Type 2 diabetes is a global public health crisis that threatens the economies of all nations, particularly developing countries. Fueled by rapid urbanization, nutrition transition, and increasingly sedentary lifestyles, the epidemic has grown in parallel with the worldwide rise in obesity. Asia's large population and rapid economic development have made it an epicenter of the epidemic. Asian populations tend to develop diabetes at younger ages and lower BMI levels than Caucasians. Several factors contribute to accelerated diabetes epidemic in Asians, including the “normal-weight metabolically obese” phenotype; high prevalence of smoking and heavy alcohol use; high intake of refined carbohydrates (e.g., white rice); and dramatically decreased physical activity levels. Poor nutrition in utero and in early life combined with overnutrition in later life may also play a role in Asia's diabetes epidemic. Recent advances in genome-wide association studies have contributed substantially to our understanding of diabetes pathophysiology, but currently identified genetic loci are insufficient to explain ethnic differences in diabetes risk. Nonetheless, interactions between Westernized diet and lifestyle and genetic background may accelerate the growth of diabetes in the context of rapid nutrition transition. Epidemiologic studies and randomized clinical trials show that type 2 diabetes is largely preventable through diet and lifestyle modifications. Translating these findings into practice, however, requires fundamental changes in public policies, the food and built environments, and health systems. To curb the escalating diabetes epidemic, primary prevention through promotion of a healthy diet and lifestyle should be a global public policy priority.

Dyslipidemia has been associated with type 2 diabetes, but it remains unclear whether dyslipidemia plays a causal role in type 2 diabetes. We aimed to examine the association between the genetic predisposition to dyslipdemia and type 2 diabetes risk. The current study included 2,447 patients with type 2 diabetes and 3,052 control participants of European ancestry from the Nurses’ Health Study and the Health Professionals Follow-up Study. Genetic predisposition to dyslipidemia was estimated by three genotype scores of lipids (LDL cholesterol, HDL cholesterol, and triglycerides) on the basis of the established loci for blood lipids. Linear relation analysis indicated that the HDL cholesterol and triglyceride genotype scores, but not the LDL cholesterol genotype score, were linearly related to elevated type 2 diabetes risk. Each point of the HDL cholesterol and triglyceride genotype scores was associated with a 3% (odds ratio [OR] 1.03 [95% CI 1.01–1.04]) and a 2% (1.02 [1.00–1.04]) increased risk of developing type 2 diabetes, respectively. The ORs were 1.39 (1.17–1.65) and 1.19 (1.01–1.41) for type 2 diabetes by comparing extreme quartiles of the HDL cholesterol genotype score and triglyceride genotype score, respectively. In conclusion, genetic predisposition to low HDL cholesterol or high triglycerides is related to elevated type 2 diabetes risk.

Background and Purpose

Few dietary protein sources have been studied prospectively in relation to stroke. We examined the relation between foods that are major protein sources and risk of stroke.

Methods

We prospectively followed 84,010 women aged 30–55 years at baseline and 43,150 men aged 40–75 years at baseline without diagnosed cancer, diabetes, or cardiovascular disease. Diet was assessed repeatedly by a standardized and validated questionnaire. We examined the association between protein sources and incidence of stroke using a proportional hazard model adjusted for stroke risk factors.

Results

During 26 and 22 years of follow-up in women and men, respectively, we documented 2,633 and 1,397 strokes, respectively. In multivariable analyses, higher intake of red meat was associated with an elevated risk of stroke, while a higher intake of poultry was associated with lower risk. In models estimating the effects of exchanging different protein sources, compared to one serving/day of red meat, one serving/day of poultry was associated with a 27% (95% CI: 12% to 39%) lower risk of stroke, nuts with a 17% (95% CI: 4% to 27%) lower risk, fish with a 17% (95% CI: 0% to 30%) lower risk, low-fat dairy with an 11% (95% CI: 5% to 17%) lower risk, and whole-fat dairy with a 10% (95% CI: 4% to 16%) lower risk. We did not see significant associations with exchanging legumes or eggs for red meat.

Conclusions

These data suggest that stroke risk may be reduced by replacing red meat with other dietary sources of protein.

OBJECTIVE

To investigate the association between vitamin D status, assessed by plasma 25-hydroxyvitamin D, and risk of incident diabetes.

RESEARCH DESIGN AND METHODS

Prospective observational study with a mean follow-up of 2.7 years in the Diabetes Prevention Program (DPP), a multicenter trial comparing different strategies for prevention of diabetes in patients with prediabetes. We assessed the association between plasma 25-hydroxyvitamin D, measured repeatedly during follow-up, and incident diabetes in the combined placebo (n = 1,022) and intensive lifestyle (n = 1,017) randomized arms of the DPP. Variables measured at multiple study time points (25-hydroxyvitamin D, BMI, and physical activity) entered the analyses as time-varying “lagged” covariates, as the mean of the previous and current visits at which diabetes status was assessed.

