Effects of social participation and physical activity on all-cause mortality among older adults in Norfolk, England: an investigation of the EPIC-Norfolk study.

OBJECTIVES: There is growing evidence of an association between social participation and improved physical and mental health among older individuals. The aims of this study were to explore the relationship between self-reported participation in groups, clubs, or organizations and all-cause mortality among older adults and examine the role of physical activity as a potential modifier of the health effects of social participation. STUDY DESIGN: EPIC-Norfolk is a prospective cohort study that recruited 25,639 individuals between the ages of 40 and 79 in Norfolk County, England. This study involved a retrospective analysis of 8623 participants who had returned for the third health check between 2004 and 2011. METHODS: Participants were categorized into those who reported participating socially and those who did not and were stratified by involvement in 0, 1, or 2 or more groups. Cox Proportional Hazards models were constructed to compare all-cause mortality between the groups. Stratum-specific hazard ratios were calculated by physical activity level to assess for effect modification. RESULTS: Of the participants, 861 (9.98%) died during the follow-up period. After adjustment for confounding, social participation was associated with lower all-cause mortality (HR 0.84, 95% CI 0.73-0.97). Involvement in 2 or more groups was associated with lower all-cause mortality (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.70-0.97), but the association was not statistically significant for people involved in only 1 group (HR 0.86, 95% CI 0.73-1.03). Physical activity appeared to modify the effect of social participation on mortality. CONCLUSIONS: This study's findings provide evidence of an association between social participation and lower all-cause mortality for older adults. They also suggest that the effect of social participation on health is greater for people who are more physically active. Population-level interventions to facilitate social participation may contribute to improving health and wellbeing among older individuals.

Body mass index and body fat distribution and new-onset atrial fibrillation: Substudy of the European Prospective Investigation into Cancer and Nutrition in Norfolk (EPIC-Norfolk) study.

BACKGROUND AND AIM: Obesity is a recognized risk factor for new-onset atrial fibrillation (AF). The association between body fat distribution, which is measured by body mass index (BMI) and waist-hip ratio (WHR), its changes, and new-onset AF is conflicting. METHODS AND RESULTS: Participants of the European Prospective Investigation into Cancer and Nutrition in Norfolk cohort study were included, with exclusion criteria of prevalent AF, rheumatic heart disease, and cancer. AF was confirmed by the International Classification of Diseases-10 hospital discharge code I48. Adjusted sex-specific Cox proportional hazards models were used to quantify the AF risk per 1 standard deviation increase and for quintiles of adiposity indices. A total of 10,885 men and 12,857 women were followed up for a median of 19 years, yielding 451,098 person-years. New-onset AF was diagnosed in 1408 (12.9%) men and 1102 (8.6%) women. Multivariable analyses showed that BMI predicted new-onset AF in all, while WHR predicted only in men. New-onset AF risk gradually increased across the range of adiposity indices: for men in the highest BMI quintile, HR: 1.59 (CI 1.32-1.91, p for trend<0.001), whereas for women in the highest BMI quintile, HR: 1.52 (CI 1.23-1.88, p for trend<0.001). Further, for men in the highest WHR quintile, HR: 1.31 (CI 1.09-1.57, p for trend: 0.01), whereas for women in the highest WHR quintile, HR: 1.12 (CI 0.90-1.41, p for trend: 0.17). The change in BMI and WHR was similar in participants with or without new-onset AF. CONCLUSIONS: An increased body mass, as measured by BMI, is associated with an increased risk of developing new-onset AF. More abdominal fat distribution, as measured by WHR, is associated with an increased risk of developing new-onset AF in men but not in women.

The descriptive epidemiology of accelerometer-measured physical activity in older adults.

