, Setting, and Participants
Individual records were supplied on 302 430 people without initial vascular disease from 68 long-term prospective studies, mostly in Europe and North America. During 2.79 million person-years of follow-up, there were 8857 nonfatal myocardial infarctions, 3928 coronary heart disease [CHD] deaths, 2534 ischemic strokes, 513 hemorrhagic strokes, and 2536 unclassified strokes.
Main Outcome Measures
Hazard ratios (HRs), adjusted for several conventional factors, were calculated for 1-SD higher values: 0.52 loge triglyceride, 15 mg/dL high-density lipoprotein cholesterol (HDL-C), 43 mg/dL non-HDL-C, 29 mg/dL apolipoprotein AI, 29 mg/dL apolipoprotein B, and 33 mg/dL directly measured low-density lipoprotein cholesterol (LDL-C). Within-study regression analyses were adjusted for within-person variation and combined using meta-analysis.
Results
The rates of CHD per 1000 person-years in the bottom and top thirds of baseline lipid distributions, respectively, were 2.6 and 6.2 with triglyceride, 6.4 and 2.4 with HDL-C, and 2.3 and 6.7 with non-HDL-C. Adjusted HRs for CHD were 0.99 (95% CI, 0.94-1.05) with triglyceride, 0.78 (95% CI, 0.74-0.82) with HDL-C, and 1.50 (95% CI, 1.39-1.61) with non-HDL-C. Hazard ratios were at least as strong in participants who did not fast as in those who did. The HR for CHD was 0.35 (95% CI, 0.30-0.42) with a combination of 80 mg/dL lower non-HDL-C and 15 mg/dL higher HDL-C. For the subset with apolipoproteins or directly measured LDL-C, HRs were 1.50 (95% CI, 1.38-1.62) with the ratio non-HDL-C/HDL-C, 1.49 (95% CI, 1.39-1.60) with the ratio apo B/apo AI, 1.42 (95% CI, 1.06-1.91) with non-HDL-C, and 1.38 (95% CI, 1.09-1.73) with directly measured LDL-C. Hazard ratios for ischemic stroke were 1.02 (95% CI, 0.94-1.11) with triglyceride, 0.93 (95% CI, 0.84-1.02) with HDL-C, and 1.12 (95% CI, 1.04-1.20) with non-HDL-C.
Conclusion
Lipid assessment in vascular disease can be simplified by measurement of either total and HDL cholesterol levels or apolipoproteins without the need to fast and without regard to triglyceride.
doi:10.1001/jama.2009.1619
PMCID: PMC3284229  PMID: 19903920
18.  Body Size, Adult BMI Gain and Endometrial Cancer Risk: The Multiethnic Cohort 
The effect of body size and change in BMI on endometrial cancer risk across different racial/ethnic groups has not been studied. We examined the association between body size and endometrial cancer risk and potential effect modification of other risk factors among 50,376 women in the Multiethnic Cohort Study. During 10.3 years of follow-up, 463 endometrial cancer cases were identified. Epidemiologic data were collected from the baseline questionnaire. “BMI change” was defined as the percentage of body mass index change from age 21 to the time of recruitment. Women who were heavier at age 21 or at baseline (weight ≥ 53.5kg or ≥ 63.9 kg, respectively) had an increased endometrial cancer risk compared to the lowest quartile of weight during the respective periods. BMI gain ≥ 35% had a RR of 4.12 (95% CI: 2.69, 6.30) compared to the reference group (−5% ≤ BMI change <+5%). Women who averaged an annual BMI gain ≥ 1% had a >3.20-fold (95% CI: 2.37, 4.33) increased risk compared to women who maintained a stable adult BMI (−0.25 to <+0.25%). The highest risk associated with BMI gain was observed among nulliparous women and postmenopausal women who never used hormone therapy. While African Americans and Whites showed an increase in risk after ≥ 35% BMI gain, Japanese Americans showed an increase in risk with much smaller gain (≥ 5%). In conclusion, adult obesity and increase in adiposity are risk factors for endometrial cancer; and the risk associated with these factors may vary across racial/ethnic groups.
doi:10.1002/ijc.24718
PMCID: PMC2795089  PMID: 19585578
Weight change; endometrial cancer; multiethnic populations
19.  Food patterns associated with blood lipids are predictive of coronary heart disease: the Whitehall II study 
The British journal of nutrition  2009;102(4):619-624.
