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1.  Gene-Lifestyle Interaction and Type 2 Diabetes: The EPIC InterAct Case-Cohort Study 
PLoS Medicine  2014;11(5):e1001647.
In this study, Wareham and colleagues quantified the combined effects of genetic and lifestyle factors on risk of T2D in order to inform strategies for prevention. The authors found that the relative effect of a type 2 diabetes genetic risk score is greater in younger and leaner participants, and the high absolute risk associated with obesity at any level of genetic risk highlights the importance of universal rather than targeted approaches to lifestyle intervention.
Please see later in the article for the Editors' Summary
Background
Understanding of the genetic basis of type 2 diabetes (T2D) has progressed rapidly, but the interactions between common genetic variants and lifestyle risk factors have not been systematically investigated in studies with adequate statistical power. Therefore, we aimed to quantify the combined effects of genetic and lifestyle factors on risk of T2D in order to inform strategies for prevention.
Methods and Findings
The InterAct study includes 12,403 incident T2D cases and a representative sub-cohort of 16,154 individuals from a cohort of 340,234 European participants with 3.99 million person-years of follow-up. We studied the combined effects of an additive genetic T2D risk score and modifiable and non-modifiable risk factors using Prentice-weighted Cox regression and random effects meta-analysis methods. The effect of the genetic score was significantly greater in younger individuals (p for interaction  = 1.20×10−4). Relative genetic risk (per standard deviation [4.4 risk alleles]) was also larger in participants who were leaner, both in terms of body mass index (p for interaction  = 1.50×10−3) and waist circumference (p for interaction  = 7.49×10−9). Examination of absolute risks by strata showed the importance of obesity for T2D risk. The 10-y cumulative incidence of T2D rose from 0.25% to 0.89% across extreme quartiles of the genetic score in normal weight individuals, compared to 4.22% to 7.99% in obese individuals. We detected no significant interactions between the genetic score and sex, diabetes family history, physical activity, or dietary habits assessed by a Mediterranean diet score.
Conclusions
The relative effect of a T2D genetic risk score is greater in younger and leaner participants. However, this sub-group is at low absolute risk and would not be a logical target for preventive interventions. The high absolute risk associated with obesity at any level of genetic risk highlights the importance of universal rather than targeted approaches to lifestyle intervention.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, more than 380 million people currently have diabetes, and the condition is becoming increasingly common. Diabetes is characterized by high levels of glucose (sugar) in the blood. Blood sugar levels are usually controlled by insulin, a hormone released by the pancreas after meals (digestion of food produces glucose). In people with type 2 diabetes (the commonest type of diabetes), blood sugar control fails because the fat and muscle cells that normally respond to insulin by removing excess sugar from the blood become less responsive to insulin. Type 2 diabetes can often initially be controlled with diet and exercise (lifestyle changes) and with antidiabetic drugs such as metformin and sulfonylureas, but patients may eventually need insulin injections to control their blood sugar levels. Long-term complications of diabetes, which include an increased risk of heart disease and stroke, reduce the life expectancy of people with diabetes by about ten years compared to people without diabetes.
Why Was This Study Done?
Type 2 diabetes is thought to originate from the interplay between genetic and lifestyle factors. But although rapid progress is being made in understanding the genetic basis of type 2 diabetes, it is not known whether the consequences of adverse lifestyles (for example, being overweight and/or physically inactive) differ according to an individual's underlying genetic risk of diabetes. It is important to investigate this question to inform strategies for prevention. If, for example, obese individuals with a high level of genetic risk have a higher risk of developing diabetes than obese individuals with a low level of genetic risk, then preventative strategies that target lifestyle interventions to obese individuals with a high genetic risk would be more effective than strategies that target all obese individuals. In this case-cohort study, researchers from the InterAct consortium quantify the combined effects of genetic and lifestyle factors on the risk of type 2 diabetes. A case-cohort study measures exposure to potential risk factors in a group (cohort) of people and compares the occurrence of these risk factors in people who later develop the disease with those who remain disease free.