RESULTS

After multivariate adjustment, including for the DPP intervention, participants in the highest tertile of 25-hydroxyvitamin D (median concentration, 30.1 ng/mL) had a hazard ratio of 0.72 (95% CI 0.56–0.90) for developing diabetes compared with participants in the lowest tertile (median concentration, 12.8 ng/mL). The association was in the same direction in placebo (0.70; 0.52–0.94) versus lifestyle arm (0.80; 0.54–1.17).

CONCLUSIONS

Higher plasma 25-hydroxyvitamin D, assessed repeatedly, was associated with lower risk of incident diabetes in high-risk patients, after adjusting for lifestyle interventions (dietary changes, increased physical activity, and weight loss) known to decrease diabetes risk. Because of the observational nature of the study, the potential association between vitamin D and diabetes needs to be confirmed in intervention studies.

The question of which statistical approach is the most effective for investigating gene-environment (G-E) interactions in the context of genome-wide association studies (GWAS) remains unresolved. By using 2 case-control GWAS (the Nurses’ Health Study, 1976–2006, and the Health Professionals Follow-up Study, 1986–2006) of type 2 diabetes, the authors compared 5 tests for interactions: standard logistic regression-based case-control; case-only; semiparametric maximum-likelihood estimation of an empirical-Bayes shrinkage estimator; and 2-stage tests. The authors also compared 2 joint tests of genetic main effects and G-E interaction. Elevated body mass index was the exposure of interest and was modeled as a binary trait to avoid an inflated type I error rate that the authors observed when the main effect of continuous body mass index was misspecified. Although both the case-only and the semiparametric maximum-likelihood estimation approaches assume that the tested markers are independent of exposure in the general population, the authors did not observe any evidence of inflated type I error for these tests in their studies with 2,199 cases and 3,044 controls. Both joint tests detected markers with known marginal effects. Loci with the most significant G-E interactions using the standard, empirical-Bayes, and 2-stage tests were strongly correlated with the exposure among controls. Study findings suggest that methods exploiting G-E independence can be efficient and valid options for investigating G-E interactions in GWAS.

Aims

To examine the relations between genetic loci, plasma lipoprotein(a) [Lp(a)] levels, and cardiovascular disease (CVD) risk among diabetic patients and compare with the observations in the general population.

Methods and results

In two prospective cohorts of patients with type 2 diabetes (n= 2308) from the Nurses' Health Study and the Health Professional Follow-Up Study, we performed (i) genome-wide association (GWA) scans for plasma Lp(a); (ii) prospective analysis of plasma Lp(a) for CVD risk and mortality; and (iii) genetic association analysis for CVD risk and mortality. Meta-analysis of the two GWA scans yielded 71 single-nucleotide polymorphisms (SNPs) on chromosome 6q associated with plasma Lp(a) levels at a genome-wide significance level (P< 5 × 10−8). The SNP rs10455872 in LPA was most strongly associated with Lp(a) (P= 4.60 × 10−39). Forward-selection analysis indicated that rs10455872 and other five SNPs in a region encompassing LPA, PLG, SLC22A3, and LPAL2 genes were independently associated with Lp(a) levels and jointly explained ∼20% of variation in diabetic patients. In prospective analysis, we did not find any significant association between plasma levels and CVD incidence; the relative risk for coronary heart disease (CHD), CVD, and CVD death was 1.05 [95% confidence interval (CI): 0.95–1.15], 1.05 (0.96–1.15), and 1.21 (0.99–1.47) per 1-SD higher log-transformed Lp(a) levels, respectively. Consistently, none of the Lp(a) SNPs were associated with CVD risk or mortality (all P> 0.09). For the best SNP rs10455872 for plasma Lp(a) levels, the OR for CHD, CVD, and CVD death was 0.94 (95% CI: 0.69–1.28), 0.97 (0.72–1.29), and 1.23 (0.79–1.92), respectively. The genetic effect on CHD risk showed a significant heterogeneity between the diabetic and the general populations (P= 0.006).

Conclusion

Our data indicate that the effect of Lp(a) on CVD risk among diabetic patients might be different from that in the general population. Diabetes status may attenuate the relation between Lp(a) and cardiovascular risk.

Background: Prospective data regarding persistent organic pollutants (POPs) and risk of type 2 diabetes (T2D) are limited, and the results for individual POPs are not entirely consistent across studies.

Objectives: We prospectively examined plasma POP concentrations in relation to incident T2D and summarized existing evidence in a meta-analysis.

Methods: Plasma polychlorinated biphenyls (PCBs), dichlorodiphenyltrichloroethane (DDT), dichlorodiphenyldichloroethylene (DDE), and hexachlorobenzene (HCB) concentrations were measured in 1,095 women who were free of diabetes at blood draw in 1989–1990 and participated in two case–control studies in the Nurses’ Health Study. We identified 48 incident T2D cases through 30 June 2008. We conducted a literature search in PubMed and EMBASE through December 2011 to identify prospective studies on POPs in relation to diabetes. We used a fixed-effects model to summarize results.

