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1.  Plasma Phospholipid Fatty Acid Concentration and Incident Coronary Heart Disease in Men and Women: The EPIC-Norfolk Prospective Study 
PLoS Medicine  2012;9(7):e1001255.
Kay-Tee Khaw and colleagues analyze data from a prospective cohort study and show associations between plasma concentrations of saturated phospholipid fatty acids and risk of coronary heart disease, and an inverse association between omega-6 polyunsaturated phospholipid fatty acids and risk of coronary heart disease.
Background
The lack of association found in several cohort studies between dietary saturated fat and coronary heart disease (CHD) risk has renewed debate over the link between dietary fats and CHD.
Methods and Findings
We assessed the relationship between plasma phospholipid fatty acid (PFA) concentration and incident CHD using a nested case control design within a prospective study (EPIC-Norfolk) of 25,639 individuals aged 40–79 years examined in 1993–1997 and followed up to 2009. Plasma PFA concentrations were measured by gas chromatography in baseline samples retrieved from frozen storage. In 2,424 men and women with incident CHD compared with 4,930 controls alive and free of cardiovascular disease, mean follow-up 13 years, saturated PFA (14:0, 16:0,18:0) plasma concentrations were significantly associated with increased CHD risk (odds ratio [OR] 1.75, 95% CI 1.27–2.41, p<0.0001), in top compared to bottom quartiles (Q), and omega-6 polyunsaturated PFA concentrations were inversely related (OR 0.77, 0.60–0.99, p<0.05) after adjusting for age, sex, body mass index, blood pressure, smoking, alcohol intake, plasma vitamin C, social class, education, and other PFAs. Monounsaturated PFA, omega-3 PFA, and trans PFA concentrations were not significantly associated with CHD. Odd chain PFA (15:0, 17:0) concentrations were significantly inversely associated with CHD (OR 0.73, 0.59–0.91, p<0.001, Q4 versus Q1). Within families of saturated PFA or polyunsaturated PFA, significantly heterogeneous relationships with CHD were observed for individual fatty acids.
Conclusions
In this study, plasma concentrations of even chain saturated PFA were found to be positively and omega-6 polyunsaturated PFA inversely related to subsequent coronary heart disease risk. These findings are consistent with accumulating evidence suggesting a protective role of omega-6 fats substituting for saturated fats for CHD prevention.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Coronary heart disease (CHD) is a condition caused by a build-up of fatty deposits on the inner walls of the blood vessels that supply the heart, causing the affected person to experience pain, usually on exertion (angina). A complete occlusion of the vessel by deposits causes a heart attack (myocardial infarction). Lifestyle factors, such as diet (particularly one high in fat), contribute to causing CHD. There are different types of fat, some of which are thought to increase risk of CHD, such as saturated fat, typically found in meat and dairy foods. However, others, such as unsaturated fats (polyunsaturated and monounsaturated fats) found in foods such as vegetable oils, fish, and nuts, may actually help prevent this condition.
Why Was This Study Done?
Although there have been many studies investigating the role of different types of dietary fat in coronary heart disease, it is still not clear whether coronary heart disease can be prevented by changing the type of dietary fat consumed from saturated to unsaturated fats or by lowering all types of dietary fat. Furthermore, many of these studies have relied on participants recalling their dietary intake in questionnaires, which is an unreliable method for different fats. So in this study, the researchers used an established UK cohort to measure the levels of different types of fatty acids in blood to investigate whether a diet high in saturated fatty acids and low in unsaturated fatty acids increases CHD risk.
What Did the Researchers Do and Find?
The researchers used a selection of 10,000 participants (all men and women aged 40–79 years) from the prospective European Prospective Investigation into Cancer (EPIC)-Norfolk cohort. Blood samples from the selected participants taken at the start of the study in 1993–1997 were analyzed to determine levels of specific fatty acids. Participants were followed up till 2011. The researchers identified 2,424 participants who were subsequently diagnosed with CHD using death certificates and hospital discharge data and matched these with 4,930 controls who were still alive and free of known coronary disease. The researchers grouped the type of blood fatty acids identified in the blood samples into six families (even chain saturated fatty acid, odd chain saturated fatty acid, omega-6 polyunsaturated fatty acid, omega-3 polyunsaturated fatty acid, monounsaturated fatty acid, and trans-fatty acid), which represented saturated and unsaturated fatty acids. Using statistical methods, the researchers then compared the risks of developing CHD between cases and controls by the concentration of fatty acid families after adjusting for age and sex and other factors, such as body mass index, physical activity, and smoking. Using these methods, the researchers found that there was no overall significant relationship between total blood fatty acid concentration and CHD but there was a positive association with increasing blood saturated fatty acid concentration after adjusting for other fatty acid concentrations, with an odds ratio of 1.83 comparing higher versus lower concentrations. This risk was attenuated after adjusting for cholesterol levels, indicating that much of the association between saturated fatty acid and CHD is likely to be mediated through blood cholesterol levels. In contrast, blood omega-6 poly-unsaturated fatty acid concentrations were associated with lower CHD risk. Blood monounsaturated fatty acids, omega-3 poly-unsaturated fatty acids, and trans-fatty acids were not consistently associated with CHD risk. The authors also noted that within families of fatty acids, individual fatty acids related differently to CHD risk.
What Do These Findings Mean?
These findings suggest that plasma concentrations of saturated fatty acids are associated with increased risk of CHD and that concentrations of omega-6 poly-unsaturated fatty acids are associated with decreased risk of CHD. These findings are consistent with other studies and with current dietary advice for preventing CHD, which encourages substituting foods high in saturated fat with n-6 polyunsaturated fats. The results also suggest that different fatty acids may relate differently to CHD risk and that the overall balance between different fatty acids is important. However, there are limitations to this study, such as that factors other than diet (genetic differences in metabolism, for example) may cause changes to blood fatty acid levels so a major question is to identify what factors influence blood fatty acid concentrations. Nevertheless, these findings suggest that individual fatty acids play a role in increasing or decreasing risks of CHD.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001255.
Information about the EPIC-Norfolk study is available
The American Heart Foundation provides patient-friendly information about different dietary fats as does Medline
The British Heart Foundation also provides patient-friendly information on heart conditions
doi:10.1371/journal.pmed.1001255
PMCID: PMC3389034  PMID: 22802735
2.  Healthy lifestyle choices: could sense of coherence aid health promotion? 
Background
A research framework based on the personal characteristic defined by a sense of coherence (SOC) focuses on the effective use of resources to maintain good health.
Objectives
To test the hypothesis that individual differences in SOC are associated with healthier lifestyle choices independently of social class and education.
Design and setting
Cross sectional. Population based cohort study recruited through 35 general practice registers. Reported dietary intakes of alcohol, fruit and vegetables, fibre, saturated fat, non‐discretionary salt (sodium), and total sugars were assessed by food frequency questionnaire. Current cigarette smoking, physical inactivity, and SOC were assessed through questionnaires.
Participants
7863 men and 10 424 women. Residents of Norfolk (UK).
