Differences in Biomarkers of Inflammation Between Novel Subgroups of Recent-Onset Diabetes.

A novel clustering approach identified five subgroups of diabetes with distinct progression trajectories of complications. We hypothesized that these subgroups differ in multiple biomarkers of inflammation. Serum levels of 74 biomarkers of inflammation were measured in 414 individuals with recent adult-onset diabetes from the German Diabetes Study (GDS) allocated to five subgroups based on data-driven cluster analysis. Pairwise differences between subgroups for biomarkers were assessed with generalized linear mixed models before (model 1) and after (model 2) adjustment for the clustering variables. Participants were assigned to five subgroups: severe autoimmune diabetes (21%), severe insulin-deficient diabetes (SIDD) (3%), severe insulin-resistant diabetes (SIRD) (9%), mild obesity-related diabetes (32%), and mild age-related diabetes (35%). In model 1, 23 biomarkers showed one or more pairwise differences between subgroups (Bonferroni-corrected P < 0.0007). Biomarker levels were generally highest in SIRD and lowest in SIDD. All 23 biomarkers correlated with one or more of the clustering variables. In model 2, three biomarkers (CASP-8, EN-RAGE, IL-6) showed at least one pairwise difference between subgroups (e.g., lower CASP8, EN-RAGE, and IL-6 in SIDD vs. all other subgroups, all P < 0.0007). Thus, novel diabetes subgroups show multiple differences in biomarkers of inflammation, underlining a prominent role of inflammatory pathways in particular in SIRD.

Persistent organic pollutants and the incidence of type 2 diabetes in the CARLA and KORA cohort studies.

BACKGROUND: Associations between several persistent organic pollutants (POPs) and type 2 diabetes have been found in humans, but the relationship has rarely been investigated in the general population. The current nested case-control study examined internal exposure to polychlorinated biphenyls (PCB) and pesticides and the incidence of type 2 diabetes among participants of two population-based German cohort studies. METHODS: We retrospectively selected 132 incident cases of type 2 diabetes and 264 age- and sex-matched controls from the CARdiovascular Living and Aging in Halle (CARLA) study (2002-2006, East Germany) and the Cooperative Health Research in the Region of Augsburg (KORA) study (1999-2001, South Germany) based on diabetes status at follow-up examinations in 2007-2010 and 2006-08, respectively (60% male, mean age 63 and 54 years). We assessed the association between baseline POP concentrations and incident diabetes by conditional logistic regression adjusted for cohort, BMI, cholesterol, alcohol, smoking, physical activity, and parental diabetes. Additionally, we examined effect modification by sex, obesity, parental diabetes and cohort. RESULTS: In both cohorts, diabetes cases showed a higher BMI, a higher frequency of parental diabetes, and higher levels of POPs. We observed an increased chance for incident diabetes for PCB-138 and PCB-153 with an odds ratio (OR) of 1.50 (95%CI: 1.07-2.11) and 1.53 (1.15-2.04) per interquartile range increase in the respective POP. In addition, explorative results suggested higher OR for women and non-obese participants. CONCLUSIONS: Our results add to the evidence on diabetogenic effects of POPs in the general population, and warrant both policies to prevent human exposure to POPs and additional research on the adverse effects of more complex chemical mixtures.

Neuropathic pain is not adequately treated in the older general population: Results from the KORA F4 survey.