What Did the Researchers Do and Find?
The InterAct study involves 12,403 middle-aged individuals who developed type 2 diabetes after enrollment (incident cases) into the European Prospective Investigation into Cancer and Nutrition (EPIC) and a sub-cohort of 16,154 EPIC participants. The researchers calculated a genetic type 2 diabetes risk score for most of these individuals by determining which of 49 gene variants associated with type 2 diabetes each person carried, and collected baseline information about exposure to lifestyle risk factors for type 2 diabetes. They then used various statistical approaches to examine the combined effects of the genetic risk score and lifestyle factors on diabetes development. The effect of the genetic score was greater in younger individuals than in older individuals and greater in leaner participants than in participants with larger amounts of body fat. The absolute risk of type 2 diabetes, expressed as the ten-year cumulative incidence of type 2 diabetes (the percentage of participants who developed diabetes over a ten-year period) increased with increasing genetic score in normal weight individuals from 0.25% in people with the lowest genetic risk scores to 0.89% in those with the highest scores; in obese people, the ten-year cumulative incidence rose from 4.22% to 7.99% with increasing genetic risk score.
What Do These Findings Mean?
These findings show that in this middle-aged cohort, the relative association with type 2 diabetes of a genetic risk score comprised of a large number of gene variants is greatest in individuals who are younger and leaner at baseline. This finding may in part reflect the methods used to originally identify gene variants associated with type 2 diabetes, and future investigations that include other genetic variants, other lifestyle factors, and individuals living in other settings should be undertaken to confirm this finding. Importantly, however, this study shows that young, lean individuals with a high genetic risk score have a low absolute risk of developing type 2 diabetes. Thus, this sub-group of individuals is not a logical target for preventative interventions. Rather, suggest the researchers, the high absolute risk of type 2 diabetes associated with obesity at any level of genetic risk highlights the importance of universal rather than targeted approaches to lifestyle intervention.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001647.
The US National Diabetes Information Clearinghouse provides information about diabetes for patients, health-care professionals and the general public, including detailed information on diabetes prevention (in English and Spanish)
The UK National Health Service Choices website provides information for patients and carers about type 2 diabetes and about living with diabetes; it also provides people's stories about diabetes
The charity Diabetes UK provides detailed information for patients and carers in several languages, including information on healthy lifestyles for people with diabetes
The UK-based non-profit organization Healthtalkonline has interviews with people about their experiences of diabetes
The Genetic Landscape of Diabetes is published by the US National Center for Biotechnology Information
More information on the InterAct study is available
MedlinePlus provides links to further resources and advice about diabetes and diabetes prevention (in English and Spanish)
doi:10.1371/journal.pmed.1001647
PMCID: PMC4028183  PMID: 24845081
2.  No Difference in Small or Large Nerve Fiber Function Between Individuals With Normal Glucose Tolerance and Impaired Glucose Tolerance 
Diabetes Care  2013;36(4):962-964.
OBJECTIVE
To assess small and large nerve fiber function in people with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes (T2D).
RESEARCH DESIGN AND METHODS
Participants were recruited consecutively from a population-based cohort: NGT (n = 39), IGT (n = 29), and T2D (n = 51). Electrophysiological measures included nerve conduction studies and thermal thresholds. Intraepidermal nerve fiber density (IENFD) in skin biopsies was calculated.
RESULTS
There was no difference between IGT and NGT in sural nerve conduction, IENFD, and thermal thresholds. IENFD was significantly lower in T2D (median = 2.8 fibers/mm [interquartile range 1.1–4.7 fibers/mm]) than NGT individuals (4.5 fibers/mm [3.4–6.1 fibers/mm]; P < 0.05). T2D participants had poorer nerve conduction and higher heat thresholds than NGT and IGT.