Results: After multivariable adjustment, plasma HCB concentration was positively associated with incident T2D [pooled odds ratio (OR) 3.59 (95% CI: 1.49, 8.64, ptrend = 0.003) comparing extreme tertiles]. Other POPs were not significantly associated with diabetes. After pooling our results with those of six published prospective studies that included 842 diabetes cases in total, we found that HCB and total PCBs both were associated with diabetes: the pooled ORs were 2.00 (95% CI: 1.13, 3.53; I2 = 21.4%, pheterogeneity = 0.28) and 1.70 (95% CI: 1.28, 2.27; I2 = 16.3%, pheterogeneity = 0.30) for HCB and total PCBs, respectively.

Conclusions: These findings support an association between POP exposure and the risk of T2D.

Aims/hypothesis: Genome-wide association studies have identified over 50 new genetic loci for type 2 diabetes (T2D). Several studies conclude that higher dietary heme iron intake increases the risk of T2D. Therefore we assessed whether the relation between genetic loci and T2D is modified by dietary heme iron intake.

Methods: We used Affymetrix Genome-Wide Human 6.0 array data [681,770 single nucleotide polymorphisms (SNPs)] and dietary information collected in the Health Professionals Follow-up Study (n = 725 cases; n = 1,273 controls) and the Nurses’ Health Study (n = 1,081 cases; n = 1,692 controls). We assessed whether genome-wide SNPs or iron metabolism SNPs interacted with dietary heme iron intake in relation to T2D, testing for associations in each cohort separately and then meta-analyzing to pool the results. Finally, we created 1,000 synthetic pathways matched to an iron metabolism pathway on number of genes, and number of SNPs in each gene. We compared the iron metabolic pathway SNPs with these synthetic SNP assemblies in their relation to T2D to assess if the pathway as a whole interacts with dietary heme iron intake.

Results: Using a genomic approach, we found no significant gene–environment interactions with dietary heme iron intake in relation to T2D at a Bonferroni corrected genome-wide significance level of 7.33 ×10-8 (top SNP in pooled analysis: intergenic rs10980508; p = 1.03 × 10-6). Furthermore, no SNP in the iron metabolic pathway significantly interacted with dietary heme iron intake at a Bonferroni corrected significance level of 2.10 × 10-4 (top SNP in pooled analysis: rs1805313; p = 1.14 × 10-3). Finally, neither the main genetic effects (pooled empirical p by SNP = 0.41), nor gene – dietary heme–iron interactions (pooled empirical p-value for the interactions = 0.72) were significant for the iron metabolic pathway as a whole.

Conclusions: We found no significant interactions between dietary heme iron intake and common SNPs in relation to T2D.

OBJECTIVE

Whether dietary habits early in life can affect risk of type 2 diabetes (T2DM) in adulthood is unknown. We evaluated the relationship between dietary patterns during adolescence and risk of T2DM in midlife.

RESEARCH DESIGN AND METHODS

We examined the 7-year incidence of T2DM in relation to dietary patterns during high school among 37,038 participants in the Nurses’ Health Study II cohort, who completed a food-frequency questionnaire about their diet during high school. Dietary patterns were derived by factor analysis. Cox proportional hazards regression was used to estimate relative risk (RR) and 95% CI.

RESULTS

The prudent pattern, characterized by healthy foods, was not associated with risk of T2DM. The Western pattern, characterized by desserts, processed meats, and refined grains, was associated with 29% greater risk of T2DM (RR 1.29; 95% CI 1.00–1.66; P trend 0.04), after adjusting for high school and adult risk factors comparing extreme quintiles, but was attenuated after adjusting for adult weight change (1.19; 0.92–1.54). Women who had high Western pattern scores in high school and adulthood had an elevated risk of T2DM compared with women who had consistent low scores (1.82; 1.35–2.45), and this association was partly mediated by adult BMI (1.15; 0.85–1.56).

CONCLUSIONS

A Western dietary pattern during adolescence may increase risk of T2DM in later life, partly through adult weight gain. Preventive measures should be aimed at developing healthy dietary habits that begin in early life and continue through adulthood.

Objective

To evaluate whether coronary heart disease (CHD)-susceptibility loci identified by genome-wide association studies of the general population also contribute to CHD in type 2 diabetes.

Background

No study has examined the effects of these genetic variants on CHD in diabetic patients.

Methods

We genotyped 15 genetic markers of 12 loci in three studies of diabetic patients: the prospective Nurses’ Health Study (309 CHD cases and 544 controls) and Health Professional Follow-up Study (345 CHD cases and 451 controls), and the cross-sectional Joslin Heart Study (422 CHD cases and 435 controls).