PURPOSE: We evaluated the pharmacological treatment of distal sensorimotor polyneuropathy (DSPN) among older subjects from the general population. METHODS: The study included subjects aged 61 to 82 years from the KORA F4 survey (2006-2008). DSPN was defined as the presence of bilaterally impaired foot-vibration perception and/or bilaterally impaired foot-pressure sensation. Pain intensity was assessed with the painDETECT questionnaire. RESULTS: From the included 1076 older persons, 172 (16%) persons reported pain in the lower extremities and DSPN was present in 150 (14%) subjects. Forty-eight people with pain in the lower extremities reported DSPN. Only 38% of the subjects with DSPN reporting an average pain level of ≥4 during the past 4 weeks received medical treatment, predominantly nonsteroidal anti-inflammatory drugs (NSAIDs 20% and opioids 12%). The medication of choice for neuropathic pain, antidepressants, anticonvulsants, and opioids was relatively being underused. However, opioids and neuropathy preparations were prescribed preferably for subjects with painful DSPN. CONCLUSIONS: In the older general population, only a small proportion of subjects with painful DSPN receive analgesic pharmacotherapy. Although not recommended by guidelines for the treatment of neuropathic pain, NSAIDs were the most frequently used class of analgesic drugs.

Circulating Levels of Interleukin 1-Receptor Antagonist and Risk of Cardiovascular Disease: Meta-Analysis of Six Population-Based Cohorts.

OBJECTIVE: Interleukin (IL)-1ß represents a key cytokine in the development of cardiovascular disease (CVD). IL-1ß is counter-regulated by IL-1 receptor antagonist (IL-1RA), an endogenous inhibitor. This study aimed to identify population-based studies on circulating IL-1RA and incident CVD in a systematic review, estimate the association between IL-1RA and incident CVD in a meta-analysis, and to test whether the association between IL-1RA and incident CVD is explained by other inflammation-related biomarkers in the MONICA/KORA Augsburg case-cohort study (Multinational Monitoring of Trends and Determinants in Cardiovascular Disease/Cooperative Health Research in the Region of Augsburg). APPROACH AND RESULTS: We performed a systematic literature search and identified 5 cohort studies on IL-1RA and incident CVD in addition to the MONICA/KORA Augsburg case-cohort study for a meta-analysis based on a total of 1855 CVD cases and 18 745 noncases with follow-up times between 5 and 16 years. The pooled standardized hazard ratio (95% confidence interval) for incident CVD was 1.11 (1.06-1.17) after adjustment for age, sex, anthropometric, metabolic, and lifestyle factors (P<0.0001). There was no heterogeneity in effect sizes (I2=0%; P=0.88). More detailed analyses in the MONICA/KORA study showed that the excess risk for CVD was attenuated by ≥10% after additional separate adjustment for serum levels of high-sensitivity C-reactive protein, IL-6, myeloperoxidase, soluble E-selectin, or soluble intercellular adhesion molecule-1. CONCLUSIONS: Serum IL-1RA levels were positively associated with risk of CVD after adjustment for multiple confounders in a meta-analysis of 6 population-based cohorts. This association may at least partially reflect a response to triggers inducing subclinical inflammation, oxidative stress, and endothelial activation.

Effectiveness of chronic care models for the management of type 2 diabetes mellitus in Europe: a systematic review and meta-analysis.

OBJECTIVES: We evaluated the effectiveness of European chronic care programmes for type 2 diabetes mellitus (characterised by integrative care and a multicomponent framework for enhancing healthcare delivery), compared with usual diabetes care. DESIGN: Systematic review and meta-analysis. DATA SOURCES: MEDLINE, Embase, CENTRAL and CINAHL from January 2000 to July 2015. ELIGIBILITY CRITERIA: Randomised controlled trials focussing on (1) adults with type 2 diabetes, (2) multifaceted diabetes care interventions specifically designed for type 2 diabetes and delivered in primary or secondary care, targeting patient, physician and healthcare organisation and (3) usual diabetes care as the control intervention. DATA EXTRACTION: Study characteristics, characteristics of the intervention, data on baseline demographics and changes in patient outcomes. DATA ANALYSIS: Weighted mean differences in change in HbA1c and total cholesterol levels between intervention and control patients (95% CI) were estimated using a random-effects model. RESULTS: Eight cluster randomised controlled trials were identified for inclusion (9529 patients). One year of multifaceted care improved HbA1c levels in patients with screen-detected and newly diagnosed diabetes, but not in patients with prevalent diabetes, compared to usual diabetes care. Across all seven included trials, the weighted mean difference in HbA1c change was -0.07% (95% CI -0.10 to -0.04) (-0.8 mmol/mol (95% CI -1.1 to -0.4)); I2=21%. The findings for total cholesterol, LDL-cholesterol and blood pressure were similar to HbA1c, albeit statistical heterogeneity between studies was considerably larger. Compared to usual care, multifaceted care did not significantly change quality of life of the diabetes patient. Finally, measured for screen-detected diabetes only, the risk of macrovascular and mircovascular complications at follow-up was not significantly different between intervention and control patients. CONCLUSIONS: Effects of European multifaceted diabetes care patient outcomes are only small. Improvements are somewhat larger for screen-detected and newly diagnosed diabetes patients than for patients with prevalent diabetes.