Results
Compared with participants with the weakest SOC, those with the strongest were 28% less likely to be current smokers (odds ratio 0.72 (95% confidence interval (CI), 0.58 to 0.89)), 36% less likely to be physically inactive (0.64 (0.55 to 0.75)), and reportedly consumed on average 63 g/day more fruit and vegetables (95% CI, 46 to 80), and 1.2 g/day more fibre (0.8 to 1.6). These associations were independent of age, sex, social class, and education. For physical inactivity and consumption of fruit, vegetables, and fibre, these differences exceeded those observed between the extremes of social class and education.
Conclusions
Individual differences in SOC are associated with healthy lifestyle choices independently of social class and education, and may therefore aid the design of future health promotion interventions.
doi:10.1136/jech.2006.056275
PMCID: PMC2652963  PMID: 17873222
sense of coherence; smoking; physical activity; alcohol; diet
3.  Age at Menopause, Reproductive Life Span, and Type 2 Diabetes Risk 
Diabetes Care  2013;36(4):1012-1019.
OBJECTIVE
Age at menopause is an important determinant of future health outcomes, but little is known about its relationship with type 2 diabetes. We examined the associations of menopausal age and reproductive life span (menopausal age minus menarcheal age) with diabetes risk.
RESEARCH DESIGN AND METHODS
Data were obtained from the InterAct study, a prospective case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition. A total of 3,691 postmenopausal type 2 diabetic case subjects and 4,408 subcohort members were included in the analysis, with a median follow-up of 11 years. Prentice weighted Cox proportional hazards models were adjusted for age, known risk factors for diabetes, and reproductive factors, and effect modification by BMI, waist circumference, and smoking was studied.
RESULTS
Mean (SD) age of the subcohort was 59.2 (5.8) years. After multivariable adjustment, hazard ratios (HRs) of type 2 diabetes were 1.32 (95% CI 1.04–1.69), 1.09 (0.90–1.31), 0.97 (0.86–1.10), and 0.85 (0.70–1.03) for women with menopause at ages <40, 40–44, 45–49, and ≥55 years, respectively, relative to those with menopause at age 50–54 years. The HR per SD younger age at menopause was 1.08 (1.02–1.14). Similarly, a shorter reproductive life span was associated with a higher diabetes risk (HR per SD lower reproductive life span 1.06 [1.01–1.12]). No effect modification by BMI, waist circumference, or smoking was observed (P interaction all > 0.05).
CONCLUSIONS
Early menopause is associated with a greater risk of type 2 diabetes.
doi:10.2337/dc12-1020
PMCID: PMC3609516  PMID: 23230098
4.  Laser Scanning Tomography in the EPIC-Norfolk Eye Study: Principal Components and Associations 
Purpose.
To describe Heidelberg Retina Tomograph (HRT) measures, their principal components, and their associations in a British population.
Methods.
The European Prospective Investigation of Cancer (EPIC)-Norfolk Eye Study is nested within a multicenter cohort study. Measurements were taken with the HRT-2 and the software subsequently updated to yield HRT-3 parameters. Principal components analysis (PCA) was used to identify distinct components of the HRT variables. Generalized estimating equation models were used to examine associations of these components with age, sex, height, body mass index (BMI), blood pressure, social class, education, alcohol intake, smoking status, axial length, IOP, and lens status.
Results.
Complete data were available from 10,859 eyes of 6430 participants with a mean age of 68 years. Principal components analysis identified three components with an eigenvalue greater than 1, explaining 79.9% of the variance of all the HRT measures. These were named cup, retinal nerve fiber layer (RNFL), and rim based on the factor loadings they were most correlated with. Older age was significantly associated with a greater cup (P = 0.003), smaller RNFL (P < 0.001), and smaller rim (P < 0.001). Female sex (P = 0.001), higher education (P < 0.001), and shorter axial length (P < 0.001) were associated with a greater RNFL. Lower BMI and higher IOP were associated with a greater cup (both, P < 0.001) and a smaller rim (BMI, P = 0.001; IOP, P < 0.001).
Conclusions.
Heidelberg Retina Tomograph measures in this cohort were largely explained by three principal components related to optic disc cup, RNFL, and rim. Associations with cup and rim were distinct to associations with RNFL, suggesting different underlying determinants.
Analysis of Heidelberg Retina Tomograph measurements from a large population-based sample identified three distinct components (optic disc “cup”, “rim” and retinal nerve fiber layer [“RNFL”]). Associations with “cup” and “rim” were distinct to associations with “RNFL”, suggesting different underlying determinants.
doi:10.1167/iovs.13-12490
PMCID: PMC3803136  PMID: 24030456
diagnostic techniques; epidemiology; axial length; glaucoma; body mass index; optic disk
5.  A new tool for converting food frequency questionnaire data into nutrient and food group values: FETA research methods and availability 
BMJ Open  2014;4(3):e004503.
Objectives
To describe the research methods for the development of a new open source, cross-platform tool which processes data from the European Prospective Investigation into Cancer and Nutrition Norfolk Food Frequency Questionnaire (EPIC-Norfolk FFQ). A further aim was to compare nutrient and food group values derived from the current tool (FETA, FFQ EPIC Tool for Analysis) with the previously validated but less accessible tool, CAFÉ (Compositional Analyses from Frequency Estimates). The effect of text matching on intake data was also investigated.
Design
Cross-sectional analysis of a prospective cohort study—EPIC-Norfolk.
Setting
East England population (city of Norwich and its surrounding small towns and rural areas).
Participants
Complete FFQ data from 11 250 men and 13 602 women (mean age 59 years; range 40–79 years).
Outcome measures
Nutrient and food group intakes derived from FETA and CAFÉ analyses of EPIC-Norfolk FFQ data.
Results
Nutrient outputs from FETA and CAFÉ were similar; mean (SD) energy intake from FETA was 9222 kJ (2633) in men, 8113 kJ (2296) in women, compared with CAFÉ intakes of 9175 kJ (2630) in men, 8091 kJ (2298) in women. The majority of differences resulted in one or less quintile change (98.7%). Only mean daily fruit and vegetable food group intakes were higher in women than in men (278 vs 212 and 284 vs 255 g, respectively). Quintile changes were evident for all nutrients, with the exception of alcohol, when text matching was not executed; however, only the cereals food group was affected.
Conclusions
FETA produces similar nutrient and food group values to the previously validated CAFÉ but has the advantages of being open source, cross-platform and complete with a data-entry form directly compatible with the software. The tool will facilitate research using the EPIC-Norfolk FFQ, and can be customised for different study populations.
doi:10.1136/bmjopen-2013-004503
PMCID: PMC3975761  PMID: 24674997
6.  A 24-Year Follow-Up Study of Blood Pressure Tracking from Childhood to Adulthood in Korea: The Kangwha Study 
Yonsei Medical Journal  2014;55(2):360-366.
Purpose
A number of longitudinal studies have tracked blood pressure over time in children and adults. Although there are a few blood pressure tracking studies for Asian populations, they are all relatively short-term studies with around only 10 years of follow-up. Accordingly, we assessed the stability of blood pressure tracking from childhood to adulthood over a 24-year follow-up period among participants in the Kangwha Study.