Results

Five SNPs, rs4977574 (CDKN2A/2B), rs12526453 (PHACTR1), rs646776 (CELSR2-PSRC1-SORT1), rs2259816 (HNF1A), and rs11206510 (PCSK9) showed directionally consistent associations with CHD in the three studies, with combined odds ratios (ORs) ranging from 1.17 to 1.25 (p=0.03 to 0.0002). None of the other SNPs reached significance in individual or combined analyses. A genetic risk score (GRS) was created by combining the risk alleles of the five significantly associated loci. The OR of CHD per GRS unit was 1.19 (95% confidence interval [CI] 1.13– 1.26; p<0.0001). Individuals with GRS ≥8 (19% of diabetic subjects) had almost a two-fold increase in CHD risk (OR=1.94, 95% CI 1.60–2.35) as compared to individuals with GRS ≤5 (30% of diabetic subjects). Prediction of CHD was significantly improved (p<0.001) when the GRS was added to a model including clinical predictors in the combined samples.

Conclusions

Our results illustrate the consistency and differences in the determinants of genetic susceptibility to CHD in diabetic patients and the general populations.

Study Objective

Sleeping more than 7 to 8 hours per day has been consistently associated with increased mortality. Whether this association is causal and what pathways explain this association are unknown. We sought to identify factors that could potentially explain the association between long sleep and mortality.

Design

Cross-sectional epidemiologic survey.

Participants

Middle-aged women (n = 60,028) participating in the Nurses Health Study II who reported a habitual sleep duration of 7 hours or more.

Results

Multiple sclerosis (odds ratio [OR] = 3.7, 95% confidence interval [3.0–4.5]), antidepressant use (OR = 3.1, [2.9–3.3]), benzodiazepine use (OR = 3.0 [2.6–3.3]), and systemic lupus erythematosus (OR = 2.9, [2.3–3.6]) were the factors most strongly associated with prolonged sleep. Combining these data with prevalence information and a range of plausible associations with mortality, the confounding rate ratio was estimated. This parameter is the ratio of the unadjusted long sleep–mortality rate ratio to the rate ratio adjusted for the factor and measures the extent that the factor can alter the long sleep—mortality association, either through confounding or as a causal intermediate. Based on this parameter, psychiatric and socioeconomic factors have the greatest potential to influence the long sleep–mortality relationship. Assuming each factor doubles mortality risk, the confounding rate ratios for depression, antidepressant use, and unemployment were 1.10, 1.18, and 1.12. Lesser influential factors were benzodiazepine use, poverty, low societal status, sedentary lifestyle, and obesity.

Conclusion

Depression and low socioeconomic status are strong candidates for producing the statistical association between long sleep and mortality, either as confounders or as causal intermediates. Future causal research on the effects of long sleep should include a detailed assessment of psychiatric disease and socioeconomic status.

Physiologic studies suggest that sleep restriction has metabolic effects that predispose to weight gain. The authors investigated the association between self-reported usual sleep duration and subsequent weight gain in the Nurses’ Health Study. The 68,183 women who reported habitual sleep duration in 1986 were followed for 16 years. In analyses adjusted for age and body mass index, women sleeping 5 hours or less gained 1.14 kg (95% confidence interval (CI): 0.49, 1.79) more than did those sleeping 7 hours over 16 years, and women sleeping 6 hours gained 0.71 kg (95% CI: 0.41, 1.00) more. The relative risks of a 15-kg weight gain were 1.32 (95% CI: 1.19, 1.47) and 1.12 (95% CI: 1.06, 1.19) for those sleeping 5 and 6 hours, respectively. The relative risks for incident obesity (body mass index: >30 kg/m2) were 1.15 (95% CI: 1.04, 1.26) and 1.06 (95% CI: 1.01, 1.11). These associations remained significant after inclusion of important covariates and were not affected by adjustment for physical activity or dietary consumption. These data suggest that short sleep duration is associated with a modest increase in future weight gain and incident obesity. Further research is needed to understand the mechanisms by which sleep duration may affect weight.

Objective

To examine prospectively the association of total and high molecular weight (HMW) adiponectin, and HMW/total adiponectin ratio with risk of incident coronary heart disease (CHD) in women, and to examine to what extent adjustment for potentially intermediary variables would explain this association.

Methods and Results

Among 30,111 women from the Nurses’ Health Study, 468 women developed non-fatal myocardial infarction or fatal CHD during 14 years of follow-up. Using risk set sampling, controls were selected 2:1 matched on age, smoking, and date of blood draw. Adjusted for matching factors, parental history of myocardial infarction, hormone replacement therapy, alcohol consumption, physical activity, body mass index, hypertension, and low-density lipoprotein cholesterol levels, the relative risk in the highest versus lowest quintile was 0.50 (95%-CI 0.33-0.75; p trend=0.001) for total adiponectin, 0.53 (95%-CI 0.35-0.80; p trend=0.004) for HMW adiponectin, and 0.63 (95%-CI 0.43-0.93; p trend=0.03) for HMW/total adiponectin ratio. After adjustment for diabetes, HDL-cholesterol, HbA1c, and CRP these associations were attenuated and no longer significant (RRs, 0.84; 95%-CI 0.53-1.33; p trend=0.62; 0.95; 95%-CI 0.60-1.52; p trend=0.98; 0.97; 95%-CI 0.64-1.47; p trend=0.80).