Differential association between biomarkers of subclinical inflammation and painful polyneuropathy: results from the KORA F4 study.

OBJECTIVE: Inflammatory processes have been implicated in the pathogenesis of painful neuropathy in rodents, but the relationship between inflammatory biomarkers and painful distal sensorimotor polyneuropathy (DSPN) has not been assessed in population-based studies. Therefore, we investigated whether circulating levels of seven pro- and anti-inflammatory immune mediators were associated with painful DSPN in older individuals in a large population-based study. RESEARCH DESIGN AND METHODS: The study population consisted of individuals with painless (n = 337) and painful DSPN (n = 54) from a source population (n = 1,047) of men and women aged 61-82 years who participated in the German KORA F4 survey (2006-2008). We measured circulating levels of seven immune mediators and assessed their associations with the presence of painful DSPN using multiple logistic regression models. RESULTS: After adjustment for age and sex, we found positive associations between serum concentrations of the cytokine interleukin (IL)-6 and the soluble intercellular adhesion molecule (sICAM)-1 and painful DSPN (P = 0.004 and P = 0.005, respectively), whereas no associations were observed for C-reactive protein, IL-18, tumor necrosis factor-α, adiponectin, and IL-1 receptor antagonist (IL-1RA, P = 0.07-0.38). Associations between IL-6 and sICAM-1 and painful DSPN remained significant after additional adjustment for waist circumference, height, hypertension, cholesterol, smoking, alcohol intake, physical activity, history of myocardial infarction and/or stroke, presence of other neurological conditions, and use of nonsteroidal anti-inflammatory drugs (P = 0.005 and P = 0.016, respectively). CONCLUSIONS: Painful DSPN is linked to systemic subclinical and vascular inflammation in the older population independent of anthropometric, lifestyle, and metabolic confounders.

High-sensitive troponin T assay for the diagnosis of acute myocardial infarction: an economic evaluation.

BACKGROUND: Delayed diagnosis and treatment of Acute Myocardial Infarction (AMI) has a major adverse impact on prognosis in terms of both morbidity and mortality. Since conventional cardiac Troponin assays have a low sensitivity for diagnosing AMI in the first hours after myocardial necrosis, high-sensitive assays have been developed. The aim of this study was to assess the cost effectiveness of a high-sensitive Troponin T assay (hsTnT), alone or combined with the heart-type fatty acid-binding protein (H-FABP) assay in comparison with the conventional cardiac Troponin (cTnT) assay for the diagnosis of AMI in patients presenting to the hospital with chest pain. METHODS: We performed a cost-utility analysis (quality adjusted life years-QALYs) and a cost effectiveness analysis (life years gained-LYGs) based on a decision analytic model, using a health care perspective in the Dutch context and a life time time-horizon. The robustness of model predictions was explored using one-way and probabilistic sensitivity analyses. RESULTS: For a life time incremental cost of 30.70 Euros, use of hsTnT over conventional cTnT results in gain of 0.006 Life Years and 0.004 QALY. It should be noted here that hsTnT is a diagnostic intervention which costs only 4.39 Euros/test more than the cTnT test. The ICER generated with the use of hsTnT based diagnostic strategy comparing with the use of a cTnT-based strategy, is 4945 Euros per LYG and 7370 Euros per QALY. The hsTnT strategy has the highest probability of being cost effective at thresholds between 8000 and 20000 Euros per QALY. The combination of hsTnT and h-FABP strategy's probability of being cost effective remains lower than hsTnT at all willingness to pay thresholds. CONCLUSION: Our analysis suggests that hsTnT assay is a very cost effective diagnostic tool relative to conventional TnT assay. Combination of hsTnT and H-FABP does not offer any additional economic and health benefit over hsTnT test alone.