CONCLUSIONS
Large and small nerve function in people with IGT did not differ from those with NGT. Our finding does not support the existence of neuropathy in a prediabetic stage.
doi:10.2337/dc12-1331
PMCID: PMC3609489  PMID: 23223347
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.  Temporal Shifts in Cardiovascular Risk Factor Distribution 
Background
Complementary strategies to shift risk factor population distributions and target high-risk individuals are required to reduce the burden of type 2 diabetes and cardiovascular disease (CVD).
Purpose
To examine secular changes in glucose and CVD risk factors over 20 years during an individual and population-based CVD prevention program in Västerbotten County, Sweden.
Methods
Population-based health promotion intervention was conducted and annual invitation for individuals turning 40, 50, and 60 years to attend a health assessment, including an oral glucose tolerance test, biochemical measures, and a questionnaire. Data were collected between 1991 and 2010, analyzed in 2012 and available for 120,929 individuals. Linear regression modeling examined age-adjusted differences in CVD risk factor means over time. Data were direct-age-standardized to compare disease prevalence.
Results
Between 1991–1995 and 2006–2010, mean age-adjusted cholesterol (men=−0.53, 95% CI=−0.55, −0.50 mmol/L; women=−0.48, 95% CI=−0.50, −0.45 mmol/L) and systolic blood pressure declined (men=−3.06, 95% CI=−3.43, −2.70 mm Hg; women=−5.27, 95% CI=−5.64, −4.90 mm Hg), with corresponding decreases in the age-standardized prevalence of hypertension and hyperlipidemia. Mean age-adjusted 2-hour plasma glucose (men=0.19, 95% CI=0.15, 0.23 mmol/L; women=0.08, 95% CI=0.04, 0.11 mmol/L) and BMI increased (men=1.12, 95% CI=1.04, 1.21; women=0.65, 95% CI=0.55, 0.75), with increases in the age-standardized prevalence of diabetes and obesity.
Conclusions
These data demonstrate the potential of combined individual- and population-based approaches to CVD risk factor control and highlight the need for additional strategies addressing hyperglycemia and obesity.
doi:10.1016/j.amepre.2013.10.011
PMCID: PMC3898870  PMID: 24439344
5.  Dietary Intakes of Individual Flavanols and Flavonols Are Inversely Associated with Incident Type 2 Diabetes in European Populations123 
The Journal of Nutrition  2013;144(3):335-343.
Dietary flavanols and flavonols, flavonoid subclasses, have been recently associated with a lower risk of type 2 diabetes (T2D) in Europe. Even within the same subclass, flavonoids may differ considerably in bioavailability and bioactivity. We aimed to examine the association between individual flavanol and flavonol intakes and risk of developing T2D across European countries. The European Prospective Investigation into Cancer and Nutrition (EPIC)–InterAct case-cohort study was conducted in 8 European countries across 26 study centers with 340,234 participants contributing 3.99 million person-years of follow-up, among whom 12,403 incident T2D cases were ascertained and a center-stratified subcohort of 16,154 individuals was defined. We estimated flavonoid intake at baseline from validated dietary questionnaires using a database developed from Phenol-Explorer and USDA databases. We used country-specific Prentice-weighted Cox regression models and random-effects meta-analysis methods to estimate HRs. Among the flavanol subclass, we observed significant inverse trends between intakes of all individual flavan-3-ol monomers and risk of T2D in multivariable models (all P-trend < 0.05). We also observed significant trends for the intakes of proanthocyanidin dimers (HR for the highest vs. the lowest quintile: 0.81; 95% CI: 0.71, 0.92; P-trend = 0.003) and trimers (HR: 0.91; 95% CI: 0.80, 1.04; P-trend = 0.07) but not for proanthocyanidins with a greater polymerization degree. Among the flavonol subclass, myricetin (HR: 0.77; 95% CI: 0.64, 0.93; P-trend = 0.001) was associated with a lower incidence of T2D. This large and heterogeneous European study showed inverse associations between all individual flavan-3-ol monomers, proanthocyanidins with a low polymerization degree, and the flavonol myricetin and incident T2D. These results suggest that individual flavonoids have different roles in the etiology of T2D.
doi:10.3945/jn.113.184945
PMCID: PMC3927546  PMID: 24368432
6.  The prospective association between total and type of fish intake and type 2 diabetes in 8 European countries: EPIC-InterAct Study123 
Background: Epidemiologic evidence of an association between fish intake and type 2 diabetes (T2D) is inconsistent and unresolved.