Analysis of the epidemiological effects of overall dietary patterns offers an alternative approach to the investigation of the role of diet in coronary heart disease (CHD).We analyzed the role of blood lipid-related dietary patterns using a two-step method to confirm the prospective association of dietary pattern with incident CHD. Analysis is based on 7314 participants of the Whitehall II study. Dietary intake was measured using a 127-item food frequency questionnaire. Reduced rank regression (RRR) was used to derive dietary pattern scores using baseline serum total and HDL cholesterol, and triglyceride levels as dependent variables. Cox proportional hazard regression was used to confirm the association between dietary patterns and incident CHD (n=243) over 15 years of follow-up. Increased CHD risk (hazard ratio for top quartile:2.01, 95%CI 1.41-2.85, adjusted for age, sex, ethnicity and energy misreporting) was observed with a diet characterised by high consumption of white bread, fried potatoes, sugar in tea and coffee, burgers & sausages, soft drinks, and low consumption of French dressing and vegetables. The diet-CHD relationship was attenuated after adjustment for employment grade and health behaviors (HR for top quartile:1.81, 95%CI 1.26-2.62), and further adjustment for blood pressure and BMI (HR for top quartile:1.57, 95% CI 1.08-2.27). Dietary patterns are associated with serum lipids and predict CHD risk after adjustment for confounders. RRR identifies dietary patterns uses prior knowledge and focuses on the pathways through which diet may influence disease. This study adds to the evidence that diet is an important risk factor for CHD.
doi:10.1017/S0007114509243030
PMCID: PMC2788758  PMID: 19327192
dietary patterns; lipids; coronary heart disease; prospective cohort study; Whitehall II study
20.  Serum selenium and serum lipids in US adults2 
Background:
Selenium, an essential micronutrient, has received considerable attention for its antioxidant properties. In addition, selenium may affect several cardiometabolic risk factors, such as glucose homeostasis and lipid concentrations. However, the effects of selenium intake on the lipid profile in selenium-replete populations, such as the United States, are largely unknown.
Objective:
We examined the relation of serum selenium concentrations with serum lipids in a representative sample of US adults.
Design:
This was a cross-sectional analysis of 5452 men and women aged ≥ 20 y participating in the third National Health and Nutrition Examination survey. Serum selenium was measured by atomic absorption spectrometry.
Results:
The multivariable adjusted differences in total cholesterol, LDL cholesterol, HDL cholesterol, apolipoprotein B (apo B), and apolipoprotein A-I (apo A-I) comparing the highest with the lowest quartile of serum selenium were 16.6 mg/dL (95% CI: 11.6, 21.4 mg/dL), 10.9 mg/dL (95% CI: 6.4, 15.4 mg/dL), 3.2 mg/dL (95% CI: 1.6, 5.0 mg/dL), 8.9 mg/dL (95% CI: 5.6, 12.2 mg/dL), and 6.9 mg/dL (95% CI: 1.7, 12.1 mg/dL), respectively. Participants in the highest quartile of serum selenium had 10% higher concentrations of triacylglycerols than did participants in the lowest quartile (ratio of triacylglycerol concentrations: 1.10; 95% CI: 1.05, 1.17). The difference in the ratios of LDL cholesterol to HDL cholesterol and apo B to apo A-I that compared the highest with the lowest selenium quartiles were 0.11 (95% CI: −0.02, 0.25) and 0.03 (95% CI: 0.00, 0.06), respectively.
Conclusion:
Elevated serum selenium was associated with elevated serum concentrations of total cholesterol, LDL cholesterol, HDL cholesterol, triacylglycerols, apo B, and apo A-I among US adults, a selenium-replete population. Experimental studies are needed to determine cause and effect relations and the potential mechanisms underlying these associations.