Association of subclinical inflammation with polyneuropathy in the older population: KORA F4 study.

OBJECTIVE: Inflammatory processes have been implicated in the pathogenesis of diabetic distal sensorimotor polyneuropathy (DSPN), but their possible relationship has not been assessed at the population level. RESEARCH DESIGN AND METHODS: We determined serum concentrations of mediators of subclinical inflammation among 1,047 participants 61-82 years of age from the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4 study (Germany). Logistic and linear regression models were fitted to assess associations between immune mediators (log-transformed) and the presence of clinical DSPN (dichotomous variable) or Michigan Neuropathy Screening Instrument (MNSI) examination score (continuous variable), respectively. RESULTS: Serum concentrations of the anti-inflammatory interleukin (IL)-1 receptor antagonist (IL-1RA) were positively associated with the presence of DSPN and higher MNSI scores in age-adjusted and sex-adjusted analyses, whereas IL-6, IL-18, and soluble intercellular adhesion molecule-1 were positively associated with only MNSI scores. No associations were observed for adiponectin, C-reactive protein, or tumor necrosis factor-α. Associations for IL-1RA and IL-6 with the MNSI score remained statistically significant after additional adjustment for waist circumference, height, hypertension, cholesterol, smoking, alcohol intake, physical activity, history of myocardial infarction or stroke, presence of neurological conditions, and use of nonsteroidal anti-inflammatory drugs. CONCLUSIONS: We conclude that DSPN is linked to proinflammatory and anti-inflammatory, possibly compensatory, processes in the older general population. Future studies should clarify the temporal sequence and causality of these associations.

Older subjects with diabetes and prediabetes are frequently unaware of having distal sensorimotor polyneuropathy: the KORA F4 study.

OBJECTIVE: Distal sensorimotor polyneuropathy (DSPN) is a severe complication of type 2 diabetes. This study aimed to assess the prevalence of unawareness of DSPN in prediabetes and diabetes in a sample of the older population of Augsburg, Germany. RESEARCH DESIGN AND METHODS: Glucose tolerance status was determined in 61- to 82-year-old participants of the population-based KORA F4 Study (2006-2008) (n = 1,100). Clinical DSPN was defined as the presence of bilaterally impaired foot-vibration perception and/or bilaterally impaired foot-pressure sensation. DSPN case subjects were considered unaware of their condition when answering "no" to the question, "Has a physician ever told you that you are suffering from nerve damage, neuropathy, polyneuropathy, or diabetic foot?" RESULTS: Clinical DSPN was prevalent in 154 (14%) participants, 140 of whom were unaware of their disorder. At a prevalence of 23.9% (95% CI 12.6-38.8), participants with combined impaired fasting glucose and impaired glucose tolerance had the highest prevalence of DSPN. Of these, 10 of 11 (91%) were unaware of having clinical DSPN. Participants with known diabetes had an equally high prevalence of DSPN [22.0% (16.2-28.9)], with 30 of the 39 (77%) DSPN case subjects unaware of having the disorder. Among subjects with known diabetes who reported to have had their feet examined by a physician, 18 of 25 (72%) clinical DSPN case subjects emerged unaware of having DSPN. CONCLUSIONS: Our findings showed a high prevalence of unawareness of having clinical DSPN among the prediabetic and diabetic groups and an insufficient frequency of professional foot examinations, suggesting inadequate attention to diabetic foot prevention practice.