Objective: The objective was to examine the association between total and type of fish intake and T2D in 8 European countries.
Design: This was a case-cohort study, nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study, with 3.99 million person-years of follow-up, 12,403 incident diabetes cases, and a random subcohort of 16,835 individuals from 8 European countries. Habitual fish intake (lean fish, fatty fish, total fish, shellfish, and combined fish and shellfish) was assessed by country-specific dietary questionnaires. HRs were estimated in each country by using Prentice-weighted Cox regression models and pooled by using a random-effects meta-analysis.
Results: No overall association was found between combined fish and shellfish intake and incident T2D per quartile (adjusted HR: 1.00; 95% CI: 0.94, 1.06; P-trend = 0.99). Total fish, lean fish, and shellfish intakes separately were also not associated with T2D, but fatty fish intake was weakly inversely associated with T2D: adjusted HR per quartile 0.97 (0.94, 1.00), with an HR of 0.84 (0.70, 1.01), 0.85 (0.76, 0.95), and 0.87 (0.78, 0.97) for a comparison of the second, third, and fourth quartiles with the lowest quartile of intake, respectively (P-trend = 0.06).
Conclusions: These findings suggest that lean fish, total fish, and shellfish intakes are not associated with incident diabetes but that fatty fish intake may be weakly inversely associated. Replication of these findings in other populations and investigation of the mechanisms underlying these associations are warranted. Meanwhile, current public health recommendations on fish intake should remain unchanged.
doi:10.3945/ajcn.111.029314
PMCID: PMC3623039  PMID: 22572642
7.  Fruit and vegetable intake and type 2 diabetes: EPIC-InterAct prospective study and meta-analysis 
European journal of clinical nutrition  2012;66(10):1082-1092.
Background/Objective
Fruit and vegetable intake (FVI) may reduce the risk of type 2 diabetes (T2D), but the epidemiological evidence is inconclusive. The aim of this study is to examine the prospective association of FVI with T2D and conduct an updated meta-analysis.
Subjects/Methods
In the EPIC-InterAct (European Prospective Investigation into Cancer-InterAct) prospective case-cohort study nested within eight European countries, a representative sample of 16 154 participants and 12 403 incident cases of T2D were identified from 340 234 individuals with 3.99 million person-years of follow-up. For the meta-analysis we identified prospective studies on FVI and T2D risk by systematic searches of MEDLINE and EMBASE until April 2011.
Results
In EPIC-InterAct, estimated FVI by dietary questionnaires varied more than two-fold between countries. In adjusted analyses the hazard ratio (95% confidence interval) comparing the highest with lowest quartile of reported intake was 0.90 (0.80-1.01) for FVI; 0.89 (0.76-1.04) for fruit, and 0.94 (0.84-1.05) for vegetables. Among FV sub-types, only root vegetables were inversely associated with diabetes 0.87 (0.77-0.99). In meta-analysis using pooled data from five studies including EPIC-InterAct, comparing the highest with lowest category for FVI was associated with a lower relative risk of diabetes (0.93 (0.87-1.00)). Fruit or vegetables separately were not associated with diabetes. Among FV sub-types, only green leafy vegetable intake (RR: 0.84 (0.74-0.94)) was inversely associated with diabetes.
Conclusions
Sub-types of vegetables, such as root vegetables or green leafy vegetables may be beneficial for the prevention of diabetes, while total FVI may exert a weaker overall effect.
doi:10.1038/ejcn.2012.85
PMCID: PMC3652306  PMID: 22854878
Fruit; vegetables; type 2 diabetes mellitus; epidemiology; meta-analysis; review
8.  Self-rated health and type 2 diabetes risk in the European Prospective Investigation into Cancer and Nutrition-InterAct study: a case-cohort study 
BMJ Open  2013;3(3):e002436.