BACKGROUND: Objectively measured physical activity between older individuals and between populations has been poorly described. We aimed to describe and compare the variation in accelerometry data in older UK (EPIC-Norfolk) and American (NHANES) adults. METHODS: Physical activity was measured by uniaxial accelerometry in 4,052 UK (49-91 years) and 3459 US older adults (49-85 years). We summarized physical activity as volume (average counts/minute), its underlying intensity distribution, and as time spent <100counts/minute, ≥809counts/minute and ≥2020counts/minute both for total activity and that undertaken in ≥10-min bouts. RESULTS: In EPIC-Norfolk 65% of wear-time was spent at <100 counts/minute and 20% spent in the range 100-500 counts/minute. Only 4.1% of this cohort accumulated more than 30 min/day of activity above 2020 counts/minute in 10-min bouts. If a cut-point of >809 counts/minute is used 18.7% of people reached the 30 min/day threshold. By comparison, 2.5% and 9.5% of American older adults accumulated activity at these levels, respectively. CONCLUSION: As assessed by objectively measured physical activity, the majority of older adults in this UK study did not meet current activity guidelines. Older adults in the UK were more active overall, but also spent more time being sedentary than US adults.

Long-term mortality of hospitalized pneumonia in the EPIC-Norfolk cohort.

Little is known about cause-specific long-term mortality beyond 30 days in pneumonia. We aimed to compare the mortality of patients with hospitalized pneumonia compared to age- and sex-matched controls beyond 30 days. Participants were drawn from the European Prospective Investigation into Cancer (EPIC)-Norfolk prospective population study. Hospitalized pneumonia cases were identified from record linkage (ICD-10: J12-J18). For this study we excluded people with hospitalized pneumonia who died within 30 days. Each case identified was matched to four controls and followed up until the end June 2012 (total 15 074 person-years, mean 6·1 years, range 0·08-15·2 years). Cox regression models were constructed to examine the all-cause, respiratory and cardiovascular mortality using date of pneumonia onset as baseline with binary pneumonia status as exposure. A total of 2465 men and women (503 cases, 1962 controls) [mean age (s.d.) 64·5 (8·3) years] were included in the study. Between a 30-day to 1-year period, hazard ratios (HRs) of all-cause and cardiovascular mortality were 7·3 [95% confidence interval (CI) 5·4-9·9] and 5·9 (95% CI 3·5-9·7), respectively (with very few respiratory deaths within the same period) in cases compared to controls after adjusting for age, sex, asthma, smoking status, pack years, systolic and diastolic blood pressure, diabetes, physical activity, waist-to-hip ratio, prevalent cardiovascular and respiratory diseases. All outcomes assessed also showed increased risk of death in cases compared to controls after 1 year; respiratory cause of death being the most significant during that period (HR 16·4, 95% CI 8·9-30·1). Hospitalized pneumonia was associated with increased all-cause and specific-cause mortality beyond 30 days.

Daytime napping, sleep duration and increased 8-year risk of type 2 diabetes in a British population.

BACKGROUND AND AIMS: Few studies have prospectively examined the relationship between daytime napping and risk of type 2 diabetes. We aimed to study the effects of daytime napping and the joint effects of napping and sleep duration in predicting type 2 diabetes risk in a middle- to older-aged British population. METHODS AND RESULTS: In 1998-2000, 13 465 individuals with no known diabetes participating in the European Prospective Investigation into Cancer-Norfolk study reported daytime napping habit and 24-h sleep duration. Incident type 2 diabetes cases were identified through multiple data sources until 31 July 2006. After adjustment for age and sex, daytime napping was associated with a 58% higher diabetes risk. Further adjustment for education, marital status, smoking, alcohol intake, physical activity, comorbidities and hypnotic drug use had little influence on the association, but additional adjustment for BMI and Waist Circumference attenuated the Odds ratio (OR) (95% CI) to 1.30 (1.01, 1.69). The adjusted ORs (95% CI) associated with short and long sleep duration were 1.46 (1.10, 1.90) and 1.64 (1.16, 2.32), respectively. When sleep duration and daytime napping were examined together, the risk of developing diabetes more than doubled for those who took day naps and had less than 6 h of sleep, compared to those who did not nap and had 6-8 h of sleep. CONCLUSION: Daytime napping was associated with an increased risk of type 2 diabetes, particularly when combined with short sleep duration. Further physiological studies are needed to confirm the interaction between different domains of sleep in relation to diabetes risk.

Habitual chocolate consumption and the risk of incident heart failure among healthy men and women.