Materials and Methods
The Kangwha Study was a community-based prospective cohort study that started in 1986 in Kangwha County, South Korea. The study dataset included 14 blood pressure measurements over a 24-year period from 266 (123 male and 143 female) participants who completed the 2010 examination. All participants were 7 years old when the study began and were followed for the next 24 years.
Results
The tracking coefficient (95% confidence interval) for systolic blood pressure was 0.81 (0.52-1.11) in men and 0.72 (0.51-0.92) in women; diastolic blood pressure was 0.53 (0.26-0.80) in men and 0.33 (0.15-0.52) in women. After adjusting for body mass index, the tracking coefficient for systolic blood pressure was 0.68 (0.39-0.97) in men and 0.67 (0.44-0.89) in women; diastolic blood pressure was 0.51 (0.24-0.78) in men and 0.33 (0.15-0.51) in women. All tracking coefficients were statistically significant (p<0.001).
Conclusion
In this 24-year longitudinal study, we confirmed the stability of blood pressure tracking from childhood to adulthood for participants in the Kangwha Study.
doi:10.3349/ymj.2014.55.2.360
PMCID: PMC3936637  PMID: 24532504
Blood pressure; tracking; longitudinal study
7.  Associations With Retinal Nerve Fiber Layer Measures in the EPIC-Norfolk Eye Study 
Purpose.
To describe GDxVCC retinal nerve fiber layer (RNFL) measures and associations in a predominantly white British population.
Methods.
The EPIC-Norfolk Eye Study is nested within a large multicenter cohort study, the European Prospective Investigation of Cancer. RNFL measurements were taken using the GDxVCC. Generalized estimating equation models were used to assess associations of RNFL measures with age, sex, body mass index (BMI), height, blood pressure, social class, education level, alcohol intake, smoking status, axial length, intraocular pressure, and lens status. Models were linearly adjusted for typical scan score to handle scans with atypical retardation.
Results.
There were complete data from 11,030 eyes of 6309 participants with mean age 68 years (48–90 years). Older age (−1.53 μm/decade [95% confidence interval {CI} −1.73, −1.33], P < 0.001), male sex (−0.44 μm [95% CI −0.04, −0.84], P = 0.031), shorter axial length (−0.15 μm/mm [95% CI −0.02, −0.28], P = 0.024), and pseudophakia (−0.49 μm [95% CI −0.94, −0.04], P = 0.033) were associated with thinner RNFL after adjustment for possible confounders. Higher BMI was associated with a thinner RNFL in men only (−0.30 μm/5 kg/m2 [95% CI −0.58, −0.02], P = 0.039).
Conclusions.
This analysis of associations with RNFL thickness in a largely healthy population may provide insight into the determinants of glaucoma, suggesting higher risk in those who are older, in men, and in men with a higher BMI.
In this predominantly white British cohort, thinner GDxVCC retinal nerve fiber layer measurements were found in participants who were older, male, of higher BMI (in men only), pseudophakic or had shorter axial length.
doi:10.1167/iovs.13-11971
PMCID: PMC3726240  PMID: 23821204
scanning laser polarimetry; epidemiology; axial length; eye; glaucoma; body mass index
8.  Social relationships and healthful dietary behaviour: Evidence from over-50s in the EPIC cohort, UK☆ 
Social Science & Medicine (1982)  2014;100(100):167-175.
Social relationships are an important aspect of a person's social environment that can protect against a wide range of chronic conditions and facilitate recovery from disease. Social relationships have also been linked to dietary behaviour which may be an important pathway through which social circumstances exert their influence on health. Yet, questions remain about which structural aspects of social relationships most affect healthful dietary behaviours and whether different structural components interact to produce a combined effect. Using data from adults (≥50 years) in the European Prospective Investigation of Cancer-Norfolk study (1996–2002), we examined marital status, living arrangement and social isolation in relation to scores for variety of fruit and vegetable intake as a marker of diet quality associated with adverse health outcomes. Data were analysed with multivariable linear regression models for gender-specific and interaction associations. We found that being single or widowed was associated with a lower variety score, particularly vegetable variety, and associations were enhanced when combined with male gender, living alone or infrequent friend contact. Lower variety scores for lone-living were also observed, especially for men. Infrequent friend contact interacted with living arrangement to amplify negative associations of lone-living with variety, with statistically significant differences in contact frequency for vegetable variety. Lower levels of friend contact were associated with reduced variety of fruits and vegetables in a graded trend for both genders; the trend was more pronounced among men. Family contact appeared to have limited association with vegetable variety in men; among women, weekly contact was significantly and positively associated with vegetable variety compared to daily family contact. Results highlight the importance of considering living arrangement and/or frequency of social contact when assessing whether widowed, single or lone-living older adults are at risk of lower fruit and vegetable variety.
Highlights
•Social relationships affect health and can also influence dietary behaviour.•We examined joint effects of diverse structural components of relationships on diet.•We used data from over-50s in an established epidemiological cohort.•Men fared worse than women in reduced variety from poorer structural social ties.•Social isolation altered dietary effects of marital status and living arrangement.
doi:10.1016/j.socscimed.2013.08.018
PMCID: PMC3969105  PMID: 24035440
Social relationships; Social ties; Gender; Interactions; Diet variety; Health behaviour; Chronic disease; UK
9.  The association of cycling with all-cause, cardiovascular and cancer mortality: findings from the population-based EPIC-Norfolk cohort 
BMJ Open  2013;3(11):e003797.
Objectives
To investigate associations between modest levels of total and domain-specific (commuting, other utility, recreational) cycling and mortality from all causes, cardiovascular disease and cancer.
Design
Population-based cohort study (European Prospective Investigation into Cancer and Nutrition study-Norfolk).
Setting
Participants were recruited from general practices in the east of England and attended health examinations between 1993 and 1997 and again between 1998 and 2000. At the first health assessment, participants reported their average weekly duration of cycling for all purposes using a simple measure of physical activity. At the second health assessment, participants reported a more detailed breakdown of their weekly cycling behaviour using the EPAQ2 physical activity questionnaire.
Participants
Adults aged 40–79 years at the first health assessment.
Primary outcome measure
All participants were followed for mortality (all-cause, cardiovascular and cancer) until March 2011.
Results
There were 22 450 participants with complete data at the first health assessment, of whom 4398 died during follow-up; and 13 346 participants with complete data at the second health assessment, of whom 1670 died during follow-up. Preliminary analyses using exposure data from the first health assessment showed that cycling for at least 60 min/week in total was associated with a 9% reduced risk of all-cause mortality (adjusted HR 0.91, 95% CI 0.84 to 0.99). Using the more precise measures of cycling available from the second health assessment, all types of cycling were associated with greater total moderate-to-vigorous physical activity; however, there was little evidence of an association between overall or domain-specific cycling and mortality.
Conclusions
Cycling, in particular for utility purposes, was associated with greater moderate-to-vigorous and total physical activity. While this study provides tentative evidence that modest levels of cycling may reduce the risk of mortality, further research is required to confirm how much cycling is sufficient to induce health benefits.
doi:10.1136/bmjopen-2013-003797
PMCID: PMC3831097  PMID: 24231462
active travel; active commuting; physical activity
10.  Longitudinal Association of C-Reactive Protein and Lung Function Over 13 Years 
American Journal of Epidemiology  2013;179(1):48-56.
