Advanced glycation end products (AGE) accumulate in human tissue proteins during aging, particularly under hyperglycemia conditions. AGEs induce oxidative stress and inflammation via the receptor for AGEs (RAGE) and soluble RAGE (sRAGE) can neutralize the effects mediated by RAGE-ligand engagement.
We examined the association between N(e)-(carboxymethyl)lysine (CML), a prominent AGE, and sRAGE and colorectal cancer risk in a prospective case-cohort study nested within a cancer prevention trial among 29,133 Finnish male smokers. Among study subjects who were alive without cancer 5 years after baseline (1985-1988), we identified 483 incident colorectal cancer cases and randomly sampled 485 subcohort participants as the comparison group with the follow-up to April 2006. Baseline serum levels of CML-AGE, sRAGE, glucose and insulin were determined. Weighted Cox proportional hazard regression models were used to calculate relative risks (RR) and 95% CI.
Comparing highest with lowest quintile of sRAGE, the RR for incident colorectal cancer was 0.65 (95% CI, 0.39-1.07; P(trend) = 0.03), adjusting for age, years of smoking, body mass index, and CML-AGE. Further adjustment for serum glucose strengthened the association (RR = 0.52; 95% CI, 0.30-0.89; P(trend) = 0.009). Highest quintile of CML-AGE was not associated with an increased risk of colorectal cancer (multivariate RR = 1.20; 95% CI, 0.64-2.26).
Higher prediagnostic levels of serum sRAGE were associated with lower risk of colorectal cancer in male smokers.
This is the first epidemiologic study to implicate the receptor for AGEs in colorectal cancer development.
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Polymorphisms in the nicotinic acetylcholine receptor gene (CHRNA5/CHRNA3 locus) have been associated with several smoking related traits such as nicotine dependence, cigarette consumption, smoking cessation, lung cancer, and COPD. The aim of this candidate gene study was to study the locus among the Finnish COPD patients and long-term smokers with regard to COPD risk, smoking behavior, cancer, and all-cause mortality. Genotyping of rs1051730, the locus tagging SNP was done in two longitudinal cohorts: Finnish COPD patients (N = 575, 74% men) and long-term smokers, all men (N = 1911). Finnish population sample (N = 1730) was used as controls. The analyses were done using logistic and Cox regression. The main findings were that the minor allele increased the risk of COPD when compared to the Finnish population at large (OR = 1.4, 95% CI 1.2-1.7, p = 3.2 × 10-5). Homozygosity for the risk allele was associated in both cohorts with all-cause mortality (crude HR 2.2, 95% CI 1.2-3.8 and 1.3, 95% CI 1.1-1.5, respectively), with any type of cancer (crude OR 2.3, 95% CI 1.0-5.1) among the COPD patients and with the number of pack-years (crude OR 1.4, 95% CI 1.1-1.9) among the male smokers. CHRNA5/CHRNA3 locus tagged by rs1051730, which has been previously associated with several smoking related diseases was now shown to be associated also with increased all-cause mortality among long-term smokers with or without clinical COPD further emphasizing the clinical importance of the finding.
Folate is hypothesized to be inversely associated with the risk of several cancers, but such a potential association has not been well studied for prostate cancer. Vitamin B-6, vitamin B-12, methionine, and alcohol can influence folate-related metabolism.
The objective was to investigate the associations between dietary factors of one-carbon metabolism and prostate cancer risk within the alpha-Tocopherol, beta-Carotene Cancer Prevention Study.
Of the cohort's 27 111 Finnish male smokers aged 50-69 y who had complete dietary data, 1270 had a diagnosis of incident prostate cancer between 1985 and 2002. Folate, vitamin B-6, vitamin B-12, methionine, and alcohol intakes were estimated from a 276-item modified dietary history questionnaire. Cox proportional hazard models, adjusted for age and vitamin supplement use, estimated relative risks (RR) and 95% CIs.
Vitamin B-6 intake was inversely associated with prostate cancer risk (RR for highest versus lowest quintile: 0.88; 95% CI: 0.72, 1.07; P for trend = 0.045), whereas vitamin B-12 intake was associated with significantly increased risk (RR = 1.36; 95% CI: 1.14, 1.96; P for trend = 0.01). No association between folate or alcohol intake and prostate cancer risk was observed. No differences were found in the above associations according to stage of disease or subgroups of several potential effect modifiers.
We found no convincing evidence for a protective role of one-carbon metabolism against prostate cancer, although these observations can be generalized only to smokers. The possible modest protective association with vitamin B-6 and the significantly elevated risk with vitamin B-12 intake warrant further investigation.
Whether intakes of dietary fat and cholesterol are associated with risk of stroke remain unclear. We examined the associations between intakes of total fat, specific types of fat, and cholesterol and risk of stroke in a prospective cohort of women.