Conclusions

High levels of total and HMW adiponectin, and HMW/total adiponectin ratio are associated with a lower risk of CHD among women. HMW adiponectin and HMW/total adiponectin ratio are not more closely related to risk than total adiponectin. These associations are largely mediated by parameters related to glucose and lipid metabolism and inflammation, especially HDL-cholesterol levels.

Although (GT)n repeats in heme oxygenase-1 (HO-1) promoter may modulate gene transcriptional activity, the association between (GT)n repeats polymorphism and risk of coronary heart disease (CHD) from different levels of oxidative stress (OS) is unknown. We determined the allelic frequencies of (GT)n repeats in the HO-1 gene promoter and plasma malonaldehyde (MDA) as biomarkers of OS in 2,298 pairs of CHD patients and controls in the Chinese population. Furthermore, we measured MDA in culture mediums and HO-1 expressions levels in cell lysates of endothelial cells carrying various (GT)n genotypes under different concentrations of H2O2. Compared with L/L genotype (>25 repeats) carriers, the adjusted odd ratios for S/S genotype (≤25 repeats) in subjects with different levels of OS (MDA < 1.83, 1.83–2.91, >2.91 μmol/L) were 1.06 (95%CI, 0.75 to 1.49), 0.79 (95%CI, 0.55 to 1.12), and 0.60 (95%CI, 0.44 to 0.81), respectively (Pinteraction = 0.002). In biological experiments, compared with endothelial cells carrying L/L genotype, cells with S/S genotype did not have a significantly higher HO-1 expression under 0 μmol/L H2O2, but displayed a significantly higher HO-1 expression under 50 μmol/L H2O2 (Pinteraction = 0.003). S/S genotype in HO-1 gene promoter is associated with a lower risk of CHD in subjects with higher levels of OS, because under conditions of high OS, the S/S genotype has higher levels of HO-1, an antioxidant.

In recent decades, temporal patterns in SSB intake have shown a close parallel between the upsurge in obesity and rising levels of SSB consumption. SSBs are beverages that contain added caloric sweeteners such as sucrose, high-fructose corn syrup or fruit-juice concentrates, all of which result in similar metabolic effects. They include the full spectrum of soft drinks, carbonated soft drinks, fruitades, fruit drinks, sports drinks, energy and vitamin water drinks, sweetened iced tea, cordial, squashes, and lemonade, which collectively are the largest contributor to added sugar intake in the US. It has long been suspected that SSBs have an etiologic role in the obesity epidemic, however only recently have large epidemiological studies been able to quantify the relationship between SSB consumption and long-term weight-gain, type 2 diabetes (T2DM) and cardiovascular disease (CVD) risk. Experimental studies have provided important insight into potential underlying biological mechanisms. It is thought that SSBs contribute to weight gain in part by incomplete compensation for energy at subsequent meals following intake of liquid calories. They may also increase risk of T2DM and CVD as a contributor to a high dietary glycemic load leading to inflammation, insulin resistance and impaired β-cell function. Additional metabolic effects from the fructose fraction of these beverages may also promote accumulation of visceral adiposity, and increased hepatic de novo lipogenesis, and hypertension due to hyperuricemia. Consumption of SSBs should therefore be replaced by healthy alternatives such as water, to reduce risk of obesity and chronic diseases.

Background

Findings from observational studies suggest that sex hormone-binding globulin (SHBG) and endogenous sex hormones may be mediators of the putative relation between coffee consumption and lower risk of type 2 diabetes. The objective of this study was to evaluate the effects of caffeinated and decaffeinated coffee on SHBG and sex hormone levels.

Findings

After a two-week run-in phase with caffeine abstention, we conducted an 8-week parallel-arm randomized controlled trial. Healthy adults (n = 42) were recruited from the Boston community who were regular coffee consumers, nonsmokers, and overweight. Participants were randomized to five 6-ounce cups of caffeinated or decaffeinated instant coffee or water (control group) per day consumed with each meal, mid-morning, and mid-afternoon. The main outcome measures were SHBG and sex hormones [i.e., testosterone, estradiol, dehydroepiandrosterone sulfate].

No significant differences were found between treatment groups for any of the studied outcomes at week 8. At 4 weeks, decaffeinated coffee was associated with a borderline significant increase in SHBG in women, but not in men. At week 4, we also observed several differences in hormone concentrations between the treatment groups. Among men, consumption of caffeinated coffee increased total testosterone and decreased total and free estradiol. Among women, decaffeinated coffee decreased total and free testosterone and caffeinated coffee decreased total testosterone.