Chronic obstructive pulmonary disease is known to be associated with systemic inflammation. We examined the longitudinal association of C-reactive protein (CRP) and lung function in a cohort of 18,110 men and women from the European Prospective Investigation Into Cancer in Norfolk who were 40–79 years of age at baseline (recruited in 1993–1997) and followed-up through 2011. We assessed lung function by measuring forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) at baseline, 4 years, and 13 years. Serum CRP levels were measured using a high-sensitivity assay at baseline and the 13-year follow up. Cross-sectional and longitudinal associations of loge-CRP and lung function were examined using multivariable linear mixed models. In the cross-sectional analysis, 1-standard-deviation increase in baseline loge-CRP (about 3-fold higher CRP on the original milligrams per liter scale) was associated with a −86.3 mL (95% confidence interval: −93.9, −78.6) reduction in FEV1. In longitudinal analysis, a 1-standard-deviation increase in loge-CRP over 13 years was also associated with a −64.0 mL (95% confidence interval: −72.1, −55.8) decline in FEV1 over the same period. The associations were similar for FVC and persisted among lifetime never-smokers. Baseline CRP levels were not predictive of the rate of change in FEV1 or FVC over time. In the present study, we found longitudinal observational evidence that suggested that increases in systemic inflammation are associated with declines in lung function.
doi:10.1093/aje/kwt208
PMCID: PMC3864708  PMID: 24064740
aging; chronic obstructive pulmonary disease; C-reactive protein; inflammation; longitudinal study; lung function
11.  Crowdsourcing as a Novel Technique for Retinal Fundus Photography Classification: Analysis of Images in the EPIC Norfolk Cohort on Behalf of the UKBiobank Eye and Vision Consortium 
PLoS ONE  2013;8(8):e71154.
Aim
Crowdsourcing is the process of outsourcing numerous tasks to many untrained individuals. Our aim was to assess the performance and repeatability of crowdsourcing for the classification of retinal fundus photography.
Methods
One hundred retinal fundus photograph images with pre-determined disease criteria were selected by experts from a large cohort study. After reading brief instructions and an example classification, we requested that knowledge workers (KWs) from a crowdsourcing platform classified each image as normal or abnormal with grades of severity. Each image was classified 20 times by different KWs. Four study designs were examined to assess the effect of varying incentive and KW experience in classification accuracy. All study designs were conducted twice to examine repeatability. Performance was assessed by comparing the sensitivity, specificity and area under the receiver operating characteristic curve (AUC).
Results
Without restriction on eligible participants, two thousand classifications of 100 images were received in under 24 hours at minimal cost. In trial 1 all study designs had an AUC (95%CI) of 0.701(0.680–0.721) or greater for classification of normal/abnormal. In trial 1, the highest AUC (95%CI) for normal/abnormal classification was 0.757 (0.738–0.776) for KWs with moderate experience. Comparable results were observed in trial 2. In trial 1, between 64–86% of any abnormal image was correctly classified by over half of all KWs. In trial 2, this ranged between 74–97%. Sensitivity was ≥96% for normal versus severely abnormal detections across all trials. Sensitivity for normal versus mildly abnormal varied between 61–79% across trials.
Conclusions
With minimal training, crowdsourcing represents an accurate, rapid and cost-effective method of retinal image analysis which demonstrates good repeatability. Larger studies with more comprehensive participant training are needed to explore the utility of this compelling technique in large scale medical image analysis.
doi:10.1371/journal.pone.0071154
PMCID: PMC3749186  PMID: 23990935
12.  Evaluation of common genetic variants identified by GWAS for early onset and morbid obesity in population-based samples 
Background
Meta-analysis of case-control genome wide association studies (GWAS) for early onset and morbid obesity identified four variants in/near the PRL, PTER, MAF and NPC1 genes.
Objective
We aimed to validate association of these variants with obesity-related traits in population-based samples.
Design
Genotypes and anthropometric traits were available in up to 31 083 adults from the Fenland, EPIC-Norfolk, Whitehall II, Ely and Hertfordshire studies and in 2 042 children and adolescents from the European Youth Heart Study. In each study, we tested associations of rs4712652 (near-PRL), rs10508503 (near-PTER), rs1424233 (near-MAF) and rs1805081 (NPC1), or proxy variants (r2>0.8), with the odds of being overweight and obese, as well as with BMI, percentage body fat (%BF) and waist circumference (WC). Associations were adjusted for sex, age and age2 in adults and for sex, age, age-group, country and maturity in children and adolescents. Summary statistics were combined using fixed effects meta-analysis methods.
Results
We had 80% power to detect ORs of 1.046 to 1.092 for overweight and 1.067 to 1.136 for obesity. Variants near PRL, PTER and MAF were not associated with the odds of being overweight or obese, or with BMI, %BF or WC after meta-analysis (P > 0.15). The NPC1 variant rs1805081 showed some evidence of association with %BF (beta=0.013 SD/allele, P =0.040), but not with any of the remaining obesity-related traits (P >0.3).
Conclusion
Overall, these variants, which were identified in a GWAS for early onset and morbid obesity, do not seem to influence obesity-related traits in the general population.
doi:10.1038/ijo.2012.34
PMCID: PMC3680864  PMID: 22430306
Obesity-susceptibility loci; genome-wide association; morbid; early-onset; anthropometric traits; children and adolescents; population-based
13.  The small eye phenotype in the EPIC-Norfolk eye study: prevalence and visual impairment in microphthalmos and nanophthalmos 
BMJ Open  2013;3(7):e003280.
Objective
To describe the prevalence and phenotypic characteristics of small eyes in the European Prospective Investigation of Cancer (EPIC)-Norfolk Eye Study.
Design
Community cross-sectional study.
Setting
East England population (Norwich, Norfolk and surrounding area).
Participants
8033 participants aged 48–92 years old from the EPIC-Norfolk Eye Study, Norfolk, UK with axial length measurements. Participants underwent a standardised ocular examination including visual acuity (LogMAR), ocular biometry, non-contact tonometry, autorefraction and fundal photography. A small eye phenotype was defined as a participant with one or both eyes with axial length of <21 mm.
Outcome measures
Prevalence of small eyes, proportion with visual impairment, demographic and biometric factors.
Results
Ninety-six participants (1.20%, 95% CI 0.98% to 1.46%) had an eye with axial length less than 21 mm, of which 74 (77%) were women. Prevalence values for shorter axial lengths were <20 mm: 0.27% (0.18% to 0.41%); <19 mm: 0.17% (0.11% to 0.29%); <18 mm: 0.14% (0.08% to 0.25%). Two participants (2.1%) had low vision (presenting visual acuity >0.48 LogMAR) and one participant was blind (>1.3 LogMAR). The prevalence of unilateral visual impairment was higher in participants with a small eye. Multiple logistic regression modelling showed presence of a small eye to be significantly associated with shorter height, lower body mass index, higher systolic blood pressure and lower intraocular pressure.