Chemokines CCL3/MIP1α, CCL5/RANTES and CCL18/PARC are independent risk predictors of short-term mortality in patients with acute coronary syndromes.

Cytokines play an important role in ischemic injury and repair. However, little is known about their prognostic value in cardiovascular disease. The aim of this study was to investigate the prognostic importance of chemokines CCL3/MIP-1α, CCL5/RANTES and CCL18/PARC for the risk of future cardiovascular events in patients with acute coronary syndromes (ACS). Baseline levels of CCL3/MIP-1α, CCL5/RANTES and CCL18/PARC were determined in ACS patients from the Bad Nauheim ACS II registry (n = 609). During the following 200 days, patients were monitored for the occurrence of fatal and non-fatal cardiovascular events. Patients with CCL3/MIP1α, CCL5/RANTES and CCL18/PARC concentrations in the highest tertile were associated with an increased risk of a fatal event during follow-up (HR: 2.19, 95%CI: 1.04-4.61 for CCL3/MIP1α, HR: 3.45, 95%CI: 1.54-7.72 for CCL5/RANTES and HR: 3.14, 95%CI: 1.33-7.46 for CCL18/PARC). This risk was highest for patients with all three biomarkers concentrations in the upper tertile (HR: 2.52, 95%CI: 1.11-5.65). Together with known risk predictors of cardiovascular events, CCL3/MIP-1α, CCL5/RANTES and CCL18/PARC combined improved the c-statistics from 0.74 to 0.81 (p = 0.007). In conclusion, CCL3/MIP-1α, CCL5/RANTES and CCL18/PARC are independently associated with the risk of short-term mortality in ACS patients. Combining all three biomarkers further increased their prognostic value.

Postchallenge hyperglycemia is positively associated with diabetic polyneuropathy: the KORA F4 study.

OBJECTIVE: To assess the prevalence of distal sensorimotor polyneuropathy (DSPN) in an older population and to examine its relationship with prediabetes. RESEARCH DESIGN AND METHODS: Glucose tolerance status was determined in 61- to 82-year-old participants (n = 1,100) of the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4 Survey (2006-2008). Clinical DSPN was defined as bilaterally impaired foot-vibration perception and/or foot-pressure sensation. RESULTS: Prevalence of clinical DSPN was similar in subjects with known diabetes (22.0%) and subjects with combined impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) (23.9%). Among prediabetic subgroups, IFG-IGT, but not isolated-IFG and -IGT, was associated with a higher risk of clinical DSPN, compared with normal glucose tolerance. A J-shaped association was observed between clinical DSPN and quartiles of 2-h postchallenge glucose, but not with fasting glucose and HbA(1c) levels. CONCLUSIONS: Subjects with IFG-IGT and known diabetes had a similar prevalence of clinical DSPN. Elevated 2-h postload glucose levels appeared important for disease risk.

Alcohol consumption, alcohol dehydrogenase 1C (ADH1C) genotype, and risk of colorectal cancer in the Netherlands Cohort Study on diet and cancer.