Conclusions

Our data do not indicate a consistent effect of caffeinated coffee consumption on SHBG in men or women, however results should be interpreted with caution given the small sample size. This is the first randomized trial investigating the effects of caffeinated and decaffeinated coffee on SHBG and sex hormones and our findings necessitate further examination in a larger intervention trial.

Background and Purpose

Depression has been associated with increased risk of coronary heart disease, but prospective data for the association with stroke are limited.

Methods

We followed 80,574 women aged 54 to 79 years in Nurses’ Health Study without a prior history of stroke from 2000 to 2006. Depressive symptoms were assessed at multiple time-points by a Mental Health Index (MHI-5) score (1992, 1996 and 2000), and clinical significant depressive symptoms were defined as a score ≤52. Antidepressant medication (ADM) use was asked biennially beginning in 1996, and physician-diagnosed depression was reported biennially beginning in 2000. Depression was defined as currently reporting or having a history of any of these three conditions.

Results

During 6 years of follow-up, 1,033 incident strokes were documented (538 ischemic, 124 hemorrhagic, and 371 unknown strokes). Having a history of depression was associated with a multivariate-adjusted hazard ratio of 1.29 (95% confidence interval, 1.13–1.48) for total stroke. Women who used ADMs were at increased risks of stroke, whether they also had a MHI-5 score ≤52 or diagnosed depression (1.39; 1.15–1.69), or not (1.31; 1.03–1.67). Furthermore, for each cycle, participants who reported current depression had an increased risk of stroke (1.41; 1.18–1.67), whereas individuals who only had a past history of depression were at a non-significantly elevated risk (1.23; 0.97–1.56), compared with women who never reported a diagnosis of depression or ADM use.

Conclusions

Our results suggest that depression is associated with a moderately increased risk of subsequent stroke.

Context

Several studies have suggested that depression is associated with an increased risk of stroke; however, the results are inconsistent.

Objective

To conduct a systematic review and meta-analysis of prospective studies assessing the association between depression and risk of developing stroke in adults.

Data Sources

A search of MEDLINE, EMBASE, and PsychINFO databases (to May 2011) was supplemented by manual searches of bibliographies of key retrieved articles and relevant reviews.

Study Selection

We included prospective cohort studies that reported risk estimates of stroke morbidity or mortality by baseline or updated depression status assessed by self-reported scales or clinician diagnosis.

Data Extraction

Two independent reviewers extracted data on depression status at baseline, risk estimates of stroke, study quality, and methods used to assess depression and stroke. Hazard ratios (HRs) were pooled using fixed-effect or random-effects models when appropriate. Associations were tested in subgroups representing different participant and study characteristics. Publication bias was evaluated with funnel plots and Begg test.

Results

The search yielded 28 prospective cohort studies (n = 317540 participants) that reported 8478 stroke cases (morbidity and mortality) during a follow-up period ranging from 2 to 29 years. The pooled adjusted HRs were 1.45 (95% confidence interval [CI], 1.29–1.63; P-for-heterogeneity <0.001; random-effects model) for total stroke, 1.55 (1.25–1.93; P-for-heterogeneity = 0.31; fixed-effects model) for fatal stroke (8 studies), and 1.25 (1.11–1.40; P-for-heterogeneity = 0.34; fixed-effects model) for ischemic stroke (6 studies). The estimated absolute risk differences associated with depression were 106 cases for total stroke, 53 cases for ischemic stroke, and 22 cases for fatal stroke per 100 000 individuals per year. The increased risk of total stroke associated with depression was consistent across most subgroups.

Conclusion

Depression is associated with a significantly increased risk of stroke morbidity and mortality.

Background:

Several biomarkers of metabolic acidosis, including lower plasma bicarbonate and higher anion gap, have been associated with greater insulin resistance in cross-sectional studies. We sought to examine whether lower plasma bicarbonate is associated with the development of type 2 diabetes mellitus in a prospective study.

Methods:

We conducted a prospective, nested case–control study within the Nurses’ Health Study. Plasma bicarbonate was measured in 630 women who did not have type 2 diabetes mellitus at the time of blood draw in 1989–1990 but developed type 2 diabetes mellitus during 10 years of follow-up. Controls were matched according to age, ethnic background, fasting status and date of blood draw. We used logistic regression to calculate odds ratios (ORs) for diabetes by category of baseline plasma bicarbonate.

Results:

After adjustment for matching factors, body mass index, plasma creatinine level and history of hypertension, women with plasma bicarbonate above the median level had lower odds of diabetes (OR 0.76, 95% confidence interval [CI] 0.60–0.96) compared with women below the median level. Those in the second (OR 0.92, 95% CI 0.67–1.25), third (OR 0.70, 95% CI 0.51–0.97) and fourth (OR 0.75, 95% CI 0.54–1.05) quartiles of plasma bicarbonate had lower odds of diabetes compared with those in the lowest quartile (p for trend = 0.04). Further adjustment for C-reactive protein did not alter these findings.