Objectives
To investigate the association between self-rated health and risk of type 2 diabetes and whether the strength of this association is consistent across five European centres.
Design
Population-based prospective case-cohort study.
Setting
Enrolment took place between 1992 and 2000 in five European centres (Bilthoven, Cambridge, Heidelberg, Potsdam and Umeå).
Participants
Self-rated health was assessed by a baseline questionnaire in 3399 incident type 2 diabetic case participants and a centre-stratified subcohort of 4619 individuals from the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study which was drawn from a total cohort of 340 234 participants in the EPIC.
Primary outcome measure
Prentice-weighted Cox regression was used to estimate centre-specific HRs and 95% CIs for incident type 2 diabetes controlling for age, sex, centre, education, body mass index (BMI), smoking, alcohol consumption, energy intake, physical activity and hypertension. The centre-specific HRs were pooled across centres by random effects meta-analysis.
Results
Low self-rated health was associated with a higher hazard of type 2 diabetes after adjusting for age and sex (pooled HR 1.67, 95% CI 1.48 to 1.88). After additional adjustment for health-related variables including BMI, the association was attenuated but remained statistically significant (pooled HR 1.29, 95% CI 1.09 to 1.53). I2 index for heterogeneity across centres was 13.3% (p=0.33).
Conclusions
Low self-rated health was associated with a higher risk of type 2 diabetes. The association could be only partly explained by other health-related variables, of which obesity was the strongest. We found no indication of heterogeneity in the association between self-rated health and type 2 diabetes mellitus across the European centres.
doi:10.1136/bmjopen-2012-002436
PMCID: PMC3612773  PMID: 23471609
Diabetes & Endocrinology; Preventive Medicine
9.  Dietary Fiber, Carbohydrate Quality and Quantity, and Mortality Risk of Individuals with Diabetes Mellitus 
PLoS ONE  2012;7(8):e43127.
Background
Dietary fiber, carbohydrate quality and quantity are associated with mortality risk in the general population. Whether this is also the case among diabetes patients is unknown.
Objective
To assess the associations of dietary fiber, glycemic load, glycemic index, carbohydrate, sugar, and starch intake with mortality risk in individuals with diabetes.
Methods
This study was a prospective cohort study among 6,192 individuals with confirmed diabetes mellitus (mean age of 57.4 years, and median diabetes duration of 4.4 years at baseline) from the European Prospective Investigation into Cancer and Nutrition (EPIC). Dietary intake was assessed at baseline (1992–2000) with validated dietary questionnaires. Cox proportional hazards analysis was performed to estimate hazard ratios (HRs) for all-cause and cardiovascular mortality, while adjusting for CVD-related, diabetes-related, and nutritional factors.
Results
During a median follow-up of 9.2 y, 791 deaths were recorded, 306 due to CVD. Dietary fiber was inversely associated with all-cause mortality risk (adjusted HR per SD increase, 0.83 [95% CI, 0.75–0.91]) and CVD mortality risk (0.76[0.64–0.89]). No significant associations were observed for glycemic load, glycemic index, carbohydrate, sugar, or starch. Glycemic load (1.42[1.07–1.88]), carbohydrate (1.67[1.18–2.37]) and sugar intake (1.53[1.12–2.09]) were associated with an increased total mortality risk among normal weight individuals (BMI≤25 kg/m2; 22% of study population) but not among overweight individuals (P interaction≤0.04). These associations became stronger after exclusion of energy misreporters.
Conclusions
High fiber intake was associated with a decreased mortality risk. High glycemic load, carbohydrate and sugar intake were associated with an increased mortality risk in normal weight individuals with diabetes.
doi:10.1371/journal.pone.0043127
PMCID: PMC3426551  PMID: 22927948
10.  HbA1c Measured in Stored Erythrocytes Is Positively Linearly Associated with Mortality in Individuals with Diabetes Mellitus 
PLoS ONE  2012;7(6):e38877.
