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Little is known about the long-term effects of dietary energy density (ED) on weight gain.
We conducted a prospective study of 50,026 women (mean age: 36.5; SD: 4.6) in the Nurses' Health Study II followed from 1991 to 1999. Dietary ED and body weight were ascertained in 1991, 1995, and 1999. Total dietary ED was calculated by dividing each subject's daily energy intake (kcal) by the reported weight (g) of all foods consumed.
Dietary ED was positively correlated with saturated fat (r=0.16), trans fat (r=0.15), and the glycemic index (r=0.16), but inversely correlated with vegetable protein (r=−0.30), vegetables (r=−0.27), and fruits (r=−0.17). ED was not significantly correlated with total fat intake (r=0.08). Women who increased their dietary ED during follow-up the most (5th quintile) had a statistical significant greater multivariate-adjusted weight gain as compared with those who decreased their dietary ED most (1st quintile) (in the 8-y time period: 6.42 kg versus 4.57 kg; p for trend < 0.001). However, the amount of weight change over time varied considerably according to the ED of individual foods and beverages.
Increases in total dietary ED were associated with long-term weight gain among younger and middle-aged women. However, public health recommendations cannot be made simply based on ED values of individual foods and beverages only. Reducing consumption of foods high in saturated and trans fats and refined carbohydrates and increasing consumption of fruits and vegetables may help to reduce dietary ED and prevent weight gain.
PMCID: PMC3977032  PMID: 18779295
2.  Does Being Overweight Really Reduce Mortality? 
Obesity (Silver Spring, Md.)  2013;21(9):10.1002/oby.20602.
There is indisputable evidence from epidemiologic and clinical studies that being overweight and obese elevates the risk of developing debilitating and costly chronic diseases, including hypertension, hypercholesterolemia, type 2 diabetes, cardiovascular diseases (CVD), and cancer (1). Nonetheless, the relationship between body mass index (BMI) and mortality remains the subject of much debate. A recent meta-analysis concluded that compared to those of normal weight (BMI<25.0), overweight individuals (BMI 25.0–29.9) had a significantly lower mortality risk (2). Even Class 1 obesity (BMI 30–34.9) was associated with marginally reduced mortality. In this Perspective, we discuss why this finding is likely to be an artifact of methodological limitations and what the clinical and public health implications may be.
PMCID: PMC3806201  PMID: 24078231
Obesity; overweight; mortality; reverse causation; chronic disease; body mass index
3.  Prepregnancy Dietary Protein Intake, Major Dietary Protein Sources, and the Risk of Gestational Diabetes Mellitus 
Diabetes Care  2013;36(7):2001-2008.
Dietary protein is an important modulator of glucose metabolism. However, studies regarding the association between dietary protein intake and gestational diabetes mellitus (GDM) risk are sparse. This study was to examine the association.
Our study included 21,457 singleton pregnancies reported among 15,294 participants of the Nurses' Health Study II cohort between 1991 and 2001. Included pregnancies were free of chronic diseases before pregnancy or previous GDM. Generalized estimating equations were used to estimate the relative risks (RRs) and 95% CIs.
After adjustment for age, parity, nondietary and dietary factors, and BMI, multivariable RRs (95% CIs) comparing the highest with lowest quintiles were 1.49 (1.03–2.17) for animal protein intake and 0.69 (0.50–0.97) for vegetable protein intake. The substitution of 5% energy from vegetable protein for animal protein was associated with a 51% lower risk of GDM (RR [95% CI], 0.49 [0.29–0.84]). For major dietary protein sources, multivariable RRs (95% CIs) comparing the highest with the lowest quintiles were 2.05 (1.55–2.73) for total red meat and 0.73 (0.56–0.95) for nuts, respectively. The substitution of red meat with poultry, fish, nuts, or legumes showed a significantly lower risk of GDM.
Higher intake of animal protein, in particular red meat, was significantly associated with a greater risk of GDM. By contrast, higher intake of vegetable protein, specifically nuts, was associated with a significantly lower risk. Substitution of vegetable protein for animal protein, as well as substitution of some healthy protein sources for red meat, was associated with a lower risk of GDM.
PMCID: PMC3687314  PMID: 23378620
4.  Low dehydroepiandrosterone sulphate is associated with increased risk of ischemic stroke among women 
Stroke; a journal of cerebral circulation  2013;44(7):10.1161/STROKEAHA.111.000485.
Background and Purpose
Previous research suggests greater risk of coronary heart disease with lower levels of the adrenal steroid dehydroepiandrosterone sulfate (DHEAS). No studies have examined the association between DHEAS and risk for ischemic stroke. DHEAS may influence ischemic stroke risk through atherosclerotic related mechanisms (endothelial function and smooth muscle cell proliferation) or insulin resistance.
Between 1989-1990, 32,826 women without prior stroke in the Nurses’ Health Study, an observational cohort, provided blood samples and were followed for cardiovascular events. Among this sample, using a nested-case control design, 461 ischemic strokes confirmed by medical records through 2006. Cases were matched to controls free of stroke at the time of the index case and by age, ancestry, menopausal status, postmenopausal hormone use, smoking status and date of sample collection. Multivariable conditional logistic regression was utilized.