PMCID: PMC2553708  PMID: 18689378
21.  Molecular sources of residual cardiovascular risk, clinical signals, and innovative solutions: relationship with subclinical disease, undertreatment, and poor adherence: implications of new evidence upon optimizing cardiovascular patient outcomes 
Residual risk, the ongoing appreciable risk of major cardiovascular events (MCVE) in statin-treated patients who have achieved evidence-based lipid goals, remains a concern among cardiologists. Factors that contribute to this continuing risk are atherogenic non-low-density lipoprotein (LDL) particles and atherogenic processes unrelated to LDL cholesterol, including other risk factors, the inherent properties of statin drugs, and patient characteristics, ie, genetics and behaviors. In addition, providers, health care systems, the community, public policies, and the environment play a role. Major statin studies suggest an average 28% reduction in LDL cholesterol and a 31% reduction in relative risk, leaving a residual risk of about 69%. Incomplete reductions in risk, and failure to improve conditions that create risk, may result in ongoing progression of atherosclerosis, with new and recurring lesions in original and distant culprit sites, remodeling, arrhythmias, rehospitalizations, invasive procedures, and terminal disability. As a result, identification of additional agents to reduce residual risk, particularly administered together with statin drugs, has been an ongoing quest. The current model of atherosclerosis involves many steps during which disease may progress independently of guideline-defined elevations in LDL cholesterol. Differences in genetic responsiveness to statin therapy, differences in ability of the endothelium to regenerate and repair, and differences in susceptibility to nonlipid risk factors, such as tobacco smoking, hypertension, and molecular changes associated with obesity and diabetes, may all create residual risk. A large number of inflammatory and metabolic processes may also provide eventual therapeutic targets to lower residual risk. Classically, epidemiologic and other evidence suggested that raising high-density lipoprotein (HDL) cholesterol would be cardioprotective. When LDL cholesterol is aggressively lowered to targets, low HDL cholesterol levels are still inversely related to MCVE. The efflux capacity, or ability to relocate cholesterol out of macrophages, is believed to be a major antiatherogenic mechanism responsible for reduction in MCVE mediated in part by healthy HDL. HDL cholesterol is a complex molecule with antioxidative, anti-inflammatory, anti-thrombotic, antiplatelet, and vasodilatory properties, among which is protection of LDL from oxidation. HDL-associated paraoxonase-1 has a major effect on endothelial function. Further, HDL promotes endothelial repair and progenitor cell health, and supports production of nitric oxide. HDL from patients with cardiovascular disease, diabetes, and autoimmune disease may fail to protect or even become proinflammatory or pro-oxidant. Mendelian randomization and other clinical studies in which raising HDL cholesterol has not been beneficial suggest that high plasma levels do not necessarily reduce cardiovascular risk. These data, coupled with extensive preclinical information about the functional heterogeneity of HDL, challenge the “HDL hypothesis”, ie, raising HDL cholesterol per se will reduce MCVE. After the equivocal AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) study and withdrawal of two major cholesteryl ester transfer protein compounds, one for off-target adverse effects and the other for lack of efficacy, development continues for two other agents, ie, anacetrapib and evacetrapib, both of which lower LDL cholesterol substantially. The negative but controversial HPS2-THRIVE (the Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) trial casts further doubt on the HDL cholesterol hypothesis. The growing impression that HDL functionality, rather than abundance, is clinically important is supported by experimental evidence highlighting the conditional pleiotropic actions of HDL. Non-HDL cholesterol reflects the cholesterol in all atherogenic particles containing apolipoprotein B, and has outperformed LDL cholesterol as a lipid marker of cardiovascular risk and future mortality. In addition to including a measure of residual risk, the advantages of using non-HDL cholesterol as a primary lipid target are now compelling. Reinterpretation of data from the Treating to New Targets study suggests that better control of smoking, body weight, hypertension, and diabetes will help lower residual risk. Although much improved, control of risk factors other than LDL cholesterol currently remains inadequate due to shortfalls in compliance with guidelines and poor patient adherence. More efficient and greater use of proven simple therapies, such as aspirin, beta-blockers, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, combined with statin therapy, may be more fruitful in improving outcomes than using other complex therapies. Comprehensive, intensive, multimechanistic, global, and national programs using primordial, primary, and secondary prevention to lower the total level of cardiovascular risk are necessary.
doi:10.2147/VHRM.S37119
PMCID: PMC3808150  PMID: 24174878
cardiovascular prevention; low-density lipoprotein; high-density lipoprotein; statin drugs; metabolic syndrome; obesity; diabetes; niacin; AIM-HIGH study; cholesteryl ester transfer protein; endothelial progenitor cells; fibrate drugs
22.  OBESITY IN RELATION TO ENDOMETRIAL CANCER RISK AND DISEASE CHARACTERISTICS IN THE WOMEN’S HEALTH INITIATIVE 
Gynecologic oncology  2011;121(2):376-382.