Introduction
Observational studies have shown that glycated haemoglobin (HbA1c) is related to mortality, but the shape of the association is less clear. Furthermore, disease duration and medication may modify this association. This observational study explored the association between HbA1c measured in stored erythrocytes and mortality. Secondly, it was assessed whether disease duration and medication use influenced the estimates or were independently associated with mortality.
Methods
Within the European Prospective Investigation into Cancer and Nutrition a cohort was analysed of 4,345 individuals with a confirmed diagnosis of diabetes at enrolment. HbA1c was measured in blood samples stored up to 19 years. Multivariable Cox proportional hazard regression models for all-cause mortality investigated HbA1c in quartiles as well as per 1% increment, diabetes medication in seven categories of insulin and oral hypoglycaemic agents, and disease duration in quartiles.
Results
After a median follow-up of 9.3 years, 460 participants died. Higher HbA1c was associated with higher mortality: Hazard Ratio for 1%-increase was 1.11 (95% CI 1.06, 1.17). This association was linear (P-nonlinearity =0.15) and persistent across categories of medication use, disease duration, and co-morbidities. Compared with metformin, other medication types were not associated with mortality. Longer disease duration was associated with mortality, but not after adjustment for HbA1c and medication.
Conclusion
This prospective study showed that persons with lower HbA1c had better survival than those with higher HbA1c. The association was linear and independent of disease duration, type of medication use, and presence of co-morbidities. Any improvement of HbA1c appears to be associated with reduced mortality risk.
doi:10.1371/journal.pone.0038877
PMCID: PMC3374773  PMID: 22719972
11.  How to diagnose and classify diabetes in primary health care: Lessons learned from the Diabetes Register in Northern Sweden (DiabNorth) 
Objective
The objective was to create a diabetes register and to evaluate the validity of the clinical diabetes diagnosis and its classification.
Design
The diabetes register was created by linkage of databases in primary and secondary care, the pharmaceutical database, and ongoing population-based health surveys in the county. Diagnosis and classification were validated by specialists in diabetology or general practitioners with special competence in diabetology. Analysis of autoantibodies associated with type 1 diabetes was used for classification. Setting. Primary and secondary health care in the county of Västerbotten, Sweden.
Patients
Patients with diabetes (median age at diagnosis 56 years, inter quartile range 50–60 years) who had participated in the Västerbotten Intervention Programme (VIP) and accepted participation in a diabetes register.
Results
Of all individuals with diabetes in VIP, 70% accepted to participate in the register. The register included 3256 (M/F 1894/1362) diabetes patients. The vast majority (95%) had data confirming the diabetes diagnoses according to WHO recommendations. Unspecified diabetes was the most common (54.6%) classification by the general practitioners. After assessment by specialists and analysis of autoantibodies the majority were classified as type 2 diabetes (76.8%). Type 1 diabetes was the second largest group (7.2%), including a sub-group of patients with latent autoimmune diabetes (4.8%).
Conclusion
It was concluded that it is feasible to create a diabetes register based on information in medical records in general practice. However, special attention should be paid to the validity of the diabetes diagnosis and its classification.
doi:10.3109/02813432.2012.675565
PMCID: PMC3378009  PMID: 22643152
Diabetes; classification; register; primary health care
12.  Self-rated health and mortality in individuals with diabetes mellitus: prospective cohort study 
BMJ Open  2012;2(1):e000760.
Objectives
To investigate whether low self-rated health (SRH) is associated with increased mortality in individuals with diabetes.
Design
Population-based prospective cohort study.
Setting
Enrolment took place between 1992 and 2000 in four centres (Bilthoven, Heidelberg, Potsdam, Umeå) in a subcohort nested in the European Prospective Investigation into Cancer and Nutrition.
Participants
3257 individuals (mean ± SD age was 55.8±7.6 years and 42% women) with confirmed diagnosis of diabetes mellitus.