Median DHEAS levels did not differ between cases (median=58.7) and controls (median=66.0; p-value=0.10). Conditional on matching factors, the lowest DHEAS quartile exhibited a relative risk (RR) of 1.30 for ischemic stroke (95% confidence interval [CI]: 0.88-1.94), compared with the highest quartile and marginally unchanged when adjusted for confounders (RR=1.33; 95%CI: 0.87-2.02). When modeled as a binary variable dichotomized at the lowest quartile, women with low DHEAS (≤the lowest quartile) had a significantly increased multivariable adjusted risk of ischemic stroke compared to those with higher levels (RR=1.41; 95%CI: 1.03-1.92).
Lower DHEAS levels were associated with a greater risk of ischemic stroke, even after adjustment for potential confounders. These novel observations warrant confirmation in other populations.
PMCID: PMC3811081  PMID: 23704104
Ischemic stroke; dehydroepiandrosterone sulphate
5.  Asian-White disparities in short sleep duration by industry of employment and occupation in the US: a cross-sectional study 
BMC Public Health  2014;14:552.
Although short sleep is associated with an increased risk of morbidity as well as mortality and has been shown to vary by industry of employment and occupation, little is known about the relationship between work and sleep among Asian Americans.
Using a nationally representative sample of US adults (n = 125,610) in the National Health Interview Survey from 2004–2011, we estimated prevalence ratios for self-reported short sleep duration (<7 hours) in Asians compared to Whites by industry of employment and occupation using adjusted Poisson regression models with robust variance.
Asians were more likely to report short sleep duration than Whites (33 vs. 28%, p < 0.001), and the Asian-White disparity was widest in finance/information and healthcare industries. Compared to Whites after adjustments, short sleep was also more prevalent among Asians employed in Public administration (PR = 1.35 [95% CI: 1.17,1.56]), Education (PR = 1.29 [95% CI: 1.08,1.53]), and Professional/Management (PR = 1.18 [95% CI: 1.03,1.36]). Short sleep, however, was lower among Asians in Accommodation/Food (PR = 0.81 [95% CI: 0.66, 0.99]) with no difference in Retail. In professional and support-service occupations, short sleep was higher among Asians, but was not different among laborers.
U.S. Asian-White disparities in short sleep varied by industries, suggesting a need to consider both race and occupational characteristics to identify high-risk individuals.
PMCID: PMC4057824  PMID: 24894508
Sleep; Work; Industry; Occupation; Asian; Race
6.  Association of Urinary Concentrations of Bisphenol A and Phthalate Metabolites with Risk of Type 2 Diabetes: A Prospective Investigation in the Nurses’ Health Study (NHS) and NHSII Cohorts 
Environmental Health Perspectives  2014;122(6):616-623.
Background: Prospective evidence regarding associations for exposures to bisphenol A (BPA) and phthalates with type 2 diabetes (T2D) is lacking.
Objective: We prospectively examined urinary concentrations of BPA and phthalate metabolites with T2D risk.
Methods: We measured BPA and eight major phthalate metabolites among 971 incident T2D case–control pairs from the Nurses’ Health Study (NHS) (mean age, 65.6 years) and NHSII (mean age, 45.6 years).
Results: In the NHSII, BPA levels were not associated with incident T2D in multivariate-adjusted analysis until body mass index was adjusted: odds ratio (OR) comparing extreme BPA quartiles increased from 1.40 (95% CI: 0.91, 2.15) to 2.08 (95% CI: 1.17, 3.69; ptrend = 0.02) with such an adjustment. In contrast, BPA concentrations were not associated with T2D in the NHS (OR = 0.81; 95% CI: 0.48, 1.38; ptrend = 0.45). Likewise, urinary concentrations of total phthalate metabolites were associated with T2D in the NHSII (OR comparing extreme quartiles = 2.14; 95% CI: 1.19, 3.85; ptrend = 0.02), but not in the NHS (OR = 0.87; 95% CI: 0.49, 1.53; ptrend = 0.29). Summed metabolites of butyl phthalates or di-(2-ethylhexyl) phthalates were significantly associated with T2D only in the NHSII; ORs comparing extreme quartiles were 3.16 (95% CI: 1.68, 5.95; ptrend = 0.0002) and 1.91 (95% CI: 1.04, 3.49; ptrend = 0.20), respectively.
Conclusions: These results suggest that BPA and phthalate exposures may be associated with the risk of T2D among middle-aged, but not older, women. The divergent findings between the two cohorts might be explained by menopausal status or simply by chance. Clearly, these results need to be interpreted with caution and should be replicated in future studies, ideally with multiple urine samples collected prospectively to improve the measurement of these exposures with short half-lives.
Citation: Sun Q, Cornelis MC, Townsend MK, Tobias DK, Eliassen AH, Franke AA, Hauser R, Hu FB. 2014. Association of urinary concentrations of bisphenol A and phthalate metabolites with risk of type 2 diabetes: a prospective investigation in the Nurses’ Health Study (NHS) and NHSII Cohorts. Environ Health Perspect 122:616–623;
PMCID: PMC4050512  PMID: 24633239
7.  Association of Nut Consumption with Total and Cause-Specific Mortality 
The New England journal of medicine  2013;369(21):2001-2011.