Objective
Obesity increases endometrial cancer risk, yet its impact on disease stage and grade is unclear. We prospectively examined the effects of body mass index (BMI) and waist-to-hip ratio (WHR) on incidence, stage, and grade of endometrial cancer.
Methods
We studied 86,937 postmenopausal women enrolled in the Women’s Health Initiative. Height, weight, and waist and hip circumference were measured at baseline. Endometrial cancer cases were adjudicated by trained physicians and pathology reports were used to determine stage and grade. Cox proportional hazards models generated hazard ratios (HR) for associations between BMI and WHR and risk of endometrial cancer. Logistic regression was used to evaluate associations between BMI and WHR and disease stage and grade.
Results
During a mean 7.8 (standard deviation 1.6) years of follow-up, 806 women were diagnosed with endometrial cancer. Though incidence was higher among Whites, stage and grade were similar between Whites and Blacks. Elevated BMI (HR 1.76, 95% confidence interval [CI] 1.41-2.19) and WHR (HR 1.33, 95% CI 1.04-1.70) increased endometrial cancer risk when comparing women in the highest and lowest categories. No associations were observed between BMI or WHR and disease stage or grade.
Conclusions
Obesity increases endometrial cancer risk independent of other factors, but is not associated with stage or grade of disease. These findings support and validate previous reports. Future research should evaluate the impact of obesity on racial disparities in endometrial cancer survival.
doi:10.1016/j.ygyno.2011.01.027
PMCID: PMC3081892  PMID: 21324514
Body Mass Index; Waist-Hip Ratio; Endometrial Neoplasms; African Americans; Caucasians
23.  Prognostic Effect of Circulating Adiponectin in a Randomized 2 × 2 Trial of Low-Dose Tamoxifen and Fenretinide in Premenopausal Women at Risk for Breast Cancer 
Journal of Clinical Oncology  2011;30(2):151-157.
Purpose
Adipokines are linked to obesity and insulin sensitivity and have recently been related to breast cancer risk and prognosis. We investigated the associations of plasma leptin and adiponectin with mammographic density and disease status and assessed their prognostic effect on recurrence-free survival in premenopausal women at risk for breast cancer.
Patients and Methods
We measured circulating lipids, insulin-like growth factor 1, glucose, insulin and insulin sensitivity (calculated by homeostasis model assessment [HOMA] index), leptin, adiponectin, and leptin-to-adiponectin ratio in 235 premenopausal women with pT1mic/pT1a breast cancer (n = 21), intraepithelial neoplasia (n = 160), or 5-year Gail risk of 1.3% or greater (n = 54) who participated in a 2 × 2 trial of low-dose tamoxifen, fenretinide, both agents, or placebo over a 2-year period.
Results
At baseline, adiponectin levels were directly associated with mammographic density and HDL cholesterol and negatively associated with leptin, leptin-to-adiponectin ratio, body mass index (BMI), and HOMA index. Median adiponectin levels were lower in affected than in unaffected women (P = .006). After a median of 7.2 years and total of 57 breast neoplastic events, there was a 12% reduction in the risk of breast neoplastic events per unit increase of adiponectin (adjusted hazard ratio, 0.88; 95% CI, 0.81 to 0.96; P = .03). There was no interaction between treatment and adiponectin levels.