BACKGROUND: We aimed to examine the association between chocolate intake and the risk of incident heart failure in a UK general population. We conducted a systematic review and meta-analysis to quantify this association. METHODS AND RESULTS: We used data from a prospective population-based study, the European Prospective Investigation into Cancer (EPIC)-Norfolk cohort. Chocolate intake was quantified based on a food frequency questionnaire obtained at baseline (1993-1997) and incident heart failure was ascertained up to March 2009. We supplemented the primary data with a systematic review and meta-analysis of studies which evaluated risk of incident heart failure with chocolate consumption. A total of 20,922 participants (53% women; mean age 58 ± 9 years) were included of whom 1101 developed heart failure during the follow up (mean 12.5 ± 2.7 years, total person years 262,291 years). After adjusting for lifestyle and dietary factors, we found 19% relative reduction in heart failure incidence in the top (up to 100 g/d) compared to the bottom quintile of chocolate consumption (HR 0.81 95%CI 0.66-0.98) but the results were no longer significant after controlling for comorbidities (HR 0.87 95%CI 0.71-1.06). Additional adjustment for potential mediators did not attenuate the results further. We identified five relevant studies including the current study (N = 75,408). The pooled results showed non-significant 19% relative risk reduction of heart failure incidence with higher chocolate consumption (HR 0.81 95%CI 0.66-1.01). CONCLUSIONS: Our results suggest that higher chocolate intake is not associated with subsequent incident heart failure.

Contribution of cod liver oil-related nutrients (vitamins A, D, E and eicosapentaenoic acid and docosahexaenoic acid) to daily nutrient intake and their associations with plasma concentrations in the EPIC-Norfolk cohort.

BACKGROUND: Total nutrient intake (TNI) is intake from food and supplements. This provides an assessment of nutrient adequacy and the prevalence of excessive intake, as well as the response with respect to biomarkers. Cod liver oil (CLO) is the most frequently consumed supplement in the UK, containing nutrients that might have varying influences on health. We calculated TNI for vitamins A, D and E, as well as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and assessed associations with the respective blood concentrations. METHODS: Seven-day diet diaries and blood samples were taken from two subsets of the European Prospective Investigation into Cancer (EPIC-Norfolk) cohort (age range 39-79 years; n = 1400 for vitamin D; n = 6656 for remaining nutrients). TNI was calculated for the subgroups: nonsupplement users, those consuming the nutrient in supplement form and those consuming a supplement without this nutrient. RESULTS: CLO-related nutrients were supplemented by 15%-33%, which approximately doubled median intakes. Almost everyone in the supplement + vitamin A group reached the estimated average requirement; however, guideline levels were likely to be exceeded. Partial correlations between intake of vitamins A and D and biomarkers were low and modestly strengthened by the inclusion of supplement sources (correlation = 0.01-0.13). Correlations between biomarker and TNI of vitamin E and EPA+DHA were in the range 0.40-0.46; however, vitamin E exceeding food intake resulted in attenuated coefficients. Linear associations between food or TNI EPA+DHA and plasma were weak but consistent across subgroups. CONCLUSIONS: CLO-related nutrients contribute substantially to nutrient intake, with a risk of over-consumption. Apart from EPA+DHA, biomarker data suggest that CLO-related nutrients in supplements are not linearly associated with vitamin status.

Rate of weight gain predicts change in physical activity levels: a longitudinal analysis of the EPIC-Norfolk cohort.