Increased nut consumption has been associated with a reduced risk of major chronic diseases, including cardiovascular disease and type 2 diabetes mellitus. However, the association between nut consumption and mortality remains unclear.
We examined the association between nut consumption and subsequent total and cause-specific mortality among 76,464 women in the Nurses’ Health Study (1980–2010) and 42,498 men in the Health Professionals Follow-up Study (1986–2010). Participants with a history of cancer, heart disease, or stroke were excluded. Nut consumption was assessed at baseline and updated every 2 to 4 years.
During 3,038,853 person-years of follow-up, 16,200 women and 11,229 men died. Nut consumption was inversely associated with total mortality among both women and men, after adjustment for other known or suspected risk factors. The pooled multivariate hazard ratios for death among participants who ate nuts, as compared with those who did not, were 0.93 (95% confidence interval [CI], 0.90 to 0.96) for the consumption of nuts less than once per week, 0.89 (95% CI, 0.86 to 0.93) for once per week, 0.87 (95% CI, 0.83 to 0.90) for two to four times per week, 0.85 (95% CI, 0.79 to 0.91) for five or six times per week, and 0.80 (95% CI, 0.73 to 0.86) for seven or more times per week (P<0.001 for trend). Significant inverse associations were also observed between nut consumption and deaths due to cancer, heart disease, and respiratory disease.
In two large, independent cohorts of nurses and other health professionals, the frequency of nut consumption was inversely associated with total and cause-specific mortality, independently of other predictors of death. (Funded by the National Institutes of Health and the International Tree Nut Council Nutrition Research and Education Foundation.)
PMCID: PMC3931001  PMID: 24256379
8.  Plasma Retinol-Binding Protein 4 (RBP4) Levels and Risk of Coronary Heart Disease: A Prospective Analysis among Women in the Nurses’ Health Study 
Circulation  2013;127(19):1938-1947.
Retinol-binding protein 4 (RBP4) may play an important role in the etiology of insulin resistance and metabolic syndrome. Few prospective data are available on the relationship between RBP4 and coronary heart disease (CHD). Further, previous studies did not distinguish among full-length and truncated forms of RBP4 that might have various biological activities.
Methods and Results
We measured plasma levels of full-length and several C-terminally truncated sub-fractions of RBP4 among 468 women who developed CHD and 472 matched controls in the Nurses’ Health Study cohort during 16 years of follow-up (1990–2006). We observed a temporal variation in the association of full-length RBP4 levels with CHD risk (P=0.04 for testing proportional hazard assumption). In the first 8 years of follow-up, after multivariate adjustment for covariates, the odds ratio (OR) of CHD risk comparing extreme quartiles of full-length RBP4 levels was 3.56 (95% CI: 1.21, 10.51; Ptrend=0.003), whereas this association was 0.77 (0.38, 1.56; Ptrend=0.44) in the follow-up period of 9–16 years. Results were similar for total RBP4 levels (summed levels of all RBP4 isoforms). Levels of the primary truncated isoform, RBP4-L, were not associated with CHD risk in any follow-up period; the ORs (95% CI) for extreme quartiles were 1.29 (0.50, 3.32) and 1.20 (0.64, 2.26) in the first and second 8 years of follow-up, respectively.
In this cohort of women, higher circulating full-length and total RBP4 levels were associated with increased risk of CHD in a time-dependent fashion. Additional data are warranted to confirm the current findings.
PMCID: PMC3741657  PMID: 23584360
acute myocardial infarction; retinol-binding protein 4; epidemiology; women; heart diseases
9.  Olive oil intake and risk of cardiovascular disease and mortality in the PREDIMED Study 
BMC Medicine  2014;12:78.
It is unknown whether individuals at high cardiovascular risk sustain a benefit in cardiovascular disease from increased olive oil consumption. The aim was to assess the association between total olive oil intake, its varieties (extra virgin and common olive oil) and the risk of cardiovascular disease and mortality in a Mediterranean population at high cardiovascular risk.
We included 7,216 men and women at high cardiovascular risk, aged 55 to 80 years, from the PREvención con DIeta MEDiterránea (PREDIMED) study, a multicenter, randomized, controlled, clinical trial. Participants were randomized to one of three interventions: Mediterranean Diets supplemented with nuts or extra-virgin olive oil, or a control low-fat diet. The present analysis was conducted as an observational prospective cohort study. The median follow-up was 4.8 years. Cardiovascular disease (stroke, myocardial infarction and cardiovascular death) and mortality were ascertained by medical records and National Death Index. Olive oil consumption was evaluated with validated food frequency questionnaires. Multivariate Cox proportional hazards and generalized estimating equations were used to assess the association between baseline and yearly repeated measurements of olive oil intake, cardiovascular disease and mortality.
During follow-up, 277 cardiovascular events and 323 deaths occurred. Participants in the highest energy-adjusted tertile of baseline total olive oil and extra-virgin olive oil consumption had 35% (HR: 0.65; 95% CI: 0.47 to 0.89) and 39% (HR: 0.61; 95% CI: 0.44 to 0.85) cardiovascular disease risk reduction, respectively, compared to the reference. Higher baseline total olive oil consumption was associated with 48% (HR: 0.52; 95% CI: 0.29 to 0.93) reduced risk of cardiovascular mortality. For each 10 g/d increase in extra-virgin olive oil consumption, cardiovascular disease and mortality risk decreased by 10% and 7%, respectively. No significant associations were found for cancer and all-cause mortality. The associations between cardiovascular events and extra virgin olive oil intake were significant in the Mediterranean diet intervention groups and not in the control group.
