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1.  Association of total protein intake with bone mineral density (BMD) and bone loss in men and women from the Framingham Offspring Study 
Public health nutrition  2013;17(11):2570-2576.
To examine the association of % of total energy from protein (protein%) with bone mineral density (BMD, g/cm2) and bone loss at the femoral neck (FN), trochanter (TR); L2–L4 spine (LS). To examine calcium as an effect modifier.
The Framingham Offspring Study.
1,280 men and 1,639 women completed an FFQ in 1992–95 or 1995–98 and baseline DXA-BMD measurement in 1996–2000. 495 men and 680 women had follow-up BMD measured in 2002–2005.
Cohort study using multivariable regression to examine the association of protein% with each BMD, adjusting for covariates. Statistical interaction between protein% and calcium (total, dietary; supplemental) intake was examined.
The mean age at baseline was 61y(±9). In the cross-sectional analyses, protein% was positively associated with all BMD sites (P:0.02–0.04) in women but not in men. Significant interactions were observed with total calcium intake (<800 vs. ≥800 mg/d) in women at all bone sites (P:0.002–0.02). Upon stratification, protein% was positively associated with all BMD sites (P:0.04–0.10) in women with low calcium intakes but not with high calcium intakes. In the longitudinal analyses, in men, higher protein% was associated with more TR-bone loss (P=0.01) while no associations were seen in women, regardless of calcium intake.
This suggests that greater protein intake benefits women especially those with lower calcium intakes. However, protein effects are not significant for short term changes in bone density. Contrastingly, in men, higher protein intakes lead to greater TR-bone loss. Longer follow-up is required to examine the impact of protein on bone loss.
PMCID: PMC4103961  PMID: 24168918
Protein; bone mineral density; bone loss; diet; calcium
2.  Milk and yogurt consumption are linked with higher bone mineral density but not with hip fracture: the Framingham Offspring Study 
Archives of osteoporosis  2013;8(0):119.
To examine associations of milk, yogurt, cheese, cream, most dairy (total dairy without cream) and fluid dairy (milk+yogurt) with bone density (BMD) at femoral neck (FN), trochanter (TR) and spine, and with incident hip fracture over 12-y follow-up in the Framingham Offspring Study.
3,212 participants completed a food frequency questionnaire (1991–1995 or 1995–1998) and were followed for hip fracture until 2007. 2,506 participants had DXA BMD (1996–2001). Linear regression was used to estimate adjusted mean BMD while Cox-proportional hazards regression was used to estimate adjusted hazard ratios (HR) for hip fracture risk. Final models simultaneously included dairy foods adjusting for each other.
Mean baseline age was 55 (±1.6)y, range: 26–85). Most dairy intake was positively associated with hip and spine BMD. Intake of fluid dairy and milk were related with hip but not spine BMD. Yogurt intake was associated with TR-BMD alone. Cheese and cream intakes were not associated with BMD. In final models, yogurt intake remained positively associated with TR-BMD, while cream tended to be negatively associated with FN-BMD. Yogurt intake showed a weak protective trend for hip fracture [HR(95%CI): ≤4 serv/wk: 0.46 (0.21–1.03) vs. >4 serv/wk: 0.43 (0.06–3.27)]. No other dairy groups showed a significant association (HRs range: 0.53–1.47) with limited power (n, fractures=43).
Milk and yogurt intakes were associated with hip but not spine BMD, while cream may adversely influence BMD. Thus, not all dairy products are equally beneficial for the skeleton. Suggestive fracture results for milk and yogurt intakes need further confirmation.
PMCID: PMC3641848  PMID: 23371478
dairy; milk; yogurt; bone mineral density; hip fracture; dietary intake; bone health
3.  Plasma Phosphatidylcholine Concentrations of Polyunsaturated Fatty Acids Are Differentially Associated With Hip Bone Mineral Density and Hip Fracture in Older Adults: The Framingham Osteoporosis Study 
Polyunsaturated fatty acids (PUFAs) may influence bone health. The objective of this work was to examine associations between plasma phosphatidylcholine (PC) PUFA concentrations and hip measures: (1) femoral neck bone mineral density (FN-BMD) (n = 765); (2) 4-year change in FN-BMD (n = 556); and (3) hip fracture risk (n = 765) over 17-year follow-up among older adults in the Framingham Osteoporosis Study. BMD measures were regressed on quintile of plasma PC PUFAs (docosahexaenoic acid [DHA], linoleic acid [LA], and arachidonic acid [AA]), adjusted for covariates. Hazard ratios (HR) and 95% confidence interval (CI) for hip fracture were estimated by quintile of plasma PC PUFAs, adjusted for covariates. Higher concentrations of PC DHA were associated with loss of FN-BMD over 4 years in women (p-trend = 0.04), but was protective in men in the uppermost quintile compared to men grouped in the lower four quintiles, in post hoc analysis (p = 0.01). PC LA concentrations were inversely associated with baseline FN-BMD in women (p-trend = 0.02), and increased hip fracture risk in women and men (p-trend = 0.05), but body mass index (BMI) adjustment attenuated these associations (p-trend = 0.12 and p-trend = 0.14, respectively). A trend toward a protective association was observed between PC AA and baseline FN-BMD in men (p-trend = 0.06). Women and men with the highest PC AA concentrations had 51% lower hip fracture risk than those with the lowest (HR = 0.49, 95% CI = 0.24–1.00). Opposing effects of PC DHA on FN-BMD loss observed in women and men need further clarification. Bone loss associated with PC LA may be confounded by BMI. High PC AA concentrations may be associated with reduced hip fracture risk.