OBJECTIVE: To investigate the relationship of body weight and its changes over time with physical activity (PA). DESIGN: Population-based prospective cohort study (Norfolk cohort of the European Prospective Investigation into Cancer and Nutrition, EPIC-Norfolk, United Kingdom). SUBJECTS: A total of 25 639 men and women aged 39-79 years at baseline. PA was self-reported. Weight and height were measured by standard clinical procedures at baseline and self-reported at 18-month and 10-year follow-ups (calibrated against clinical measures). Main outcome measure was PA at the 10-year follow-up. RESULTS: Body weight and PA were inversely associated in cross-sectional analyses. In longitudinal analyses, an increase in weight was associated with higher risk of being inactive 10 years later, after adjusting for baseline activity, 18-month activity, sex, baseline age, prevalent diseases, socioeconomic status, education, smoking, total daily energy intake and alcohol intake. Compared with stable weight, a gain in weight of >2 kg per year in the short-, medium- and long-term was consistently and significantly associated with greater likelihood of physical inactivity after 10 years, with the most pronounced effect for long-term weight gain, OR=1.89 (95% CI: 1.30-2.70) in fully adjusted analysis. Weight gain of 0.5-2 kg per year over long-term was substantially associated with physical inactivity after full adjustment, OR=1.26 (95% CI: 1.11-1.41). CONCLUSION: Weight gain (during short-, medium- and long-term) is a significant determinant of future physical inactivity independent of baseline weight and activity. Compared with maintaining weight, moderate (0.5-2 kg per year) and large weight gain (>2 kg per year) significantly predict future inactivity; a potentially vicious cycle including further weight gain, obesity and complications associated with a sedentary lifestyle. On the basis of current predictions of obesity trends, we estimate that the prevalence of inactivity in England would exceed 60% in the year 2020.

The association between social stress and global cognitive function in a population-based study: the European Prospective Investigation into Cancer (EPIC)-Norfolk study.

BACKGROUND: Stress is thought to exert both positive and negative effects on cognition, but the precise cognitive effects of social stress and individuals' response to stress remain unclear. We aimed to investigate the association between different measures of social stress and cognitive function in a middle- to older-aged population using data from the European Prospective Investigation into Cancer (EPIC)-Norfolk study. METHOD: Participants completed a comprehensive assessment of lifetime social adversity between 1993 and 1997 and the short form of the Mini Mental State Examination (SF-MMSE), an assessment of global cognitive function, during the third health check between 2004 and 2011 (a median of 10.5 years later). A low MMSE score was defined as a score in the bottom quartile (20-26). RESULTS: Completed MMSE scores and stress measures were available for 5129 participants aged 48-90 years. Participants who reported that their lives had been more stressful over the previous 10 years were significantly more likely to have low MMSE scores [odds ratio (OR) 1.14, 95% confidence interval (CI) 1.04-1.24 per unit increase in perceived stress], independently of sociodemographic factors, physical and emotional health. The effects were restricted to the highest level of stress and the association was stronger among participants with a lower educational level. Adaptation following life event experiences also seemed to be associated with MMSE scores after adjusting for sociodemographic factors, but the association was attenuated with further adjustment. CONCLUSIONS: In this generally high-functioning population, individuals' interpretations and responses to stressful events, rather than the events themselves, were associated with cognitive function.

A common variant in BRCA2 is associated with both breast cancer risk and prenatal viability.

Inherited mutations in the gene BRCA2 predispose carriers to early onset breast cancer, but such mutations account for fewer than 2% of all cases in East Anglia. It is likely that low penetrance alleles explain the greater part of inherited susceptibility to breast cancer; polymorphic variants in strongly predisposing genes, such as BRCA2, are candidates for this role. BRCA2 is thought to be involved in DNA double strand break-repair. Few mice in which Brca2 is truncated survive to birth; of those that do, most are male, smaller than their normal littermates and have high cancer incidence. Here we show that a common human polymorphism (N372H) in exon 10 of BRCA2 confers an increased risk of breast cancer: the HH homozygotes have a 1.31-fold (95% CI, 1.07-1.61) greater risk than the NN group. Moreover, in normal female controls of all ages there is a significant deficiency of homozygotes compared with that expected from Hardy-Weinberg equilibrium, whereas in males there is an excess of homozygotes: the HH group has an estimated fitness of 0.82 in females and 1.38 in males. Therefore, this variant of BRCA2 appears also to affect fetal survival in a sex-dependent manner.

The association between prior infection with five serotypes of Coxsackievirus B and incident type 2 diabetes mellitus in the EPIC-Norfolk study.