Conclusions
The prevalence of people with small eyes is higher than previously thought. While small eyes were more common in women, this appears to be related to shorter height and lower body mass index. Participants with small eyes were more likely to be blind or to have unilateral visual impairment.
doi:10.1136/bmjopen-2013-003280
PMCID: PMC3731707  PMID: 23883889
Ophthalmology; Epidemiology
14.  A Prospective Study of the Association Between Quantity and Variety of Fruit and Vegetable Intake and Incident Type 2 Diabetes 
Diabetes Care  2012;35(6):1293-1300.
OBJECTIVE
The association between quantity of fruit and vegetable (F&V) intake and risk of type 2 diabetes (T2D) is not clear, and the relationship with variety of intake is unknown. The current study examined the association of both quantity and variety of F&V intake and risk of T2D.
RESEARCH DESIGN AND METHODS
We examined the 11-year incidence of T2D in relation to quantity and variety of fruit, vegetables, and combined F&V intake in a case-cohort study of 3,704 participants (n = 653 diabetes cases) nested within the European Prospective Investigation into Cancer and Nutrition-Norfolk study, who completed 7-day prospective food diaries. Variety of intake was derived from the total number of different items consumed in a 1-week period. Multivariable, Prentice-weighted Cox regression was used to estimate hazard ratios (HRs) and 95% CIs.
RESULTS
A greater quantity of combined F&V intake was associated with 21% lower hazard of T2D (HR 0.79 [95% CI 0.62–1.00]) comparing extreme tertiles, in adjusted analyses including variety. Separately, quantity of vegetable intake (0.76 [0.60–0.97]), but not fruit, was inversely associated with T2D in adjusted analysis. Greater variety in fruit (0.70 [0.53–0.91]), vegetable (0.77 [0.61–0.98]), and combined F&V (0.61 [0.48–0.78]) intake was associated with a lower hazard of T2D, independent of known confounders and quantity of intake comparing extreme tertiles.
CONCLUSIONS
These findings suggest that a diet characterized by a greater quantity of vegetables and a greater variety of both F&V intake is associated with a reduced risk of T2D.
doi:10.2337/dc11-2388
PMCID: PMC3357245  PMID: 22474042
15.  The association of the mitochondrial DNA OriB variant (16184–16193 polycytosine tract) with type 2 diabetes in Europid populations 
Diabetologia  2013;56:1907-1913.
Aims/hypothesis
The association between the mitochondrial DNA 16181–16193 polycytosine variant (known as the OriB variant as it maps to the OriB origin of replication) and type 2 diabetes has not been reliably characterised, with studies reporting conflicting results. We report a systematic review of published literature in Europid populations, new data from the Norfolk Diabetes Case–Control Study and a meta-analysis to help quantify this association.
Methods
We performed a systematic review identifying all the studies of the OriB variant and type 2 diabetes in Europid populations published before January 2013. We typed the OriB variant by pyrosequencing and sequencing in the Norfolk Diabetes Case–Control Study, which comprised 5,574 type 2 diabetes cases and 6,950 population-based controls.
Results
Overall, the meta-analysis included eight published studies plus the current new results, with a total of 11,794 type 2 diabetes cases and 14,465 controls. In the Norfolk Diabetes Case–Control Study, the OR for type 2 diabetes for the OriB variant was 1.09 (95% CI 0.96, 1.24). In a combined analysis, the relative risk for type 2 diabetes for the OriB variant in Europid populations was 1.10 (95% CI 1.01, 1.20; p = 0.03)
Conclusions/interpretation
Results from this systematic review and meta-analysis suggest that the mitochondrial DNA OriB variant is modestly associated with an increased risk of type 2 diabetes in Europid populations, with an effect size comparable with that of recently identified variants from genome-wide association studies.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-013-2945-6) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
doi:10.1007/s00125-013-2945-6
PMCID: PMC3737432  PMID: 23702607
Europid populations; Meta-analysis; Mitochondrial DNA; OriB variant; Pyrosequencing; Systematic review; Type 2 diabetes
16.  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.
Design
Population-based prospective cohort study (Norfolk cohort of the European Prospective Investigation into Cancer and Nutrition, EPIC-Norfolk, United Kingdom)
Subjects
25639 men and women aged 39-79 years at baseline. Physical activity was self-reported. Weight and height were measured by standard clinical procedures at baseline and self-reported at 18-month and 10-y follow-ups (calibrated against clinical measures). Main outcome measure was physical activity at the 10-y follow-up
Results
Body weight and physical activity 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/y during short-, medium- and long-term was consistently and significantly associated with greater likelihood of physical inactivity after 10 y, 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/y 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/y) and large weight gain (>2 kg/y) significantly predict future inactivity; a potentially vicious cycle including further weight gain, obesity and complications associated with a sedentary lifestyle. Based on current predictions of obesity trends, we estimate that the prevalence of inactivity in England would exceed 60% in year 2020.
doi:10.1038/ijo.2012.58
PMCID: PMC3635037  PMID: 22531093
physical activity; obesity; weight gain; cohort study; epidemiology
17.  Meta-analysis and imputation refines the association of 15q25 with smoking quantity 
Liu, Jason Z. | Tozzi, Federica | Waterworth, Dawn M. | Pillai, Sreekumar G. | Muglia, Pierandrea | Middleton, Lefkos | Berrettini, Wade | Knouff, Christopher W. | Yuan, Xin | Waeber, Gérard | Vollenweider, Peter | Preisig, Martin | Wareham, Nicholas J | Zhao, Jing Hua | Loos, Ruth J.F. | Barroso, Inês | Khaw, Kay-Tee | Grundy, Scott | Barter, Philip | Mahley, Robert | Kesaniemi, Antero | McPherson, Ruth | Vincent, John B. | Strauss, John | Kennedy, James L. | Farmer, Anne | McGuffin, Peter | Day, Richard | Matthews, Keith | Bakke, Per | Gulsvik, Amund | Lucae, Susanne | Ising, Marcus | Brueckl, Tanja | Horstmann, Sonja | Wichmann, H.-Erich | Rawal, Rajesh | Dahmen, Norbert | Lamina, Claudia | Polasek, Ozren | Zgaga, Lina | Huffman, Jennifer | Campbell, Susan | Kooner, Jaspal | Chambers, John C | Burnett, Mary Susan | Devaney, Joseph M. | Pichard, Augusto D. | Kent, Kenneth M. | Satler, Lowell | Lindsay, Joseph M. | Waksman, Ron | Epstein, Stephen | Wilson, James F. | Wild, Sarah H. | Campbell, Harry | Vitart, Veronique | Reilly, Muredach P. | Li, Mingyao | Qu, Liming | Wilensky, Robert | Matthai, William | Hakonarson, Hakon H. | Rader, Daniel J. | Franke, Andre | Wittig, Michael | Schäfer, Arne | Uda, Manuela | Terracciano, Antonio | Xiao, Xiangjun | Busonero, Fabio | Scheet, Paul | Schlessinger, David | St Clair, David | Rujescu, Dan | Abecasis, Gonçalo R. | Grabe, Hans Jörgen | Teumer, Alexander | Völzke, Henry | Petersmann, Astrid | John, Ulrich | Rudan, Igor | Hayward, Caroline | Wright, Alan F. | Kolcic, Ivana | Wright, Benjamin J | Thompson, John R | Balmforth, Anthony J. | Hall, Alistair S. | Samani, Nilesh J. | Anderson, Carl A. | Ahmad, Tariq | Mathew, Christopher G. | Parkes, Miles | Satsangi, Jack | Caulfield, Mark | Munroe, Patricia B. | Farrall, Martin | Dominiczak, Anna | Worthington, Jane | Thomson, Wendy | Eyre, Steve | Barton, Anne | Mooser, Vincent | Francks, Clyde | Marchini, Jonathan
Nature genetics  2010;42(5):436-440.