Conclusion
Low adiponectin levels are associated with a history of prior intraepithelial neoplasia or pT1mic/pT1a breast cancer and higher risk of second breast neoplastic events in premenopausal women. The associations are independent of BMI, mammographic density, and treatment. Our findings support the role of adiponectin as a potential target for premenopausal breast cancer prevention and treatment.
doi:10.1200/JCO.2011.35.2237
PMCID: PMC3255561  PMID: 22162577
24.  Body Mass Index, Waist-circumference and Cardiovascular Disease Risk Factors in Iranian Adults: Isfahan Healthy Heart Program 
Considering the main effect of obesity on chronic non-communicable diseases, this study was performed to assess the association between body mass index (BMI), waist-circumference (WC), cardiometabolic risk factors and to corroborate whether either or both BMI and WC are independently associated with the risk factors in a sample of Iranian adults. This cross-sectional study was performed on data from baseline survey of Isfahan Healthy Heart Program (IHHP). The study was done on 12,514 randomly-selected adults in Isfahan, Najafabad and Arak counties in 2000-2001. Ages of the subjects were recorded. Fasting blood glucose (FBG), 2-hour post-load glucose (2hpp), serum lipids, systolic and diastolic blood pressure (SBP and DBP), BMI, WC, smoking status, and total daily physical activity were determined. Increase in BMI and WC had a significant positive relation with the mean of FBG, 2hpp, SBP, DBP, serum lipids, except for HDL-C (p<0.001 for all). After adjustment for age, smoking, physical activity, socioeconomic status (SES), and BMI, the highest odds ratio (OR) (95% CI) for diabetes mellitus (DM) according to WC was 3.13 (1.93-5.08) and 1.99 (1.15-3.44) in women and men respectively. Moreover, the highest ORs based on BMI with adjustment for age, smoking, physical activity, SES, and WC were for dyslipidaemia (DLP) [1.97 (1.58-2.45) in women and 2.96 (2.41-3.63) in men]. The use of BMI or WC alone in the models caused to enhance all ORs. When both BMI and WC were entered in the model, the ORs for all risk factors, in men, according to BMI, were more compared to WC. However, in women, ORs for DM and hypertension (HTN) in WC quartiles were more than in BMI quartiles. BMI is the better predictor of DM, HTN, and DLP in men compared to WC. Conversely, in women, WC is a superior predictor than BMI, particularly for DM and HTN. Furthermore, the measurement of both WC and BMI in Iranian adults may be a better predictor of traditional risk factors of CVDs compared to BMI or WC alone.
PMCID: PMC3805889  PMID: 24288953
Body mass index; Diabetes mellitus; Dyslipidaemia; Hypertension; Obesity; Risk Factor; Waist-circumference; Iran
25.  Low Body Mass Index and Dyslipidemia in Dialysis Patients linked to Elevated Plasma Fibroblast Growth Factor 23 
American journal of nephrology  2013;37(3):183-190.
Background
Fibroblast growth factor 23 (FGF23) has been associated with death in dialysis patients. Since FGF23 shares structural features with FGF19-subfamily members that exert hormonal control of fat mass, we hypothesized that high circulating FGF23 concentrations would be associated with the development of a uremic lipid profile and lower body mass index.
Methods
This study was conducted among 654 patients receiving chronic hemodialysis. C-terminal FGF23 concentrations were measured in stored plasma samples. Linear regression was used to examine the cross-sectional associations of plasma FGF23 concentrations with body mass index (BMI), total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) and triglycerides (TG). Cox-proportional hazard models were used to examine the association between FGF23 concentrations and all-cause mortality.
Results
Participants had a mean age of 60 ± 11 years and a median [IQR] FGF23 concentration of 4212 [1411-13816] RU/mL. An increase per SD in log10 FGF23 was associated with lower BMI (β= −1.11; p=0.008), TC (β= −6.46; p=0.02), LDL-C (β= −4.73; p=0.04) and HDL-C (β= −2.14; p=0.03); after adjusting for age, gender, race, cardiovascular risk factors, serum albumin, markers of mineral metabolism, and use of lipid lowering drugs. The association of FGF23 with death was attenuated after adjustment for HDL-C (HR of highest quartile 1.53, 95% CI 1.06-2.20 compared to lowest quartile).
Conclusion
These results indicate that higher plasma FGF23 levels are associated with lower BMI and dyslipidemia in dialysis patients. The association between FGF23 and death may be mediated through unexplored metabolic risk factors unrelated to mineral metabolism.
doi:10.1159/000346941
PMCID: PMC3717381  PMID: 23428834
Hemodialysis; fibroblast growth factor 23; dyslipidemia; body mass index

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