Primary outcome measure
The authors used Cox proportional hazards modelling to estimate HRs for total mortality controlling for age, centre, sex, educational level, body mass index, physical inactivity, smoking, insulin treatment, hypertension, hyperlipidaemia and history of myocardial infarction, stroke or cancer.
Results
During follow-up (mean follow-up ± SD was 8.6±2.3 years), 344 deaths (241 men/103 women) occurred. In a multivariate model, individuals with low SRH were at higher risk of mortality (HR 1.38, 95% CI 1.10 to 1.73) than those with high SRH. The association was mainly driven by increased 5-year mortality and was stronger among individuals with body mass index of <25 kg/m2 than among obese individuals. In sex-specific analyses, the association was statistically significant in men only. There was no indication of heterogeneity across centres.
Conclusions
Low SRH was associated with increased mortality in individuals with diabetes after controlling for established risk factors. In patients with diabetes with low SRH, the physician should consider a more detailed consultation and intensified support.
Article summary
Article focus
Is low self-rated health (SRH) associated with increased mortality in individuals with diabetes?
If so, is the association between SRH and mortality in individuals with diabetes moderated by socio-demographic and health-related variables?
Key messages
Low SRH was associated with increased mortality in individuals with diabetes after controlling for established risk factors. The association was homogeneous across the four European Prospective Investigation into Cancer and Nutrition centres situated in three different European countries.
The association between low SRH and mortality was mainly driven by increased 5-year mortality in men and was stronger among individuals with body mass index <25 than among obese individuals.
Strengths and limitations of this study
To our knowledge, this is the first study that evaluates this research question in a population-based cohort of individuals with diabetes with long-term follow-up (up to a maximum of 14 years) in different European countries.
The association between SRH and mortality remained robust after controlling for potential confounders, including previous myocardial infarction, stroke or cancer, but we cannot rule out residual confounding from other comorbidity that was not assessed at baseline.
doi:10.1136/bmjopen-2011-000760
PMCID: PMC3282291  PMID: 22337818
13.  Detailed Investigation of the Role of Common and Low-Frequency WFS1 Variants in Type 2 Diabetes Risk 
Diabetes  2009;59(3):741-746.
OBJECTIVE
Wolfram syndrome 1 (WFS1) single nucleotide polymorphisms (SNPs) are associated with risk of type 2 diabetes. In this study we aimed to refine this association and investigate the role of low-frequency WFS1 variants in type 2 diabetes risk.
RESEARCH DESIGN AND METHODS
For fine-mapping, we sequenced WFS1 exons, splice junctions, and conserved noncoding sequences in samples from 24 type 2 diabetic case and 68 control subjects, selected tagging SNPs, and genotyped these in 959 U.K. type 2 diabetic case and 1,386 control subjects. The same genomic regions were sequenced in samples from 1,235 type 2 diabetic case and 1,668 control subjects to compare the frequency of rarer variants between case and control subjects.
RESULTS
Of 31 tagging SNPs, the strongest associated was the previously untested 3′ untranslated region rs1046320 (P = 0.008); odds ratio 0.84 and P = 6.59 × 10−7 on further replication in 3,753 case and 4,198 control subjects. High correlation between rs1046320 and the original strongest SNP (rs10010131) (r2 = 0.92) meant that we could not differentiate between their effects in our samples. There was no difference in the cumulative frequency of 82 rare (minor allele frequency [MAF] <0.01) nonsynonymous variants between type 2 diabetic case and control subjects (P = 0.79). Two intermediate frequency (MAF 0.01–0.05) nonsynonymous changes also showed no statistical association with type 2 diabetes.
CONCLUSIONS
We identified six highly correlated SNPs that show strong and comparable associations with risk of type 2 diabetes, but further refinement of these associations will require large sample sizes (>100,000) or studies in ethnically diverse populations. Low frequency variants in WFS1 are unlikely to have a large impact on type 2 diabetes risk in white U.K. populations, highlighting the complexities of undertaking association studies with low-frequency variants identified by resequencing.
doi:10.2337/db09-0920
PMCID: PMC2828659  PMID: 20028947
14.  News from the Nordic countries 
doi:10.3109/02813432.2010.544910
PMCID: PMC3347926  PMID: 21171928
15.  Detailed investigation of the role of common and low frequency WFS1 variants in type 2 diabetes risk 
Diabetes  2009;59(3):741-746.