Smoking is a leading global cause of disease and mortality1. We performed a genomewide meta-analytic association study of smoking-related behavioral traits in a total sample of 41,150 individuals drawn from 20 disease, population, and control cohorts. Our analysis confirmed an effect on smoking quantity (SQ) at a locus on 15q25 (P=9.45e-19) that includes three genes encoding neuronal nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3, CHRNB4). We used data from the 1000 Genomes project to investigate the region using imputation, which allowed analysis of virtually all common variants in the region and offered a five-fold increase in coverage over the HapMap. This increased the spectrum of potentially causal single nucleotide polymorphisms (SNPs), which included a novel SNP that showed the highest significance, rs55853698, located within the promoter region of CHRNA5. Conditional analysis also identified a secondary locus (rs6495308) in CHRNA3.
doi:10.1038/ng.572
PMCID: PMC3612983  PMID: 20418889
18.  Seropositivity and Higher Immunoglobulin G Antibody Levels Against Cytomegalovirus Are Associated With Mortality in the Population-Based European Prospective Investigation of Cancer–Norfolk Cohort 
After adjustment for a range of possible confounders, cytomegalovirus seropositivity and cytomegalovirus immunoglobulin G antibody levels were associated with all-cause mortality in the EPIC-Norfolk population-based cohort study.
Background. The relationship between cytomegalovirus (CMV) infection and mortality among immunocompetent individuals is uncertain. We aimed to examine whether seropositivity for CMV and the level of CMV immunoglobulin G (IgG) antibody are associated with all-cause and cause-specific mortality.
Methods. We used data from a random sample of 13 090 participants aged 40–79 years at recruitment in 1993–1997 to the European Prospective Investigation of Cancer–Norfolk population-based cohort study. We measured baseline IgG antibody levels against CMV. Death certificates were obtained for all participants who died before 31 March 2011. Codes for the underlying cause of death were used to investigate cause-specific mortality.
Results. A total of 2514 deaths occurred during a mean follow-up of 14.3 years (SD, 3.3 years). Compared to seronegative participants (age- and sex-adjusted mortality rate, 12.4 [95% confidence interval {CI}, 11.3–13.2] per 1000 person-years at risk), rates increased across thirds of IgG antibody levels (score test of trend P < .0001). CMV seropositivity (prevalence 59%) was associated with increased all-cause mortality (age- and sex-adjusted hazard ratio [HR], 1.16 [95% CI, 1.07–1.26]), similarly in men and women (P for interaction = .52). The association persisted after additionally adjusting for measures of socioeconomic status and possible confounders. Cause-specific analyses suggested that increased mortality from cardiovascular disease (HR, 1.06 [95% CI, .91–1.24]), cancer (HR, 1.13 [95% CI, .98–1.31]), and other causes (HR, 1.23 [95% CI, 1.04–1.47) all appeared to contribute to the overall associations.
Conclusions. Seropositivity and higher IgG antibody levels against CMV are associated with increased mortality and after adjustment for a range of potential confounders in the general population.
doi:10.1093/cid/cit083
PMCID: PMC3634310  PMID: 23442763
cytomegalovirus; cancer; mortality; cohort study; cardiovascular disease
19.  N-Acetyltransferase 2 Polymorphisms, Tobacco Smoking, and Breast Cancer Risk in the Breast and Prostate Cancer Cohort Consortium 
American Journal of Epidemiology  2011;174(11):1316-1322.
Common polymorphisms in the N-acetyltransferase 2 gene (NAT2) modify the association between cigarette smoking and bladder cancer and have been hypothesized to determine whether active cigarette smoking increases breast cancer risk. The authors sought to replicate the latter hypothesis in a prospective analysis of 6,900 breast cancer cases and 9,903 matched controls drawn from 6 cohorts (1989–2006) in the National Cancer Institute’s Breast and Prostate Cancer Cohort Consortium. Standardized methods were used to genotype the 3 most common polymorphisms that define NAT2 acetylation phenotype (rs1799930, rs1799931, and rs1801280). In unconditional logistic regression analyses, breast cancer risk was higher in women with more than 20 pack-years of active cigarette smoking than in never smokers (odds ratio (OR) = 1.28, 95% confidence interval (CI): 1.17, 1.39), after controlling for established risk factors other than alcohol consumption and physical inactivity. However, associations were similar for the slow (OR = 1.25, 95% CI: 1.11, 1.39) and rapid/intermediate (OR = 1.24, 95% CI: 1.08, 1.42) acetylation phenotypes, with no evidence of interaction (P = 0.87). These results provide some support for the hypothesis that long-term cigarette smoking may be causally associated with breast cancer risk but underscore the need for caution when interpreting sparse data on gene-environment interactions.
doi:10.1093/aje/kwr257
PMCID: PMC3390163  PMID: 22074863
arylamine N-acetyltransferase; breast neoplasms; NAT2 protein, human; polymorphism, single nucleotide; smoking
20.  Influence of Inflammatory Polyarthritis on Quantitative Heel Ultrasound Measurements 
Background
There are few data concerning the impact of inflammatory polyarthritis (IP) on quantitative heel ultrasound (QUS) measurements. The aims of this analysis were i) to determine the influence of IP on QUS measurements at the heel and, ii) among those with IP to determine the influence of disease related factors on these measurements.
Methods
Men and women aged 16 years and over with recent onset IP were recruited to the Norfolk Arthritis Register (NOAR). Individuals with an onset of joint symptoms between 1989 and 1999 were included in this analysis. At the baseline visit subjects underwent a standardised interview and clinical examination with blood taken for rheumatoid factor. A population-based prospective study of chronic disease (EPIC-Norfolk) independently recruited men and women aged 40 to 79 years from the same geographic area between 1993 and 1997. At a follow up assessment between 1998 and 2000 subjects in EPIC-Norfolk were invited to have quantitative ultrasound measurements of the heel (CUBA-Clinical) performed. We compared speed of sound (SOS) and broadband ultrasound attenuation (BUA), in those subjects recruited to NOAR who had ultrasound measurements performed (as part of EPIC-Norfolk) subsequent to the onset of joint symptoms with a group of age and sex matched non-IP controls who had participated in EPIC-Norfolk. Fixed effect linear regression was used to explore the influence of IP on the heel ultrasound parameters (SOS and BUA) so the association could be quantified as the mean difference in BUA and SOS between cases and controls. In those with IP, linear regression was used to examine the association between these parameters and disease related factors.