Interpretation:

Higher plasma bicarbonate levels were associated with lower odds of incident type 2 diabetes mellitus among women in the Nurses’ Health Study. Further studies are needed to confirm this finding in different populations and to elucidate the mechanism for this relation.

We conducted a genome-wide association study on cutaneous basal cell carcinoma (BCC) among 2045 cases and 6013 controls of European ancestry, with follow-up replication in 1426 cases and 4845 controls. A non-synonymous SNP in the MC1R gene (rs1805007 encoding Arg151Cys substitution), a previously well-documented pigmentation gene, showed the strongest association with BCC risk in the discovery set (rs1805007[T]: OR (95% CI) for combined discovery set and replication set [1.55 (1.45–1.66); P= 4.3 × 10−17]. We identified that an SNP rs12210050 at 6p25 near the EXOC2 gene was associated with an increased risk of BCC [rs12210050[T]: combined OR (95% CI), 1.24 (1.17–1.31); P= 9.9 × 10−10]. In the locus on 13q32 near the UBAC2 gene encoding ubiquitin-associated domain-containing protein 2, we also identified a variant conferring susceptibility to BCC [rs7335046 [G]; combined OR (95% CI), 1.26 (1.18–1.34); P= 2.9 × 10−8]. We further evaluated the associations of these two novel SNPs (rs12210050 and rs7335046) with squamous cell carcinoma (SCC) risk as well as melanoma risk. We found that both variants, rs12210050[T] [OR (95% CI), 1.35 (1.16–1.57); P= 7.6 × 10−5] and rs7335046 [G] [OR (95% CI), 1.21 (1.02–1.44); P= 0.03], were associated with an increased risk of SCC. These two variants were not associated with melanoma risk. We conclude that 6p25 and 13q32 are novel loci conferring susceptibility to non-melanoma skin cancer.

The authors prospectively examined the association between the Dietary Approaches to Stop Hypertension diet score, overall, animal-based, and vegetable-based low-carbohydrate-diet scores, and major plant food groups and the risk of postmenopausal breast cancer in 86,621 women in the Nurses’ Health Study. Diet scores were calculated by using data from up to 7 food frequency questionnaires, with follow-up from 1980 to 2006. The authors ascertained 5,522 incident cases of breast cancer, including 3,314 estrogen receptor-positive (ER+) cancers and 826 estrogen receptor-negative (ER−) cancers. After adjustment for potential confounders, the Dietary Approaches to Stop Hypertension diet score was associated with a lower risk of ER− cancer (relative risk comparing extreme quintiles = 0.80, 95% confidence interval: 0.64, 1.01; P trend = 0.02). However, this was largely explained by higher intakes of fruits and vegetables. The authors also observed an inverse association between risk of ER− cancer and the vegetable-based, low-carbohydrate-diet score (corresponding relative risk = 0.81, 95% confidence interval: 0.65, 1.01; P trend = 0.03). High total fruit and low-protein vegetable intakes were associated with a lower risk of ER− cancer (relative risk comparing extreme quintiles = 0.71, 95% confidence interval: 0.55, 0.90; P trend = 0.005). No association was found between ER+ tumors and fruit and vegetable intakes. A diet high in fruits and vegetables, such as one represented by the Dietary Approaches to Stop Hypertension diet score, was associated with a lower risk of ER− breast cancer. In addition, a diet high in plant protein and fat and moderate in carbohydrate content was associated with a lower risk of ER− cancer.

Background

Many foods are associated with chronic obstructive pulmonary disease (COPD) symptoms or lung function. Because foods are consumed together and nutrients may interact, dietary patterns are an alternative way of characterising diet. A study was undertaken to assess the relation between dietary patterns and newly diagnosed COPD in men.

Methods

Data were collected from a large prospective cohort of US men (Health Professionals Follow‐up Study). Using principal component analysis, two dietary patterns were identified: a prudent pattern (high intake of fruits, vegetables, fish and whole grain products) and a Western pattern (high intake of refined grains, cured and red meats, desserts and French fries). Dietary patterns were categorised into quintiles and Cox proportional hazards models were adjusted for age, smoking, pack‐years, (pack‐years)2, race/ethnicity, physician visits, US region, body mass index, physical activity, multivitamin use and energy intake.

Results

Between 1986 and 1998, 111 self‐reported cases of newly diagnosed COPD were identified among 42 917 men. The prudent pattern was inversely associated with the risk of newly diagnosed COPD (RR for highest vs lowest quintile 0.50 (95% CI 0.25 to 0.98), p for trend = 0.02), and the Western pattern was positively associated with the risk of newly diagnosed COPD (RR for highest vs lowest quintile 4.56 (95% CI 1.95 to 10.69), p for trend <0.001).