PMCID: PMC3565380  PMID: 22392875
4.  Acculturation and Sociocultural Influences on Dietary Intake and Health Status among Puerto Rican Adults in Massachusetts 
Previous studies have shown negative consequences of acculturation on lifestyle factors, health status, and dietary intake of Hispanic immigrants in the US. Despite prevalent type 2 diabetes and low socioeconomic status (SES) among Puerto Rican adults living on the US mainland, little is known about acculturation in this group.
We investigated associations among acculturation, lifestyle characteristics, health status, and carbohydrate nutrition in Puerto Rican adults. A secondary objective was to investigate possible confounding and/or effect modification on these associations by SES.
Cross-sectional data from the Boston Puerto Rican Health Study, which included 1219 Puerto Ricans in the Boston area, aged 45–75 years.
Statistical analyses
Characteristics were compared using ANCOVA, linear trend and Pearson’s chi-square tests across quartiles of acculturation. Tests for interaction by poverty status were conducted. Proportional contributions of foods to intake of total carbohydrate and fiber were assessed using SAS RANK.
Levels of acculturation were low, despite young age at first arrival to the US mainland (25.4 ± 12.3 y) and long length of stay (34.2 ± 12.2 y). Greater English language use was associated with higher SES, alcohol consumption, physical activity, better perceived health, and less central obesity. Acculturation was associated with lower legume fiber and greater cereal fiber intake. Among those above the poverty threshold, acculturation was associated with lower dietary glycemic index and starch intake, and greater fruit and non-starchy vegetable intake.
In contrast to studies with Mexican Americans, the association of acculturation with dietary quality in these Puerto Rican adults was mixed, but tended toward better carbohydrate quality. Dietary recommendations should include maintenance of traditional, healthful dietary practices including consumption of legumes, but also reduction in refined grains, and greater inclusion of fruit, non-starchy vegetables, and whole grains. Interventions to improve access to better quality carbohydrate sources are necessary for this group disproportionately affected by diabetes.
PMCID: PMC3289968  PMID: 22389874
acculturation; glycemic index; dietary fiber; Puerto Rican
5.  A meat, processed meat, and french fries dietary pattern is associated with high allostatic load in Puerto Rican older adults 
PMCID: PMC3185297  PMID: 21963016
dietary pattern; allostatic load; Puerto Ricans
6.  The folate hydrolase 1561 C>T polymorphism is associated with depressive symptoms in Puerto Rican adults 
Psychosomatic medicine  2011;73(5):385-392.
To examine associations between variants of genes involved in the uptake, retention and metabolism of folate and depressive symptoms, and whether such associations are direct or through mediation by folate or homocysteine.
We performed a cross-sectional analysis of data from 976 Puerto Rican adults, aged 45-75 years, residing in the greater Boston area, Massachusetts. Twelve single nucleotide polymorphisms (SNPs) in genes involved in folate uptake, retention and metabolism were investigated. These include folate hydrolase (FOLH1), folate polyglutamate synthase (FPGS), r-glutamyl hydrolase (GGH), methylene tetrahydrofolate reductase (MTHFR), methionine synthase (MTR), proton-coupled folate transporter (PCFT), and reduced folate carrier (RFC1). The Center for Epidemiologic Studies Depression Scale (CES-D) was used to measure depressive symptoms.
The FOLH1 rs61886492 C>T (or 1561C>T) polymorphism was significantly associated with lower CES-D score (p = .0025), after adjusting for age, sex, population admixture, smoking, and educational attainment. Individuals with the TT and TC genotypes were 49% less likely (odds ratio (OR): 95% confidence interval [CI]: 0.51: 0.29, 0.89) to report mild depressive symptoms (CES-D score ≥16 & ≤26) and 64% less likely (OR: 95% CI: 0.36: 0.18, 0.69) to report moderate to severe depressive symptoms (CES-D score >26), compared to those with the CC genotype. No significant mediation effects by plasma folate or homocysteine on the associations between this SNP and CES-D score were observed.
The FOLH1 1561C>T polymorphism may be associated with risk of depressive symptoms.
PMCID: PMC3110520  PMID: 21597034
Depressive symptoms; genetics; polymorphisms; folate; folate hydrolase; glutamate carboxypeptidase II
7.  Dietary intake of vitamin B6, plasma pyridoxal 5′-phosphate and homocysteine in Puerto Rican adults 
Vitamin B6 is an important cofactor in many metabolic processes. However, vitamin B6 intake and plasma status have not been well studied in the Puerto Rican population, a group with documented health disparities.