Olive oil consumption, specifically the extra-virgin variety, is associated with reduced risks of cardiovascular disease and mortality in individuals at high cardiovascular risk.
Trial registration
This study was registered at ( International Standard Randomized Controlled Trial Number (ISRCTN): 35739639. Registration date: 5 October 2005.
PMCID: PMC4030221  PMID: 24886626
Olive oil; Cardiovascular; Mortality; Mediterranean Diet; PREDIMED
10.  Intimate Partner Violence and Incidence of Type 2 Diabetes in Women 
Diabetes Care  2013;36(5):1159-1165.
We sought to estimate the association between intimate partner violence, a prevalent psychosocial stressor, and the incidence of type 2 diabetes in women.
In 2001, 68,376 Nurses’ Health Study II participants answered questions on physical, sexual, and psychological intimate partner violence in adulthood (age ≥18 years) and reported the years in which any abuse occurred. We used Cox proportional hazards models to estimate the associations between intimate partner violence exposures and incidence of type 2 diabetes from 2001 to 2007. We also estimated effects of duration and time since intimate partner violence on type 2 diabetes incidence.
Of 68,376 respondents, 64,732 met inclusion criteria at the 2001 baseline; of these, 23% reported lifetime physical intimate partner violence, 11% reported lifetime sexual intimate partner violence, and 8% reported moderate and <2% reported severe psychological intimate partner violence. Hazard ratios (HRs) and 95% CIs for type 2 diabetes, adjusted for potential confounders, were 1.18 (1.00–1.39) and 1.08 (0.86–1.35) for more than one lifetime episode of physical and sexual intimate partner violence, respectively, and 1.78 (1.21–2.61) for severe psychological abuse. Addition of updated BMI and other diabetes risk factors reduced the physical intimate partner violence HR to 1.12 (0.94–1.33) and the psychological intimate partner violence HR to 1.61 (1.09–2.38).
Physical intimate partner violence is modestly associated with incidence of type 2 diabetes in this population. Severe psychological violence may substantially increase type 2 diabetes risk.
PMCID: PMC3631851  PMID: 23248189
11.  Novel locus including FGF21 is associated with dietary macronutrient intake 
Human Molecular Genetics  2013;22(9):1895-1902.
Dietary intake of macronutrients (carbohydrate, protein, and fat) has been associated with risk of chronic conditions such as obesity and diabetes. Family studies have reported a moderate contribution of genetics to variation in macronutrient intake. In a genome-wide meta-analysis of a population-based discovery cohort (n = 33 533), rs838133 in FGF21 (19q13.33), rs197273 near TRAF family member-associated NF-kappa-B activator (TANK) (2p24.2), and rs10163409 in FTO (16q12.2) were among the top associations (P < 10−5) for percentage of total caloric intake from protein and carbohydrate. rs838133 was replicated in silico in an independent sample from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE) Nutrition Working Group (n = 38 360) and attained genome-wide significance in combined analysis (Pjoint = 7.9 × 10−9). A cytokine involved in cellular metabolism, FGF21 is a potential susceptibility gene for obesity and type 2 diabetes. Our results highlight the potential of genetic variation for determining dietary macronutrient intake.
PMCID: PMC3612009  PMID: 23372041
12.  Blood 25-Hydroxy Vitamin D Levels and Incident Type 2 Diabetes 
Diabetes Care  2013;36(5):1422-1428.
To quantitatively assess the strength and shape of the association between blood 25-hydroxy vitamin D [25(OH)D] levels and incident risk of type 2 diabetes.
A systematic search of the MEDLINE and Embase databases and a hand search of references from original reports were conducted up to 31 October 2012. Prospective observational studies that assessed the association between blood levels of 25(OH)D and risk of incident type 2 diabetes were included for meta-analysis. DerSimonian and Laird’s random-effects model was used. A quadratic spline regression analysis was used to examine the shape of the association with a generalized least-squares trend test performed for the dose-response relation.
A total of 21 prospective studies involving 76,220 participants and 4,996 incident type 2 diabetes cases were included for meta-analysis. Comparing the highest to the lowest category of 25(OH)D levels, the summary relative risk for type 2 diabetes was 0.62 (95% CI 0.54–0.70). A spline regression model showed that higher 25(OH)D levels were monotonically associated with a lower diabetes risk. This inverse association did not differ by sex, duration of follow-up, study sample size, diabetes diagnostic criteria, or 25(OH)D assay method. A linear trend analysis showed that each 10 nmol/L increment in 25(OH)D levels was associated with a 4% lower risk of type 2 diabetes (95% CI 3–6; P for linear trend < 0.0001).
Our meta-analysis showed an inverse and significant association between circulating 25(OH)D levels and risk of type 2 diabetes across a broad range of blood 25(OH)D levels in diverse populations.
PMCID: PMC3631862  PMID: 23613602
13.  Genetics of Type 2 Diabetes in European Populations 
Journal of diabetes  2012;4(3):203-212.