AIMS/HYPOTHESIS: Infections with Coxsackieviruses have been linked to beta cell dysfunction. Given the importance of beta cell dysfunction in the aetiology of type 2 diabetes, we hypothesised that prior infection with Coxsackieviruses B would increase the risk of type 2 diabetes. The aims of the study were to estimate cross-sectional associations between potential predictors of previous infection and seropositivity for Coxsackievirus B serotypes 1-5 (CBV1-5), and then to assess the association between seropositivity and incident type 2 diabetes. METHODS: Using a case-cohort design nested within the European Prospective Investigation of Cancer (EPIC)-Norfolk study, we ascertained n = 603 cases of incident type 2 diabetes. From within the entire cohort we identified a random subcohort of n = 835, without diabetes at baseline. The presence of Coxsackievirus B neutralising antibodies against serotypes 1-5 was assessed using a plaque neutralisation assay. Weighted Cox regression was used to examine the association between presence of antibodies to CBV1-5 and the development of type 2 diabetes. RESULTS: Seropositivity in the subcohort for CBV1-5 was 50%, 67%, 66%, 75% and 45%, respectively. After adjustment for age, sex, BMI, physical activity and family history of diabetes, the presence of antibodies against CBV1-5 was not associated with incident type 2 diabetes, over a mean follow-up of 5.7 years (HR [95% CIs] 0.94 [0.72,1.25], 0.92 [0.68, 1.23], 1.33 [0.98,1.81], 1.16 [0.83,1.61] and 1.03 [0.77,1.39] for CBV1-5, respectively). CONCLUSIONS/INTERPRETATION: The presence of antibodies against any of five serotypes of Coxsackievirus B was not associated with incident type 2 diabetes.

Circulating 25-hydroxyvitamin D concentration and the risk of type 2 diabetes: results from the European Prospective Investigation into Cancer (EPIC)-Norfolk cohort and updated meta-analysis of prospective studies.

AIMS/HYPOTHESIS: Epidemiological evidence is suggestive, but limited, for an association between circulating 25-hydroxyvitamin D (25[OH]D) and risk of type 2 diabetes. We conducted a systematic review and meta-analysis that included new data from previously unpublished studies. METHODS: Using a nested case-cohort design in the European Prospective Investigation into Cancer (EPIC)-Norfolk study, we identified a random subcohort and incident type 2 diabetes cases occurring between baseline (1993-1997) and 2006. In the Ely prospective study we identified incident type 2 diabetes cases between 1990 and 2003. We conducted a systematic review of prospective studies on 25(OH)D and type 2 diabetes published in MEDLINE or EMBASE until 31 January 2012, and performed a random-effects meta-analysis combining available evidence with results from the EPIC-Norfolk and Ely studies. RESULTS: In EPIC-Norfolk, baseline 25(OH)D was lower among incident type 2 diabetes cases (mean [SD] 61.6 [22.4] nmol/l; n=621) vs non-case subcohort participants (mean 65.3 [23.9] nmol/l; n=826). There was an inverse association between baseline 25(OH)D and incident type 2 diabetes in multivariable-adjusted analyses: HR (95% CI) 0.66 (0.45, 0.97), 0.53 (0.34, 0.82), 0.50 (0.32, 0.76), p trend <0.001, comparing consecutive increasing 25(OH)D quartiles with the lowest. In Ely, 37 incident type 2 diabetes cases were identified among 777 participants. In meta-analysis, the combined RR of type 2 diabetes comparing the highest with lowest quartile of 25(OH)D was 0.59 (0.52, 0.67), with little heterogeneity (I (2) =2.7%, p=0.42) between the 11 studies included (3,612 cases and 55,713 non-cases). CONCLUSIONS/INTERPRETATION: These findings demonstrate an inverse association between circulating 25(OH)D and incident type 2 diabetes. However, causal inference should be addressed through adequately dosed randomised trials of vitamin D supplementation or genetic Mendelian randomisation experiments.

Body fat mass is a predictor of risk of osteoporotic fractures in women but not in men: a prospective population study.