Conclusions

In men, a diet rich in fruits, vegetables and fish may reduce the risk of COPD whereas a diet rich in refined grains, cured and red meats, desserts and French fries may increase the risk of COPD.

Background

Common genetic variants in the IRS1 gene have been recently associated with insulin resistance and hyperinsulinemia. We examined whether the best-associated variant modifies the long-term changes in insulin resistance and body weight in response to weight-loss diets in the Pounds Lost Trial.

Methods and Results

We genotyped IRS1 rs2943641 in 738 overweight adults (61% were women) who were randomly assigned to one of four diets varying in macronutrient contents for 2 years. We assessed the progress in fasting insulin, insulin resistance (HOMA-IR) and weight loss by genotypes. At 6 months, participants with the risk-conferring CC genotype had greater decreases in insulin (P=0.009), HOMA-IR (P=0.015) and weight loss (P=0.058) than those without this genotype in the highest carbohydrate diet group, while an opposite genotype effect on changes in insulin and HOMA-IR (P≤0.05) was observed in participants assigned to the lowest carbohydrate diet group. No significant differences were observed across genotypes in other 2 diet groups. The tests for genotype by intervention interactions were all significant (P<0.05). At 2 years, the genotype effect on changes in insulin and HOMA-IR remained significant in the highest carbohydrate diet group (P<0.05). The highest carbohydrate diet led to a greater improvement of insulin and HOMA-IR (P for genotype-time interaction≤0.009) in participants with the CC genotype than those without this genotype across 2-year intervention.

Conclusions

Individuals with the IRS1 rs2943641 CC genotype might obtain more benefits in weight loss and improvement of insulin resistance than those without this genotype by choosing a high-carbohydrate and low-fat diet.

OBJECTIVE

High molecular weight (HMW) adiponectin is a predominant isoform of circulating adiponectin and has been related to type 2 diabetes. Previous linkage studies suggest that different genetic components might be involved in determining HMW and total adiponectin levels.

RESEARCH DESIGN AND METHODS

We performed a genome-wide association study (GWAS) of serum HMW adiponectin levels in individuals of European ancestry drawn from the Nurses’ Health Study (NHS) (N = 1,591). The single nucleotide polymorphisms (SNPs) identified in the GWAS analysis were replicated in an independent cohort of Europeans (N = 626). We examined the associations of the identified variations with diabetes risk and metabolic syndrome.

RESULTS

We identified a novel locus near the FER gene (5q21) at a genome-wide significance level, best represented by SNP rs10447248 (P = 4.69 × 10−8). We also confirmed that variations near the adiponectin-encoding ADIPOQ locus (3q27) were related to serum HMW adiponectin levels. In addition, we found that FER SNP rs10447248 was related to HDL cholesterol levels (P = 0.009); ADIPOQ variation was associated with fasting glucose (P = 0.04), HDL cholesterol (P = 0.04), and a metabolic syndrome score (P = 0.002).

CONCLUSIONS

Our results suggest that different loci may be involved in regulation of circulating HMW adiponectin levels and provide novel insight into the mechanisms that affect HMW adiponectin homeostasis.

Background

High body iron store has been associated with an increased risk of type 2 diabetes (T2D); it remains unknown whether the genetic variants related to body iron status affect T2D risk. We aimed at comprehensively investigating the associations between the genetic variants related to body iron status and the T2D risk.

Methodology/Principal Findings

Six common SNPs related to body iron status from recent genome-wide association (GWA) studies were determined in the Nurses’ Health Study (NHS; 1,467 diabetic cases and 1,754 controls) and the Health Professionals Follow-up Study (HPFS; 1,124, diabetic cases and 1,298 controls). Plasma levels of ferritin, soluble transferrin receptor (sTfR), and transferrin were measured in NHS. Significant associations were observed for loci in TPMRSS6 with sTfR (P = 3.47×10−6), TF with transferrin (P = 0.0002 to 1.72×10−10); and HFE with ferritin (P = 0.017 to 1.6×10−8), sTfR (P = 0.007 to 7.9×10−6), and transferrin (P = 0.006 to 0.0007). The six SNPs together explained 5.7%, 2.7%, and 13.3% of the variation in plasma levels of ferritin, sTfR, and transferrin. After adjustment for the conventional risk factors, the T allele of SNP rs855791 in the TPMRSS6 gene was significantly associated with a 19% decreased risk of T2D (OR = 0.81; 95% CI = 0.66–0.98; P = 0.03) in men. Multiple tests attenuated this significant association to null. No associations were observed in women. SNPs at HFE and TF were not associated with diabetes risk in either sex. Dietary iron intake did not modify the associations of the newly identified loci with diabetes risk.

Conclusions/Significance

The newly identified iron-related SNP rs855791 in TPMRSS6 was nominally associated with a decreased risk of T2D in men but not in women. The apparent differences by gender warrant further study.