Type 2 diabetes (T2D) has become a leading health problem throughout the world. It is caused by both environmental and genetic factors and interactions between them. However, until very recently, the T2D susceptibility genes have been poorly understood. During the past 5 years, with the advent of genome-wide association studies (GWAS), a total of 58 T2D susceptibility loci have been associated with T2D risk at a genome-wide significance level (P <5×10−8) and evidence shows that most of these genetic variants influence pancreatic β-cell function. Most novel T2D susceptibility loci were identified through GWAS in European populations and later confirmed in other ethnic groups. Although the recent discovery of novel T2D susceptibility loci has contributed substantially to our understanding of the pathophysiology of the disease, clinical utility of these loci in disease prediction and prognosis is limited. More studies using multiethnic meta-analysis, gene-environment interaction analysis, sequencing analysis, epigenetic analysis, and functional experiments are needed to identify new susceptibility T2D loci and causal variants and to establish biological mechanisms.
PMCID: PMC3422419  PMID: 22781158
Europeans; Genetics; Genome-wide association studies; Type 2 diabetes
14.  Dietary quality and mortality among myocardial infarction survivors 
JAMA internal medicine  2013;173(19):10.1001/jamainternmed.2013.9768.
Information on diet after myocardial infarction (MI) and mortality is limited, despite the growing number of MI survivors in the United States.
To examine the association of post-MI dietary quality, and changes from pre- to post-MI, with all-cause and cardiovascular mortality among MI survivors.
Design, Setting, and Participants
We included 2,258 women from the Nurses’ Health Study and 1,840 men from the Health Professional Follow-Up Study. Participants survived an initial MI during study follow up and provided both pre- and post-MI food frequency questionnaire (FFQ). Diet quality was measured using Alternative Healthy Eating Index 2010 (AHEI2010), which consists of food and nutrients associated with risk of chronic disease in the literature. We adjusted for medication use, medical history, and lifestyle risk factors using Cox proportional hazards models.
Main Outcome Measures
all-cause and cardiovascular mortality.
During follow-up, we confirmed 682 all-cause deaths for women, and 451 for men. The median survival time after initial MI onset was 8.7 years for women and 9.0 years for men. After pooling results together, the adjusted HR was 0.76 (95% CI: 0.60–0.96) for all-cause and 0.73 (95% CI: 0.51–1.04) for cardiovascular mortality, comparing extreme quintiles of post-MI AHEI2010. A greater increase in the AHEI2010 score from pre- to post-MI was significantly associated with lower all-cause (pooled HR= 0.71, 95% CI: 0.56–0.91) and cardiovascular mortality (pooled HR= 0.60, 95% CI: 0.41–0.86), comparing extreme quintiles. The adjusted HR associated with post-MI AHEI2010 were 0.73 (95% CI: 0.58–0.93) for all-cause mortality and 0.81 (95% CI: 0.64–1.04) for cardiovascular mortality when the alcohol component was excluded.
Conclusions and Relevance
MI survivors who consume a higher quality diet, which has been associated with lower risk of CHD in primary prevention, have lower subsequent all-cause mortality.
PMCID: PMC3874045  PMID: 23999993
Diet quality; myocardial infarction; secondary prevention
15.  Exporting Diabetes to Asia: The Impact of Western-Style Fast Food 
Circulation  2012;126(2):163-165.
PMCID: PMC3401093  PMID: 22753305
cardiovascular disease risk factors; China; diabetes mellitus type 2; diet; Editorials; nutrition
16.  Melatonin secretion and the incidence of type 2 diabetes 
Loss-of-function mutations in the melatonin receptor are associated with insulin resistance and type 2 diabetes. Additionally, lower nocturnal melatonin secretion is associated with increased insulin resistance in a cross-sectional analysis of non-diabetics.
We aimed to study the association between melatonin secretion and the risk of developing type 2 diabetes.
Design, Setting, and Participants
Case-control study nested within the Nurses’ Health Study cohort. Among non-diabetic participants who provided urine and blood samples at baseline in 2000, we identified 370 women who developed type 2 diabetes from 2000-2012 and matched 370 controls using risk-set sampling.
Main outcome measures
Associations between melatonin secretion at baseline and incidence of type 2 diabetes were evaluated with multivariable conditional logistic regression controlling for demographic characteristics, lifestyle habits, measures of sleep quality, and biomarkers of inflammation and endothelial dysfunction.
Median urinary 6-sulfatoxymelatonin levels were 28.5ng/mg creatinine (5-95%, 5.5 to 84.2) among cases and 36.3ng/mg (5-95%, 6.9 to 110.8) among controls. Women with lower 6-sulfatoxymelatonin measurements had an increased OR of diabetes with multivariate OR 1.48 (95% CI, 1.11 to 1.98) per unit decrease in loge aMT6s/creatinine ratio. Compared with women in the highest 6-sulfatoxymelatonin category, those in the lowest 6-sulfatoxymelatonin category had a multivariable odds ratio 2.17, 95% CI 1.18 to 3.98 of developing type 2 diabetes. Women in the highest 6-sulfatoxymelatonin category had an estimated incident rate of diabetes 427 cases per 100,000 person years compared to 927 cases per 100,000 patient years in the lowest category.
Conclusions and Relevance
Lower melatonin secretion was independently associated with a higher risk of developing type 2 diabetes. Further research is warranted to assess if melatonin secretion is a modifiable risk factor for diabetes within the general population.