OBJECTIVES: Obesity has generally been associated with higher bone density and lower fracture risk. However, weight-related indices of obesity may be related differently to health end-points, compared with fat-related indices (such as body fat distribution and fat mass), as they may capture different dimensions of obesity and the associated biological effects. The aim of this study was to examine the association between percentage body fat (%BF) and prospective risk of fracture. METHODS: The European Prospective Investigation into Cancer (EPIC) in Norfolk was a population-based prospective study. A total of 14 789 participants (6470 men, aged 42-82 years at baseline) were included. The main outcome measures were quantitative ultrasound of the heel and incident hip and any osteoporotic fractures. RESULTS: A total of 556 participants suffered a fracture (184 hip fractures) during 8.7 ± 0.8 years of follow-up. Risk of hip fracture decreased linearly with increasing %BF amongst women but not men. After adjustment for age, history of fracture, height, smoking, alcohol intake and heel broadband ultrasound attenuation (BUA), the hazard ratio (95% CI) for a 10% higher %BF on risk of hip fracture was 0.56 (0.39-0.79) in women and 0.92 (0.39-2.21) in men. The effect size in women was approximately equivalent to a difference of 5 years in age or 1 standard deviation (17 dB MHz(-1) ) increased BUA. A nonlinear negative association was also observed between %BF and risk of 'any type of fracture' amongst women but not men. CONCLUSIONS: The %BF appears to predict hip fracture risk in women with an effect size comparable to that of bone density as measured by heel ultrasound. This effect was not observed in men. Understanding the differences in relationships between different indices of obesity as well as sex differences may help to elucidate the metabolic and other underlying mechanisms involved in bone health and fracture risk.

Self-reported and measured anthropometric data and risk of colorectal cancer in the EPIC-Norfolk study.

BACKGROUND: Epidemiological studies have shown inconsistent results for the association between body size and colorectal cancer (CRC) risk. Inconsistencies may be because of the reliance on self-reported measures of body size. OBJECTIVE: We examined the association of self-reported and directly assessed anthropometric data (body height, weight, body mass index (BMI), waist, hip, waist-to-hip ratio (WHR) and chest circumference) with CRC risk in the EPIC-Norfolk study. DESIGN: A total of 20,608 participants with complete self-reported and measured height and weight and without any history of cancer were followed up an average of 11 years, during which 357 incident CRC cases were recorded. Hazard Ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. RESULTS: After adjustment for confounders, HRs among women in the highest quintile of the body size measure relative to the lowest quintile showed that measured height (HR=1.98, 95% CI=1.19-3.28, P (trend)=0.009), measured waist circumference (HR=1.65, 95% CI=0.97-2.86, P (trend)=0.009) and measured WHR (HR=2.07, 95% CI=1.17-3.67, P (trend)=0.001) were associated with increased CRC risk. Associations using corresponding self-reported measures were attenuated and not statistically significant. Conversely, the association of BMI with CRC risk in women was weaker using measured BMI (HR=1.57, 95% CI=0.91-2.73, P (trend)=0.05) compared with self-reported BMI (HR=1.97, 95% CI=1.18-3.30, P (trend)=0.02). In men no significantly increased CRC risk was observed with any of the anthropometric measures. CONCLUSIONS: Measured height, waist circumference and WHR were associated with CRC risk in women, whereas any significant associations with those measures were attenuated when self-reported data were used.

No evidence of an increased mortality risk associated with low levels of glycated haemoglobin in a non-diabetic UK population.

AIMS/HYPOTHESIS: There is debate about increased mortality risk associated with low levels of glycaemia. To address this issue, we examined the shape of the risk relationship between glycated haemoglobin and mortality in a UK population. METHODS: In 17,196 men and women aged 39-82 years participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study in Norfolk without known diabetes or cardiovascular disease, we estimated HRs for total and cause-specific mortality comparing categories of glycated haemoglobin (<4.5%, 4.5% to <5.0%, 5.0% to <5.5% [reference], 5.5% to <6.0%, 6.0% to <6.5%, and ≥6.5%) using Cox regression. RESULTS: During a mean (±SD) follow-up of 11.2 (±2.1) years 1,953 participants died. The HR for all-cause mortality increased with categories of increasing glycated haemoglobin in adjusted analyses (HR 0.94 [95% CI 0.72-1.22], 0.99 [0.86-1.13], 1.00 [0.92-1.08], 1.10 [1.02-1.19], 1.29 [1.14-1.46] and 1.45 [1.16-1.80]). Spline regression suggested no increased risk at the low end of the distribution. Indeed, the HR for all-cause mortality was virtually constant in the low range and only started to rise when the level was approximately 5.5%. There were similar associations of glycated haemoglobin with cause-specific mortality, with the strongest association being seen for cardiovascular mortality. CONCLUSIONS/INTERPRETATION: Our findings in a large non-diabetic population do not support the concern about increased mortality risk with low glycated haemoglobin. Differences in population characteristics might explain contrary results of earlier studies and need further exploration.