Results
139 men and women with IP and 278 controls (mean age 63.2 years) were studied. Among those with IP, mean BUA was 76.3 dB/MHz and SOS 1621.8 m/s. SOS was lower among those with IP than the controls (difference = −10.0; 95% confidence interval (CI) –17.4, -2.6) though BUA was similar (difference = −1.2; 95% CI −4.5, +2.1). The difference in SOS persisted after adjusting for body mass index and steroid use. Among those with IP, disease activity as determined by the number of swollen joints at baseline, was associated with a lower SOS. In addition SOS was lower in the subgroup that satisfied the 1987 ACR criteria. By contrast, disease duration, steroid use and HAQ score were not associated with either BUA or SOS.
Conclusions
In this general population derived cohort of individuals with inflammatory polyarthritis there is evidence from ultrasound of a potentially adverse effect on the skeleton. The effect appears more marked in those with active disease.
doi:10.1186/1471-2474-13-133
PMCID: PMC3441510  PMID: 22834652
21.  A prospective study of the association between quantity and variety of fruit and vegetable intake and incident type 2 diabetes 
Diabetes care  2012;35(6):1293-1300.
Objective
The association between quantity of fruit and vegetable intake and risk of type 2 diabetes (T2D) is not clear, and the relationship with variety of intake is unknown. The current study examined the association of both quantity and variety of fruit and vegetable intake and risk of T2D.
Research Design and Methods
We examined the 11-year incidence of T2D in relation to quantity and variety of fruit, vegetables and combined fruit and vegetable intake in a case-cohort study of 3,704 participants (n=653 T2D cases) nested within the European Prospective Investigation into Cancer and Nutrition-Norfolk Study, who completed 7-day prospective food diaries. Variety of intake was derived from the total number of different items consumed in a one week period. Multivariable Prentice-weighted Cox regression was used to estimate hazard ratios (HR) and 95% CI.
Results
Greater quantity of combined fruit and vegetable intake was associated with 21% lower hazard of T2D (HR 0.79; 0.62-1.00) comparing extreme tertiles, in adjusted analyses including variety. Separately, quantity of vegetable intake (HR 0.76; 0.60-0.97), but not fruit, was inversely associated with T2D in adjusted analysis. Greater variety in fruit (HR 0.70; 0.53-0.91), vegetable (HR 0.77; 0.61-0.98), and combined fruit and vegetable (HR 0.61; 0.48-0.78) intake was associated with a lower hazard of T2D, independent of known confounders and quantity of intake comparing extreme tertiles.
Conclusions
These findings suggest that a diet characterised by greater quantity of vegetable and greater variety of both fruit and vegetable intake is associated with a reduced risk of T2D.
doi:10.2337/dc11-2388
PMCID: PMC3357245  PMID: 22474042
22.  R1: The relationship between plasma Angiopoietin-like protein 4 (Angptl4) levels, ANGPTL4 genotype and coronary heart disease risk 
Objective
To investigate the relationship between Angiopoietin-like protein 4 (Angptl4) levels, CHD biomarkers and ANGPTL4 variants.
Methods and Results
Plasma Angptl4 was quantified in 666 subjects of the Northwick Park Heart Study II using a validated ELISA. Seven ANGPTL4 SNPs were genotyped and CHD biomarkers assessed in the whole cohort (n=2775). Weighted mean (±SD) plasma Angptl4 levels were 10.0(±11.0) ng/ml. Plasma Angptl4 concentration correlated positively with age (r=0.15, P<0.001), body fat mass (r=0.19, P=0.003) but negatively with plasma HDL-cholesterol (r=−0.13, P=0.01). No correlation with triglycerides was observed. T266M was independently associated with plasma Angptl4 levels (P<0.001), but not associated with triglycerides or with CHD risk in the meta-analysis of five studies (4,061 cases/15,395 controls). E40K showed no independent association with plasma Angptl4 levels. In HEK293 and Huh7 cells compared to wild-type, E40K and T266M showed significantly altered synthesis and secretion, respectively.
Conclusions
These data suggest that circulating Angptl4 levels do not influence triglyceride levels or CHD risk since (1) Angptl4 levels were not correlated with triglycerides, (2) T266M, although associated with Angptl4 levels, showed no association with plasma triglycerides (3) Triglyceride-lowering E40K did not influence Angptl4 levels. These results provide new insights into the role of Angptl4 in triglyceride metabolism.
doi:10.1161/ATVBAHA.110.212209
PMCID: PMC3319296  PMID: 20829508
Angplt4; E40K; T266M; cardiovascular disease; LPL
23.  Incidence of Type 2 Diabetes Using Proposed HbA1c Diagnostic Criteria in the European Prospective Investigation of Cancer–Norfolk Cohort 
Diabetes Care  2011;34(4):950-956.
OBJECTIVE
To evaluate the incidence and relative risk of type 2 diabetes defined by the newly proposed HbA1c diagnostic criteria in groups categorized by different baseline HbA1c levels.
RESEARCH DESIGN AND METHODS
Using data from the European Prospective Investigation of Cancer (EPIC)-Norfolk cohort with repeat HbA1c measurements, we estimated the prevalence of known and previously undiagnosed diabetes at baseline (baseline HbA1c ≥6.5%) and the incidence of diabetes over 3 years. We also examined the incidence and corresponding odds ratios (ORs) by different levels of baseline HbA1c. Incident diabetes was defined clinically (self-report at follow-up, prescribed diabetes medication, or inclusion on a diabetes register) or biochemically (HbA1c ≥6.5% at the second health assessment), or both.
RESULTS
The overall prevalence of diabetes was 4.7%; 41% of prevalent cases were previously undiagnosed. Among 5,735 participants without diabetes at baseline (identified clinically or using HbA1c criteria, or both), 72 developed diabetes over 3 years (1.3% [95% CI 1.0–1.5]), of which 49% were identified using the HbA1c criteria. In 6% of the total population, the baseline HbA1c was 6.0–6.4%; 36% of incident cases arose in this group. The incidence of diabetes in this group was 15 times higher than in those with a baseline HbA1c of <5.0% (OR 15.5 [95% CI 7.2–33.3]).
CONCLUSIONS
The cumulative incidence of diabetes defined using a newly proposed HbA1c threshold in this middle-aged British cohort was 1.3% over 3 years. Targeting interventions to individuals with an HbA1c of 6.0–6.4% might represent a feasible preventive strategy, although complementary population-based preventive strategies are also needed to reduce the growing burden of diabetes.
doi:10.2337/dc09-2326
PMCID: PMC3064056  PMID: 20622160
24.  A Latent Variable Partial Least Squares Path Modeling Approach to Regional Association and Polygenic Effect with Applications to a Human Obesity Study 
PLoS ONE  2012;7(2):e31927.