PMCID: PMC3804914  PMID: 23549584
17.  Nutritional genomics and metabolomics in obesity and type 2 diabetes 
BMC Genomics  2014;15(Suppl 2):O10.
PMCID: PMC4075441
Cancer causes & control : CCC  2013;24(4):695-704.
Recognition of the complex, multidimensional relationship between excess adiposity and cancer control outcomes has motivated the scientific community to seek new research models and paradigms.
The National Cancer Institute developed an innovative concept to establish a centers grant mechanism in nutrition, energetics, and physical activity; referred to as the Transdisciplinary Research on Energetics and Cancer (TREC) Initiative. This paper gives an overview of the 2011-2016 TREC Collaborative Network and the 15 research projects being conducted at the Centers.
Four academic institutions were awarded TREC center grants in 2011: Harvard University, University of California San Diego, University of Pennsylvania, and Washington University in St. Louis. The Fred Hutchinson Cancer Research Center is the Coordination Center. The TREC research portfolio includes 3 animal studies, 3 cohort studies, 4 randomized clinical trials, 1 cross-sectional study, and 2 modeling studies. Disciplines represented by TREC investigators include basic science, endocrinology, epidemiology, biostatistics, behavior, medicine, nutrition, physical activity, genetics, engineering, health economics, and computer science. Approximately 41,000 participants will be involved in these studies, including children, healthy adults, and breast and prostate cancer survivors. Outcomes include biomarkers of cancer risk, changes in weight and physical activity, persistent adverse treatment effects (e.g., lymphedema, urinary and sexual function), and breast and prostate cancer mortality.
The NIH Science of Team Science group will evaluate the value-added by this collaborative science. However, the most important outcome will be whether this transdisciplinary initiative improves the health of Americans at risk for cancer as well as cancer survivors.
PMCID: PMC3602225  PMID: 23378138
energetics; obesity; diet; physical activity; cancer; transdisciplinary
19.  Changes in water and beverage intake and long-term weight changes: results from three prospective cohort studies 
To examine the long-term relationship between changes in water and beverage intake and weight change.
Prospective cohort studies of 50 013 women aged 40-64 in the Nurses’ Health Study (NHS, 1986-2006), 52 987 women aged 27-44 in the NHS II (1991-2007), and 21 988 men aged 40-64 in the Health Professionals Follow-up Study (1986-2006) without obesity and chronic diseases at baseline.
We assessed the association of weight change within each 4-year interval with changes in beverage intakes and other lifestyle behaviors during the same period. Multivariate linear regression with robust variance and accounting for within-person repeated measures were used to evaluate the association. Results across the three cohorts were pooled by an inverse-variance-weighted meta-analysis.
Participants gained an average of 1.45 kg (5th to 95th percentile, −1.87 to 5.46) within each 4-year period. After controlling for age, baseline body mass index, and changes in other lifestyle behaviors (diet, smoking habits, exercise, alcohol, sleep duration, TV watching), each 1-cup/d increment of water intake was inversely associated with weight gain within each 4-year period (−0.13 kg; 95% CI: −0.17, −0.08). The associations for other beverages were: SSBs (0.36 kg; 0.24, 0.48), fruit juice (0.22 kg; 0.15, 0.28), coffee (−0.14 kg; −0.19, −0.09), tea (−0.03 kg; −0.05, −0.01), diet beverages (−0.10 kg; −0.14, −0.06), low-fat milk (0.02 kg; −0.04, 0.09), and whole milk (0.02 kg; −0.06, 0.10). We estimated that replacement of 1 serving/d of SSBs by 1 cup/d of water was associated with 0.49 kg (95% CI: 0.32, 0.65) less weight gain over each 4-year period, and the replacement estimate of fruit juices by water was 0.35 kg (95% CI: 0.23, 0.46). Substitution of SSBs or fruit juices by other beverages (coffee, tea, diet beverages, low-fat and whole milk) were all significantly and inversely associated with weight gain.
Our results suggest that increasing water intake in place of SSBs or fruit juices is associated with lower long-term weight gain.
PMCID: PMC3628978  PMID: 23318721
water; beverage; body weight; prospective cohort study
20.  Intake of specific fruits and vegetables in relation to risk of estrogen receptor-negative breast cancer among postmenopausal women 
In previous studies of postmenopausal women, overall intake of fruits and vegetables groups has been inversely associated with estrogen receptor negative (ER−) breast cancer. In this analysis, we prospectively examined the associations of specific fruits and vegetables with risk of ER− postmenopausal breast cancer among 75,929 women aged 38 to 63 years at baseline and followed for up to 24 years. Dietary data were collected seven times during this period. Cox proportional hazard models were used, adjusting for potential confounders, including a modified Alternate Mediterranean Diet score. We ascertained 792 incident cases of ER− post-menopausal breast cancer. The multivariate relative risk (RR) for every 2 servings/week consumption for total berries was 0.82 (95% CI=0.71–0.96, p=0.01), and the RR for women who consumed at least one serving of blueberries a week was 0.69 (95% CI=0.50–0.95, p=0.02) compared with non-consumers. Also, the RR for consuming at least 2 servings of peaches/nectarines per week was 0.59 (95% CI=0.37–0.93, p = 0.02). Risk of ER− breast cancer was not associated with intakes of other specific fruits or vegetables. In conclusion, higher intake of berries and peaches was associated with lower risk of ER− breast cancer among post-menopausal women. These results are considered exploratory and need to be confirmed in further studies.