Individual and cumulative effect of type 2 diabetes genetic susceptibility variants on risk of coronary heart disease.

AIMS/HYPOTHESIS: Type 2 diabetes is a major risk factor for CHD. We hypothesised that diabetes genetic susceptibility variants might be associated with increased CHD risk. METHODS: We examined the individual and cumulative effect of 38 common genetic variants previously reported to be associated with type 2 diabetes on risk of incident CHD in 20,467 participants of the European Prospective Investigation into Cancer and Nutrition (EPIC) Norfolk Study who had been free of CHD at baseline. RESULTS: During a mean follow-up of 10.7 years, 2,190 participants had a CHD event. Two individual variants next to the TSPAN8 (HR 1.07, 95% CI 1.00-1.14) and the CDKN2A/B region (1.11, 1.04-1.17) were significantly associated with increased CHD risk. A genetic score based on the 38 diabetes variants was significantly associated with an increased risk of CHD (1.08, 1.01-1.14 per score tertile). Adjustment for prevalent and incident diabetes attenuated the association of the TSPAN8 variant (1.06, 0.99-1.13) and the genetic score (1.05, 0.99-1.12 per score tertile) with CHD risk, but not that of the CDKN2A/B variant (1.11, 1.05-1.18). Addition of the genetic score did not improve risk discrimination based on clinical risk factors. CONCLUSIONS/INTERPRETATION: The increased risk of CHD observed with genetic susceptibility to type 2 diabetes was at least partly mediated by its diabetes-predisposing effect and was not useful for clinical risk discrimination. The potential role of pathways associated with the variant CDKN2A/B in linking diabetes and CHD needs further exploration.

No evidence for a causal link between uric acid and type 2 diabetes: a Mendelian randomisation approach.

AIMS/HYPOTHESIS: Epidemiological and experimental evidence suggests that uric acid has a role in the aetiology of type 2 diabetes. Using a Mendelian randomisation approach, we investigated whether there is evidence for a causal role of serum uric acid for development of type 2 diabetes. METHODS: We examined the associations of serum-uric-acid-raising alleles of eight common variants recently identified in genome-wide association studies and summarised this in a genetic score with type 2 diabetes in case-control studies including 7,504 diabetes patients and 8,560 non-diabetic controls. We compared the observed effect size to that expected based on: (1) the association between the genetic score and uric acid levels in non-diabetic controls; and (2) the meta-analysed uric acid level to diabetes association. RESULTS: The genetic score showed a linear association with uric acid levels, with a difference of 12.2 µmol/l (95% CI 9.3, 15.1) by score tertile. No significant associations were observed between the genetic score and potential confounders. No association was observed between the genetic score and type 2 diabetes with an OR of 0.99 (95% CI 0.94, 1.04) per score tertile, significantly different (p = 0.046) from that expected (1.04 [95% CI 1.03, 1.05]) based on the observed uric acid difference by score tertile and the uric acid to diabetes association of 1.21 (95% CI 1.14, 1.29) per 60 µmol/l. CONCLUSIONS/INTERPRETATION: Our results do not support a causal role of serum uric acid for the development of type 2 diabetes and limit the expectation that uric-acid-lowering drugs will be effective in the prevention of type 2 diabetes.

Genetic predisposition to obesity leads to increased risk of type 2 diabetes.