The study population consisted of 34,670 women, aged 49-83 years, in the Swedish Mammography Cohort who were free of cardiovascular disease and completed a food-frequency questionnaire in 1997. Cox proportional hazard regression models were used to estimate relative risks (RR) with 95% confidence intervals (CI).
During a mean follow-up of 10.4 years, we ascertained 1680 stroke events, including 1310 cerebral infarctions, 233 hemorrhagic strokes, and 137 unspecified strokes. After adjustment for other stroke risk factors, intake of long-chain omega-3 polyunsaturated fatty acids (PUFA) was inversely associated with risk of total stroke. The multivariable RR of total stroke for the highest compared with the lowest quintile of long-chain omega-3 PUFA intake was 0.84 (95% CI, 0.72-0.99; P for trend=0.04). Dietary cholesterol was positively associated with risk of total stroke (highest versus lowest quintile: RR=1.20; 95% CI, 1.00-1.44; P for trend=0.01) and cerebral infarction (corresponding RR=1.29; 95% CI, 1.05-1.58; P for trend=0.004). Total fat, saturated fat, monounsaturated fat, polyunsaturated fat, a-linolenic acid, and omega-6 PUFA intakes were not associated with stroke.
These findings suggest that intake of long-chain omega-3 PUFAs is inversely associated with risk of stroke, whereas dietary cholesterol is positively associated with risk.
A high protein intake may reduce the risk of stroke but epidemiologic data on protein intake in relation to stroke risk are limited and inconsistent. Our objective was to test the hypothesis that protein intake would be inversely associated with risk of stroke.
We conducted a population-based prospective cohort study consisting of 34,670 Swedish women who were free of cardiovascular disease and cancer in 1997. Diet was assessed with a food-frequency questionnaire. Incident cases of stroke were ascertained from the Swedish Hospital Discharge Registry. We estimated relative risks (RR) with 95% confidence intervals (CI) using Cox proportional hazard regression model. During 10.4 years of follow-up, 1680 stroke events were identified, including 1310 cerebral infarctions, 154 intracerebral hemorrhages, 79 subarachnoid hemorrhages, and 137 unspecified strokes. Intake of total and animal protein, but not vegetable protein, was statistically significantly inversely associated with risk of total stroke and cerebral infarction after adjustment for other risk factors for stroke. The multivariable RRs of total stroke for the highest versus lowest quintile of intake were 0.74 (95% CI: 0.61, 0.91; P for trend = 0.006) for total protein and 0.71 (95% CI: 0.57, 0.88; P for trend = 0.01) for animal protein. The associations were stronger in women with a history of hypertension (RR of total stroke = 0.56; 95% CI: 0.40, 0.78 for highest versus lowest quintile of total protein).
These findings suggest that dietary protein intake is inversely associated with risk of stroke in women with hypertension.
This study investigated the effects of alpha-tocopherol and beta-carotene supplementation on the incidence of gastric cancer.
A total of 29,133 male smokers, aged 50-69 years, participated in a placebo-controlled prevention trial, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study in southwestern Finland between 1985 and 1993. The men were randomly assigned to receive alpha-tocopherol (50 mg/day) or beta-carotene (20 mg/day) supplementation in a 2 x 2 factorial design. We identified 126 gastric cancer cases during the median follow-up of six years. Of these, 122 were adenocarcinomas: 75 of intestinal type, 30 of diffuse type, and 17 of mixed type.
There was no significant effect for either supplementation on the overall incidence of gastric cancer: relative risk (RR) 1.21, 95% confidence interval (CI) 0.85-1.74 for alpha-tocopherol, and RR 1.26, 95% Cl 0.88-1.80 for beta-carotene. Subgroup analyses by histologic type suggested an increased risk for beta-carotene on intestinal type cancers, RR 1.59, 95% CI 0.99-2.56. There were no differences across anatomic locations (cardia/noncardia) in the effects of alpha-tocopherol or beta-carotene supplementation.
Our study found no overall preventive effect of long-term supplementation with alpha-tocopherol or beta-carotene on gastric cancer in middle-aged male smokers.
Low urine pH may be an important risk factor for bladder cancer, although few studies have evaluated this association. We examined the relationship between estimated renal net acid excretion (NAE), an indirect measure of urine pH based on nutrient intake and anthropometry, and bladder cancer risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study.
At baseline, 27,096 male smokers 50-69 years old completed a dietary questionnaire that assessed usual frequency of consumption and portion sizes for the previous 12 months, had height and weight measured, and provided a history of smoking. A total of 446 incident bladder cancer cases were identified during up to 17.4 years of follow-up.