PMCID: PMC3641647  PMID: 23532538
21.  A Genome-Wide Association Study of Depressive Symptoms 
Hek, Karin | Demirkan, Ayse | Lahti, Jari | Terracciano, Antonio | Teumer, Alexander | Cornelis, Marilyn C. | Amin, Najaf | Bakshis, Erin | Baumert, Jens | Ding, Jingzhong | Liu, Yongmei | Marciante, Kristin | Meirelles, Osorio | Nalls, Michael A. | Sun, Yan V. | Vogelzangs, Nicole | Yu, Lei | Bandinelli, Stefania | Benjamin, Emelia J. | Bennett, David A. | Boomsma, Dorret | Cannas, Alessandra | Coker, Laura H. | de Geus, Eco | De Jager, Philip L. | Diez-Roux, Ana V. | Purcell, Shaun | Hu, Frank B. | Rimma, Eric B. | Hunter, David J. | Jensen, Majken K. | Curhan, Gary | Rice, Kenneth | Penman, Alan D. | Rotter, Jerome I. | Sotoodehnia, Nona | Emeny, Rebecca | Eriksson, Johan G. | Evans, Denis A. | Ferrucci, Luigi | Fornage, Myriam | Gudnason, Vilmundur | Hofman, Albert | Illig, Thomas | Kardia, Sharon | Kelly-Hayes, Margaret | Koenen, Karestan | Kraft, Peter | Kuningas, Maris | Massaro, Joseph M. | Melzer, David | Mulas, Antonella | Mulder, Cornelis L. | Murray, Anna | Oostra, Ben A. | Palotie, Aarno | Penninx, Brenda | Petersmann, Astrid | Pilling, Luke C. | Psaty, Bruce | Rawal, Rajesh | Reiman, Eric M. | Schulz, Andrea | Shulman, Joshua M. | Singleton, Andrew B. | Smith, Albert V. | Sutin, Angelina R. | Uitterlinden, André G. | Völzke, Henry | Widen, Elisabeth | Yaffe, Kristine | Zonderman, Alan B. | Cucca, Francesco | Harris, Tamara | Ladwig, Karl-Heinz | Llewellyn, David J. | Räikkönen, Katri | Tanaka, Toshiko | van Duijn, Cornelia M. | Grabe, Hans J. | Launer, Lenore J. | Lunetta, Kathryn L. | Mosley, Thomas H. | Newman, Anne B. | Tiemeier, Henning | Murabito, Joanne
Biological psychiatry  2013;73(7):10.1016/j.biopsych.2012.09.033.
Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms.
In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p < 1 × 10−5) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies.
The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05 × 10−7). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19 × 10−3). This 5q21 region reached genome-wide significance (p = 4.78 × 10−8) in the overall meta-analysis combining discovery and replication studies (n = 51,258).
The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms.
PMCID: PMC3845085  PMID: 23290196
Center for Epidemiologic Studies Depression Scale; CHARGE consortium; depression; depressive symptoms; genetics; genome-wide association study; meta-analysis
22.  Genetic Determinant for Amino Acid Metabolites and Changes in Body Weight and Insulin Resistance in Response to Weight-loss Diets: the POUNDS LOST Trial 
Circulation  2013;127(12):10.1161/CIRCULATIONAHA.112.000586.
Circulating branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) were recently related to insulin resistance and diabetes in prospective cohorts. We tested the effects of a genetic determinant of BCAA/AAA ratio on changes in body weight and insulin resistance in a 2-year diet intervention trial.
Methods and Results
We genotyped BCAA/AAA ratio associated variant rs1440581 near PPM1K gene in 734 overweight or obese adults who were randomly assigned to one of four diets varying in macronutrient content. At 6 months, we observed that dietary fat significantly modified genetic effects on changes in weight, fasting insulin and homeostasis model assessment of insulin resistance (HOMA-IR), after adjustment for confounders (all P for interaction ≤ 0.006). Further adjustment for weight change did not appreciably change the interactions for fasting insulin and HOMA-IR. In the high-fat diet group, the C allele was related to less weight loss and smaller decreases in serum insulin and HOMA-IR (all P ≤ 0.02 in an additive pattern); while an opposite genotype effect on changes in insulin and HOMA-IR was observed in low-fat diet group (P = 0.02 and 0.04, respectively). At 2 years, the gene–diet interactions remained significant for weight loss (P = 0.008); but became null for changes in serum insulin and HOMA-IR due to weight regain.
Individuals carrying C allele of BCAA/AAA ratio associated variant rs1440581 may benefit less in weight loss and improvement of insulin sensitivity than those without this allele when undertake an energy restricted high-fat diet.
PMCID: PMC3860590  PMID: 23446828
Branched-chain amino acids; gene-diet interaction; insulin resistance; weight loss
23.  The Relationship of Coffee Consumption with Total and Disease-Specific Mortality: a Cohort Study 
Annals of internal medicine  2008;148(12):904-914.