Within the Netherlands Cohort Study (1986), we examined associations between alcohol consumption, the alcohol dehydrogenase 1C (ADH1C) genotype, and risk of colorectal cancer (CRC). After a follow-up period of 7.3 years, 594 CRC cases with information on genotype and baseline alcohol intake were available for analyses. Adjusted incidence rate ratios (RRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. In subjects who reported to have consumed equal amounts of total alcohol both 5 years before baseline and at baseline, drinkers of ≥30g of alcohol per day with the ADH1C*2/*2 genotype were associated-although not statistically significant-with an increased risk of CRC relative to abstainers with the ADH1C*1/*1 genotype (RR: 1.91, 95% CI: 0.68, 5.34). The risk estimate in this exposure group increased slightly when compared with light drinkers of ≥0.5-<5g/day with the ADH1C*1/*1 genotype (RR: 2.32, 95% CI: 0.80, 6.72). The interaction term however, was not statistically significant (P>.05). In subjects who reported to have consumed equal amounts of total alcohol both 5 years before baseline and at baseline, drinkers of ≥30g of alcohol per day were associated-although not statistically significant-with an increased risk of CRC relative to abstainers (RR: 1.38, 95% CI: 0.80, 2.38). This risk estimate for high-level drinkers became stronger when compared with light drinkers (RR: 1.74, 95% CI: 1.01, 2.99). As main effect of genotype, we observed that the ADH1C*2/*2 genotype was associated with a 42% increase in risk of CRC when compared with the ADH1C*1/*1 genotype. In conclusion, both genotype and alcohol consumption were associated with an increased risk of CRC. Owing to limited statistical power, we found no apparent evidence for the ADH1C genotype as effect modifier of the relationship between alcohol intake and CRC. Nevertheless, the interaction deserves further investigation in larger genetic epidemiologic studies.

Alcohol consumption, type of alcoholic beverage and risk of colorectal cancer at specific subsites.

Within the Netherlands Cohort Study on diet and cancer, we investigated associations between total alcohol consumption, specific alcoholic beverage consumption and risk of colorectal cancer (CRC) according to anatomical subsite. Hazard Ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. Analyses were performed on 2,323 CRC cases, available after 13.3 years of follow-up. Compared to abstaining, alcohol consumption of >/=30.0 g/day ( approximately 3 alcoholic drinks) was positively associated with the risk of CRC (HR: 1.32, 95% CI: 1.06-1.65). Analyses restricted to subjects who reported to have consumed equal amounts of alcohol 5 years before baseline compared to baseline, showed elevated risk estimates for consumers of >/=30.0 g of total alcohol per day as well (HR: 1.53, 95% CI: 1.16-2.01). Suggestive of a subsite-specific effect, cancer risk seemed to increase from proximal colon through rectum; HR: 1.29, 95% CI: 0.85-1.96 for proximal colon cancer, HR: 1.41, 95% CI: 0.94-2.11 for distal colon cancer, HR: 2.07, 95% CI: 1.03-4.18 for rectosigmoid cancer and HR: 1.69, 95% CI: 1.08-2.64 for rectal cancer. No associations were observed between consumption of alcoholic beverages and CRC risk when compared with the nondrinkers of the specific beverage and after adjustment for total alcohol intake. No evidence was found for sex-specific effects of alcohol and alcoholic beverages. In conclusion, our data showed a positive association between alcohol consumption and risk of CRC, which seemed to be mainly explained by the alcoholic content of alcoholic beverages, rather than other constituents. Also, cancer risk may vary according to anatomical subsite.

Associations of dietary methyl donor intake with MLH1 promoter hypermethylation and related molecular phenotypes in sporadic colorectal cancer.

Intake of dietary factors that serve as methyl group donors may influence promoter hypermethylation in colorectal carcinogenesis. We investigated whether dietary folate, vitamin B2 and vitamin B6, methionine and alcohol were associated with mutL homologue 1 (MLH1) hypermethylation and the related molecular phenotypes of MLH1 protein expression, microsatellite instability (MSI) and BRAF mutations in patients with colorectal carcinomas. Within the Netherlands Cohort Study on diet and cancer (n = 120 852), 648 cases (367 men and 281 women) and 4059 subcohort members were available for data analyses from a follow-up period between 2.3 and 7.3 years after baseline. Gender-specific adjusted incidence rate ratios (RRs) were calculated over categories of dietary intake in case-cohort analyses. The intakes of folate, vitamin B2, methionine and alcohol were not associated with risk of tumors showing MLH1 hypermethylation, those lacking MLH1 protein expression or with MSI. Among men, we observed strong positive associations between folate and BRAF-mutated tumors (RR = 3.04 for the highest versus lowest tertile of intake, P(trend) = 0.03) and between vitamin B6 and tumors showing MLH1 hypermethylation (highest versus lowest tertile: RR = 3.23, P(trend) = 0.03). Among women, the relative risks of tumors with BRAF mutations or MLH1 hypermethylation were also increased in the highest tertiles of folate and vitamin B6 intake, respectively, but these did not reach statistical significance. The positive associations between folate intake and tumors harboring BRAF mutations and between vitamin B6 intake and those showing MLH1 hypermethylation were most pronounced among men and may suggest that these vitamins enhance colorectal cancer risk through genetic as well as epigenetic aberrations.