AIMS/HYPOTHESIS: Obesity is a major risk factor for type 2 diabetes. Recent genome-wide association (GWA) studies have identified multiple loci robustly associated with BMI and risk of obesity. However, information on their associations with type 2 diabetes is limited. Such information could help increase our understanding of the link between obesity and type 2 diabetes. We examined the associations of 12 obesity susceptibility loci, individually and in combination, with risk of type 2 diabetes in the population-based European Prospective Investigation of Cancer (EPIC) Norfolk cohort. METHODS: We genotyped 12 SNPs, identified by GWA studies of BMI, in 20,428 individuals (aged 39-79 years at baseline) with an average follow-up of 12.9 years, during which 729 individuals developed type 2 diabetes. A genetic predisposition score was calculated by adding the BMI-increasing alleles across the 12 SNPs. Associations with incidence of type 2 diabetes were examined by logistic regression models. RESULTS: Of the 12 SNPs, eight showed a trend with increased risk of type 2 diabetes, consistent with their BMI-increasing effects. Each additional BMI-increasing allele in the genetic predisposition score was associated with a 4% increased odds of developing type 2 diabetes (OR 1.041, 95% CI 1.005-1.078; p = 0.02). Adjustment for BMI completely abolished the association with incident type 2 diabetes (OR 1.003, 95% CI 0.967-1.039; p = 0.89). CONCLUSIONS/INTERPRETATION: The genetic predisposition to obesity leads to increased risk of developing type 2 diabetes, which is completely mediated by its obesity-predisposing effect.

Alcohol intake and risk of colorectal cancer: results from the UK Dietary Cohort Consortium.

BACKGROUND: Epidemiological studies have suggested that excessive alcohol intake increases colorectal cancer (CRC) risk. However, findings regarding tumour subsites and sex differences have been inconsistent. METHODS: We investigated the prospective associations between alcohol intake on overall and site- and sex-specific CRC risk. Analyses were conducted on 579 CRC cases and 1996 matched controls nested within the UK Dietary Cohort Consortium using standardised data obtained from food diaries as a main nutritional method and repeated using data from food frequency questionnaire (FFQ). RESULTS: Compared with individuals in the lightest category of drinkers (>0-<5 g per day), the multivariable odds ratios of CRC were 1.16 (95% confidence interval (95% CI): 0.88, 1.53) for non-drinkers, 0.91 (95% CI: 0.67, 1.24) for drinkers with 5-<15 g per day, 0.90 (95% CI: 0.65, 1.25) for drinkers with 15-<30 g per day, 1.02 (95% CI: 0.66, 1.58) for drinkers with 30-<45 g per day and 1.19 (95% CI: 0.75, 1.91) for drinkers with >or=45 g per day. No clear associations were observed between site-specific CRC risk and alcohol intake in either sex. Analyses using FFQ showed similar results. CONCLUSION: We found no significantly increased risk of CRC up to 30 g per day of alcohol intake within the UK Dietary Cohort Consortium.

Association of C-reactive protein with type 2 diabetes: prospective analysis and meta-analysis.

AIMS/HYPOTHESIS: We examined the association between serum C-reactive protein (CRP) and incident diabetes in a prospective study, and added these data to a literature-based meta-analysis to explore potential sources of heterogeneity between studies. METHODS: We analysed a case-control study nested within the European Prospective Investigation of Cancer (EPIC)-Norfolk cohort, including 293 incident diabetes cases and 708 controls. We combined 16 published studies on CRP and incident diabetes in a random-effect meta-analysis. RESULTS: In the EPIC-Norfolk cohort, serum CRP was associated with a higher risk of diabetes after adjusting for age, sex, BMI, family history of diabetes, smoking and physical activity (OR 1.49, comparing the extreme thirds of CRP distribution [95% CI 1.03-2.15], p = 0.03). However, the association was completely attenuated after further adjustment for WHR, serum gamma-glutamyltransferase and serum adiponectin (OR 1.00; 95% CI 0.66-1.51, p = 1.0). In a meta-analysis of 16 published studies with 3,920 incident diabetes cases and 24,914 controls, the RR was 1.72 (95% CI 1.54-1.92), comparing the extreme thirds of CRP distribution, with substantial heterogeneity between studies (I (2) = 52.8%, p = 0.007). CONCLUSIONS/INTERPRETATION: Initial evidence of association between CRP and incident diabetes was confounded by central adiposity, markers of liver dysfunction and adiponectin in the primary analysis. Despite an overall positive association in the meta-analysis, considerable heterogeneity existed between studies. The degree of adjustment for central adiposity and baseline glycaemia explained some of this heterogeneity and suggests that CRP may not be an independent risk factor for type 2 diabetes.