Coffee consumption has been linked to various beneficial and detrimental health effects, but data on the relation with mortality are sparse.
To assess the association between coffee consumption and mortality from cardiovascular disease (CVD), cancer, and all causes during 18 years of follow-up in men and 24 years of follow-up in women.
Sex-specific Cox proportional hazards models were used to investigate the association between coffee consumption and incidence of death from all causes and specific mortality in a prospective cohort study.
Health Professionals Follow-up Study and Nurses' Health Study.
41,736 men and 86,214 women, without history of CVD or cancer at baseline.
Coffee consumption was first assessed in 1986 for men and in 1980 for women, and then repeatedly every 2-4 years; the follow-up continued through 2004. We documented 6,888 deaths (2,049 due to CVD and 2,491 due to cancer) among men, and 11,095 deaths (2,368 due to CVD and 5,011 due to cancer) among women.
For men, after adjustment for age, smoking, and other CVD and cancer risk factors, the relative risks (RRs) of all cause mortality across categories of coffee consumption (<1cup/mo, 1/mo-4/wk, 5-7/wk, 2-3/d, 4-5/d, and ≥6/d) were: 1.0, 1.07 (95% confidence interval: 0.99-1.16), 1.02 (0.95-1.11), 0.97 (0.89-1.05), 0.93 (0.81-1.07), and 0.80 (0.62-1.04) (p for trend= 0.008); for women, the RRs were: 1.0, 0.98 (0.91-1.05), 0.93 (0.87-0.98), 0.82 (0.77-0.87), 0.74 (0.68-0.81), and 0.83 (0.73-0.95) (p for trend<0.001). This inverse association was mainly due to a moderately reduced risk of CVD mortality, and was independent of caffeine intake. By contrast, coffee consumption was not significantly associated with risk of cancer death after adjustment for potential confounders. Decaffeinated coffee consumption was associated with a small reduction in all cause and CVD mortality.
Some measurement error in the assessment of coffee consumption is inevitable because we estimated the consumption from self-reports.
Regular coffee consumption was not associated with an increased mortality in either men or women. The possibility of a modest benefit of coffee consumption on all cause and CVD mortality needs to be further investigated.
PMCID: PMC3958951  PMID: 18559841
coffee; all causes death; cardiovascular death; cancer death; Health Professionals Follow-up Study; Nurses' Health Study
24.  Diabetes Genetic Predisposition Score and Cardiovascular Complications Among Patients With Type 2 Diabetes 
Diabetes Care  2013;36(3):737-739.
To examine the association between genetic predisposition to type 2 diabetes (T2D) and risk of cardiovascular disease (CVD) among patients with T2D.
The current study included 1,012 men and 1,310 women with T2D from the Health Professionals Follow-up Study and Nurses’ Health Study, including 677 patients with CVD and 1,645 non-CVD control subjects. A genetic predisposition score (GPS) was calculated on the basis of 36 established independent diabetes-predisposing variants.
Each additional diabetes-risk allele in the GPS was associated with a 3% increased risk of CVD (odds ratio [OR] 1.03 [95% CI 1.00–1.06]). The OR was 1.47 (1.11–1.95) for CVD risk by comparing extreme quartiles of the GPS (P for trend = 0.01). We also found that the GPS was positively associated with hemoglobin A1c levels (P = 0.009).
Genetic predisposition to T2D is associated with an increased risk of cardiovascular complications in patients with T2D.
PMCID: PMC3579364  PMID: 23069839
25.  Common Variations in Perilipin Gene, Central Obesity, and Risk of Type 2 diabetes in US Women 
Obesity (Silver Spring, Md.)  2008;16(5):1061-1065.
The variations in perilipin gene (PLIN) were previously associated with obesity and insulin sensitivity. We examined whether PLIN variability was associated with diabetes risk and whether obesity status modified such associations.
Research Methods and Procedures
We conducted a nested case-control study of 431 incident cases of type 2 diabetes and 791 healthy control women from the Nurses' Health Study. Obesity was defined by body mass index or waist circumference (central obesity).
In the sample of all participants, PLIN variations were not significantly associated with the incidence of diabetes. The central obesity status (By NCEP ATP III definition of waist circumference greater than 35 inches) significantly interacted with PLIN polymorphisms in relation to diabetes risk (P for interaction=0.027, 0.009, and 0.02 for rs2289487, rs8179043, and rs894160 respectively). In non-obese (central) women, carriers of rs2289487, rs8179043 and rs894160 had significantly greater risk of type 2 diabetes, adjusting for diabetes risk factors (OR=1.52, 1.03–2.25; 1.54, 1.07–2.23, and 1.57, 1.09–2.27 respectively). Haplotypes possessing the three polymorphisms were also significantly associated with diabetes risk (global test, P=0.01). As compared with the most common haplotype 111, haplotype 222 and 211 (1 codes the common and 2 codes the minor alleles) were associated with 44% (OR=1.44, 95% CI 1.09–1.91), P=0.01) and 70% (OR=1.70, 95% CI 1.04–2.77; P=0.03) greater risk respectively. The PLIN variations were not significantly associated with the disease risk among women with central obesity.
Our data indicate that central obesity may modify the associations between PLIN variations and diabetes risk in women.
PMCID: PMC3925667  PMID: 18356850

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