Genetic association studies are now routinely used to identify single nucleotide polymorphisms (SNPs) linked with human diseases or traits through single SNP-single trait tests. Here we introduced partial least squares path modeling (PLSPM) for association between single or multiple SNPs and a latent trait that can involve single or multiple correlated measurement(s). Furthermore, the framework naturally provides estimators of polygenic effect by appropriately weighting trait-attributing alleles. We conducted computer simulations to assess the performance via multiple SNPs and human obesity-related traits as measured by body mass index (BMI), waist and hip circumferences. Our results showed that the associate statistics had type I error rates close to nominal level and were powerful for a range of effect and sample sizes. When applied to 12 candidate regions in data (N = 2,417) from the European Prospective Investigation of Cancer (EPIC)-Norfolk study, a region in FTO was found to have stronger association (rs7204609∼rs9939881 at the first intron P = 4.29×10−7) than single SNP analysis (all with P>10−4) and a latent quantitative phenotype was obtained using a subset sample of EPIC-Norfolk (N = 12,559). We believe our method is appropriate for assessment of regional association and polygenic effect on a single or multiple traits.
doi:10.1371/journal.pone.0031927
PMCID: PMC3288051  PMID: 22384102
25.  Mendelian Randomization Study of B-Type Natriuretic Peptide and Type 2 Diabetes: Evidence of Causal Association from Population Studies 
PLoS Medicine  2011;8(10):e1001112.
Using mendelian randomization, Roman Pfister and colleagues demonstrate a potentially causal link between low levels of B-type natriuretic peptide (BNP), a hormone released by damaged hearts, and the development of type 2 diabetes.
Background
Genetic and epidemiological evidence suggests an inverse association between B-type natriuretic peptide (BNP) levels in blood and risk of type 2 diabetes (T2D), but the prospective association of BNP with T2D is uncertain, and it is unclear whether the association is confounded.
Methods and Findings
We analysed the association between levels of the N-terminal fragment of pro-BNP (NT-pro-BNP) in blood and risk of incident T2D in a prospective case-cohort study and genotyped the variant rs198389 within the BNP locus in three T2D case-control studies. We combined our results with existing data in a meta-analysis of 11 case-control studies. Using a Mendelian randomization approach, we compared the observed association between rs198389 and T2D to that expected from the NT-pro-BNP level to T2D association and the NT-pro-BNP difference per C allele of rs198389. In participants of our case-cohort study who were free of T2D and cardiovascular disease at baseline, we observed a 21% (95% CI 3%–36%) decreased risk of incident T2D per one standard deviation (SD) higher log-transformed NT-pro-BNP levels in analysis adjusted for age, sex, body mass index, systolic blood pressure, smoking, family history of T2D, history of hypertension, and levels of triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. The association between rs198389 and T2D observed in case-control studies (odds ratio = 0.94 per C allele, 95% CI 0.91–0.97) was similar to that expected (0.96, 0.93–0.98) based on the pooled estimate for the log-NT-pro-BNP level to T2D association derived from a meta-analysis of our study and published data (hazard ratio = 0.82 per SD, 0.74–0.90) and the difference in NT-pro-BNP levels (0.22 SD, 0.15–0.29) per C allele of rs198389. No significant associations were observed between the rs198389 genotype and potential confounders.
Conclusions
Our results provide evidence for a potential causal role of the BNP system in the aetiology of T2D. Further studies are needed to investigate the mechanisms underlying this association and possibilities for preventive interventions.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, nearly 250 million people have diabetes, and this number is increasing rapidly. Diabetes is characterized by dangerous amounts of sugar (glucose) in the blood. Blood sugar levels are normally controlled by insulin, a hormone that the pancreas releases after meals (digestion of food produces glucose). In people with type 2 diabetes (the most common form of diabetes), blood sugar control fails because the fat and muscle cells that usually respond to insulin by removing sugar from the blood become insulin resistant. Type 2 diabetes can be controlled with diet and exercise, and with drugs that help the pancreas make more insulin or that make cells more sensitive to insulin. The long-term complications of diabetes, which include kidney failure and an increased risk of cardiovascular problems such as heart disease and stroke, reduce the life expectancy of people with diabetes by about 10 years compared to people without diabetes.
Why Was This Study Done?
Because the causes of type 2 diabetes are poorly understood, it is hard to devise ways to prevent the condition. Recently, B-type natriuretic peptide (BNP, a hormone released by damaged hearts) has been implicated in type 2 diabetes development in cross-sectional studies (investigations in which data are collected at a single time point from a population to look for associations between an illness and potential risk factors). Although these studies suggest that high levels of BNP may protect against type 2 diabetes, they cannot prove a causal link between BNP levels and diabetes because the study participants with low BNP levels may share some another unknown factor (a confounding factor) that is the real cause of both diabetes and altered BNP levels. Here, the researchers use an approach called “Mendelian randomization” to examine whether reduced BNP levels contribute to causing type 2 diabetes. It is known that a common genetic variant (rs198389) within the genome region that encodes BNP is associated with a reduced risk of type 2 diabetes. Because gene variants are inherited randomly, they are not subject to confounding. So, by investigating the association between BNP gene variants that alter NT-pro-BNP (a molecule created when BNP is being produced) levels and the development of type 2 diabetes, the researchers can discover whether BNP is causally involved in this chronic condition.
What Did the Researchers Do and Find?
The researchers analyzed the association between blood levels of NT-pro-BNP at baseline in 440 participants of the EPIC-Norfolk study (a prospective population-based study of lifestyle factors and the risk of chronic diseases) who subsequently developed diabetes and in 740 participants who did not develop diabetes. In this prospective case-cohort study, the risk of developing type 2 diabetes was associated with lower NT-pro-BNP levels. They also genotyped (sequenced) rs198389 in the participants of three case-control studies of type 2 diabetes (studies in which potential risk factors for type 2 diabetes were examined in people with type 2 diabetes and matched controls living in the East of England), and combined these results with those of eight similar published case-control studies. Finally, the researchers showed that the association between rs198389 and type 2 diabetes measured in the case-control studies was similar to the expected association calculated from the association between NT-pro-BNP level and type 2 diabetes obtained from the prospective case-cohort study and the association between rs198389 and BNP levels obtained from the EPIC-Norfolk study and other published studies.
What Do These Findings Mean?
The results of this Mendelian randomization study provide evidence for a causal, protective role of the BNP hormone system in the development of type 2 diabetes. That is, these findings suggest that low levels of BNP are partly responsible for the development of type 2 diabetes. Because the participants in all the individual studies included in this analysis were of European descent, these findings may not be generalizable to other ethnicities. Moreover, they provide no explanation of how alterations in the BNP hormone system might affect the development of type 2 diabetes. Nevertheless, the demonstration of a causal link between the BNP hormone system and type 2 diabetes suggests that BNP may be a potential target for interventions designed to prevent type 2 diabetes, particularly since the feasibility of altering BNP levels with drugs has already been proven in patients with cardiovascular disease.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001112.
The International Diabetes Federation provides information about all aspects of diabetes
The US National Diabetes Information Clearinghouse provides detailed information about diabetes for patients, health-care professionals, and the general public (in English and Spanish)
The UK National Health Service Choices website also provides information for patients and carers about type 2 diabetes and includes people's stories about diabetes
MedlinePlus provides links to further resources and advice about diabetes (in English and Spanish)
Wikipedia has pages on BNP and on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The charity Healthtalkonline has interviews with people about their experiences of diabetes; the charity Diabetes UK has a further selection of stories from people with diabetes
doi:10.1371/journal.pmed.1001112
PMCID: PMC3201934  PMID: 22039354

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