Alcohol consumption and distinct molecular pathways to colorectal cancer.

High alcohol consumption is related to colorectal cancer (CRC). Our objective was to study associations between alcohol consumption and risk of CRC according to characteristics of aetiological pathways: the chromosomal instability (CIN) and the microsatellite instability (MIN) pathway. We classified CIN+ tumours (tumours with either a truncating APC mutation, an activating K-ras mutation or overexpression of p53), MIN+ tumours (tumours lacking hMLH1 expression) and CIN- /MIN- tumours (tumours without these defects). In the Netherlands Cohort Study on diet and cancer, 120852 men and women, aged 55-69 years, completed a questionnaire on risk factors for cancer at baseline (1986). Case-cohort analyses were conducted using 573 CRC cases with complete data after 7 x 3 years of follow-up, excluding the first 2 x 3 years. Adjusted incidence rate ratios (RR) and 95 % confidence intervals (CI) were estimated. Compared with abstaining, alcohol consumption of >or=30 g/d was positively associated with the risk of CRC irrespective of genetic or molecular aberrations present, although statistical significance was not reached (RR 1 x 35 (95 % CI 0 x 9-2 x 0) for the CIN+ tumours, RR 1 x 59 (95 % CI 0 x 4-5 x 8) for the MIN+ tumours and RR 1.15 (95 % CI 0 x 5-2 x 7) for the CIN- /MIN- tumours). Beer, wine and liquor consumption were, independent of their alcoholic content, not consistently associated with the risk of CRC within the defined subgroups. In conclusion, our results indicate that a daily alcohol consumption of >or=30 g is associated with an increase in risk of CRC, independent of the presence or absence of the studied characteristics of different aetiological pathways.

Alcohol and the risk of colon and rectal cancer with mutations in the K-ras gene.

The first metabolite of alcohol, acetaldehyde, may trigger replication errors and mutations in DNA, which may predispose to developing colorectal cancer (CRC). In a prospective study on colon and rectal cancer, we investigated the following hypotheses: alcohol consumption is associated with an increased risk of mutations in the K-ras oncogene, and beer consumption is associated with an increased risk of G-->A mutations in this gene. Therefore, we studied the associations between consumption of alcohol and alcoholic beverages and the risk of CRC without and with specific K-ras gene mutations. In 1986, 120,852 men and women, aged 55-69 years, completed a questionnaire on risk factors for cancer. The case-cohort approach was used for data processing and analyses. After 7.3 years of follow-up, excluding the first 2.3 years, complete data from 4,076 subcohort members, 428 colon and 150 rectal cancer patients, were available for data analyses. Incidence rate ratios (RRs) and corresponding 95% confidence intervals (95% CIs) were estimated using Cox proportional hazards models. Compared to abstaining, a total alcohol consumption of 30.0 g/day and more was associated with the risk of colon and rectal cancer with and without a K-ras mutation in both men and women. Independent from alcohol intake, liquor consumption when compared to nonliquor consumption was associated with an increased risk of rectal cancer with a wild type K-ras in men (RR: 2.25, 95% CI: 1.0-5.0). Beer consumption was not clearly associated with the risk of colon and rectal tumors harboring G-->A mutations in the K-ras gene in men. This association could not be assessed in women because of sparse beer consumption. In conclusion, alcohol does not seem to be involved in predisposing to CRC through mutations in the K-ras gene, and specifically beer consumption is not associated with colon and rectal tumors harboring a G-->A mutation.