OBJECTIVE
WFS1 (Wolfram Syndrome 1) SNPs are associated with risk of type 2 diabetes (T2D). Here, we aimed to refine this association and investigate the role of low frequency WFS1 variants in T2D risk.
RESEARCH DESIGN AND METHODS
For fine-mapping, we sequenced WFS1 exons, splice junctions and conserved non-coding sequences in 24 T2D cases and 68 controls, selected tagging SNPs, and genotyped these in 959 UK T2D cases and 1386 controls. The same genomic regions were sequenced in 1235 T2D cases and 1668 controls to compare the frequency of rarer variants between cases and controls.
RESULTS
Of 31 tagging SNPs, the strongest associated was the previously untested 3′ UTR rs1046320 (P=0.008); OR=0.84, P=6.59 × 10−7 on further replication in 3753 cases and 4198 controls. High correlation between rs1046320 and the original strongest SNP (rs10010131) (r2=0.92) meant that we could not differentiate between their effects in our samples. There was no difference in the cumulative frequency of 82 rare (MAF<0.01) non-synonymous variants between T2D cases and controls (P=0.79). Two intermediate frequency (MAF 0.01-0.05) non-synonymous changes also showed no statistical association with T2D.
CONCLUSION
We identified six highly correlated SNPs that show strong and comparable associations with risk of T2D association but further refinement of these associations will require large sample sizes (>100,000), or studies in ethnically diverse populations. Low frequency variants in WFS1 are unlikely to have a large impact on T2D risk in white UK populations, highlighting the complexities of undertaking association studies with low frequency variants identified by re-sequencing.
doi:10.2337/db09-0920
PMCID: PMC2828659  PMID: 20028947
16.  Replication and extension of genome-wide association study results for obesity in 4923 adults from northern Sweden 
Human Molecular Genetics  2009;18(8):1489-1496.
Recent genome-wide association studies (GWAS) have identified multiple risk loci for common obesity (FTO, MC4R, TMEM18, GNPDA2, SH2B1, KCTD15, MTCH2, NEGR1 and PCSK1). Here we extend those studies by examining associations with adiposity and type 2 diabetes in Swedish adults. The nine single nucleotide polymorphisms (SNPs) were genotyped in 3885 non-diabetic and 1038 diabetic individuals with available measures of height, weight and body mass index (BMI). Adipose mass and distribution were objectively assessed using dual-energy X-ray absorptiometry in a sub-group of non-diabetics (n = 2206). In models with adipose mass traits, BMI or obesity as outcomes, the most strongly associated SNP was FTO rs1121980 (P < 0.001). Five other SNPs (SH2B1 rs7498665, MTCH2 rs4752856, MC4R rs17782313, NEGR1 rs2815752 and GNPDA2 rs10938397) were significantly associated with obesity. To summarize the overall genetic burden, a weighted risk score comprising a subset of SNPs was constructed; those in the top quintile of the score were heavier (+2.6 kg) and had more total (+2.4 kg), gynoid (+191 g) and abdominal (+136 g) adipose tissue than those in the lowest quintile (all P < 0.001). The genetic burden score significantly increased diabetes risk, with those in the highest quintile (n = 193/594 cases/controls) being at 1.55-fold (95% CI 1.21–1.99; P < 0.0001) greater risk of type 2 diabetes than those in the lowest quintile (n = 130/655 cases/controls). In summary, we have statistically replicated six of the previously associated obese-risk loci and our results suggest that the weight-inducing effects of these variants are explained largely by increased adipose accumulation.
doi:10.1093/hmg/ddp041
PMCID: PMC2664142  PMID: 19164386

Results 1-16 (16)