In multivariate proportional hazards models, the relative risk (RR) for bladder cancer was 1.15 (95% confidence interval (CI)=0.86-1.55) for individuals in the highest (i.e., most acidic) versus the lowest (i.e., least acidic) NAE quintile (p=0.38). Among men who smoked for more than 45 years, there was a suggestion of increased risk with higher NAE levels (RR=1.72, 95% CI=0.96-3.10, p=0.08).
These findings do not indicate that urine pH is a major risk factor for bladder cancer, although certain subsets of individuals may be at increased risk.
Cigarette smoking, obesity, type 2 diabetes, and, to a lesser extent, meat cooked at high temperatures are associated with pancreatic cancer. Cigarette smoke and foods cooked at higher temperatures are major environmental sources of advanced glycation end products (AGE). AGEs accumulate during hyperglycemia and elicit oxidative stress and inflammation through interaction with the receptor for AGEs (RAGE). Soluble RAGE (sRAGE) acts as an anti-inflammatory factor to neutralize AGEs and block the effects mediated by RAGE. In this study, we investigated the associations of prediagnostic measures of N(e)-(carboxymethyl)-lysine (CML)-AGE and sRAGE with pancreatic cancer in a case-cohort study within a cohort of 29,133 Finnish male smokers. Serum samples and exposure information were collected at baseline (1985-1988). We measured CML-AGE, sRAGE, glucose, and insulin concentrations in fasting serum from 255 incident pancreatic cancer cases that arose through April 2005 and from 485 randomly sampled subcohort participants. Weighted Cox proportional hazard regression models were used to calculate relative risks (RR) and 95% CI, adjusted for age, years of smoking, and body mass index. CML-AGE and sRAGE were mutually adjusted. CML-AGE levels were not associated with pancreatic cancer [fifth compared with first quintile, RR (95% CI): 0.68 (0.38-1.22), P(trend) = 0.27]. In contrast, sRAGE levels were inversely associated with pancreatic cancer [fifth compared with first quintile, RR (95% CI): 0.46 (0.23-0.73), P(trend) = 0.002]. Further adjustment for glucose or insulin levels did not change the observed associations. Our findings suggest that sRAGE is inversely associated with pancreatic cancer risk among Finnish male smokers.
Cites: Am J Epidemiol. 1999 Mar 15;149(6):531-4010084242
Epidemiologic studies of fish consumption in relation to risk of stroke have yielded inconsistent results.
In this study, we examined the association between fish consumption and stroke incidence in women.
We analyzed data from a population-based prospective cohort of 34,670 women in the Swedish Mammography Cohort who were free of cardiovascular disease and cancer at baseline. Information on fish consumption was obtained by a self-administered questionnaire in 1997. Incident cases of stroke were ascertained from the Swedish Hospital Discharge Registry. We used Cox proportional hazards regression to estimate relative risks (RRs) and 95% CIs.
Over a mean follow-up of 10.4 y, we ascertained 1680 incident cases of stroke, including 1310 cerebral infarctions, 233 hemorrhagic strokes, and 137 unspecified strokes. Fish consumption was significantly inversely associated with risk of total stroke but not with cerebral infarction or hemorrhagic stroke. Compared with women in the lowest quintile of fish consumption (3.0 servings of fish/wk) was 0.84 (95% CI: 0.71, 0.98; P for trend = 0.049). Consumption of lean fish but not of other fish types was inversely associated with risk of stroke. The multivariable RR of total stroke was 0.67 (95% CI: 0.49, 0.93; P for trend = 0.07) for =3 servings of lean fish/wk compared with that for no consumption.
These results suggest that the consumption of fish, especially of lean fish, may reduce risk of stroke in women. This trial was registered at clinicaltrials.gov as NCT01127698.
Comment In: Womens Health (Lond Engl). 2011 May;7(3):279-8121612349
Fish, vitamin D, flavonoids, and flavonoid-containing foods may have cardiovascular benefits and therefore may also reduce the risk of renal cell cancer. Risk was prospectively assessed in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (1985-2002) cohort (N = 27,111; 15.2 mean person-years of follow-up). At enrollment, demographic, health, and dietary history information was recorded. Individuals who smoked less than 5 cigarettes/day, with chronic renal insufficiency or prior cancer, were excluded. Hazard ratios and 95% confidence intervals from Cox regression were used to compare upper quartiles (quartiles 2-4) with the lowest quartile (quartile 1) of dietary intake. Among 228 cases, risk (quartile 4 vs. quartile 1) was associated with consumption of the flavonoid quercetin (hazard ratio = 0.6, 95% confidence interval: 0.4, 0.9; P(trend) = 0.015) and Baltic herring (hazard ratio = 2.0, 95% confidence interval: 1.4, 3.0; P(trend)
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