To assess dietary intake of vitamin B6, food sources, and plasma status of pyridoxal 5′-phosphate (PLP), and their associations with plasma homocysteine in 1236 Puerto Rican adults, aged 45–75 years, living in the greater Boston area.
Baseline data were analyzed cross-sectionally.
Questionnaire data were collected by home interview. Dietary intake was assessed with a semi-quantitative food frequency questionnaire. Plasma PLP and homocysteine were assayed from blood samples collected in the home.
The mean daily intake of vitamin B6 was 2.90 ± 1.28 mg (mean ± SD) for men and 2.61 ± 1.29 mg for women (P <0.001). Approximately 11% were deficient (PLP <20 nmol/L) and another 17 % insufficient (PLP ≥20 but <30 nmol/L). Household income below the poverty threshold, physical inactivity and current smoking were significantly associated with lower plasma PLP (P <0.05). Food groups contributing most to vitamin B6 intake included ready-to-eat cereals, poultry, rice, potatoes and dried beans. However, only intake of ready-to-eat cereals and use of supplements with vitamin B6 were significantly associated with plasma PLP sufficiency (≥30 vs. <30 nmol/L, P <0.01). Both vitamin B6 intake and PLP were significantly associated with plasma total homocysteine (P < 0.001). The association between PLP and homocysteine remained statistically significant after further adjustment for plasma vitamin B12 and folate (P = 0.028).
Given the known importance of vitamin B6 to health, the high prevalence of low vitamin B6 status in this Puerto Rican population is of concern. Further work is needed to clarify the potential role that insufficient vitamin B6 may have in relation to the observed health disparities in this population.
PMCID: PMC2989853  PMID: 21034879
vitamin B6; pyridoxal 5′-phosphate; homocysteine; Puerto Rican
8.  Variants of the CD36 Gene and Metabolic Syndrome in Boston Puerto Rican Adults 
Atherosclerosis  2010;211(1):210-215.
Puerto Ricans experience a high prevalence of several chronic conditions, including metabolic syndrome. Genetic variants of the CD36 gene have been associated with metabolic syndrome. We aimed to determine the association between 6 single nucleotide polymorphisms (SNPs) for CD36 and metabolic syndrome and its components in Puerto Ricans (45-75 y) living in the Greater Boston area.
Associations between each SNP, metabolic syndrome and its components were examined using multivariate logistic regression models. Haplotype trend regression analysis was used to determine associations between haplotypes and metabolic syndrome.
For two SNPs of CD36 (rs1049673 and rs3211931), homozygous subjects of the minor allele (G and T, respectively) were associated with a higher likelihood of metabolic syndrome (odd ratio (OR) (95% confidence interval (CI): 1.89 (1.0, 3.5) and 1.77 (1.0, 3.1), respectively) relative to carriers of the major allele. Although CD36 haplotypes were not significantly associated with metabolic syndrome overall (global significance, P=0.23), one haplotype (G-C-C vs. C-C-C (reference haplotype) was marginally associated (P=0.049).
SNPs of CD36 were associated with metabolic syndrome in Puerto Ricans. Prospective studies should further explore the role of CD36 variants in the development of this condition.
PMCID: PMC2923842  PMID: 20223461
Puerto Rican; Hispanic; CD36; metabolic syndrome
9.  Protective effect of total and supplemental vitamin C intake on the risk of hip fracture - A 17-year follow-up from the Framingham Osteoporosis Study 
Dietary antioxidants such as vitamin C may play a role in bone health. We evaluated associations of vitamin C intake (total, dietary and supplemental) with incident hip fracture and non-vertebral osteoporotic fracture, over a 15 to 17-y follow-up, in the Framingham Osteoporosis Study.
366 men and 592 women (mean age 75 yr ± 5) completed a food frequency questionnaire (FFQ) in 1988–89 and were followed for non-vertebral fracture until 2003 and hip fracture until 2005. Tertiles of vitamin C intake were created from estimates obtained using the Willett FFQ, after adjusting for total energy (residual method). Hazard Ratios were estimated using Cox-proportional hazards regression, adjusting for covariates.
Over follow-up 100 hip fractures occurred. Subjects in the highest tertile of total vitamin C intake had significantly fewer hip fractures (P trend=0.04) and non-vertebral fractures (P trend=0.05) compared to subjects in the lowest tertile of intake. Subjects in the highest category of supplemental vitamin C intake had significantly fewer hip fractures (P trend=0.02) and non-vertebral fractures (P trend=0.07) compared to non-supplement users. Dietary vitamin C intake was not associated with fracture risk (all P>0.22).
These results suggest a possible protective effect of vitamin C on bone health in older adults.
PMCID: PMC2766028  PMID: 19347239
ageing; bone; fracture; nutrition; population studies; vitamin C
10.  Vitamin D Is Associated With Cognitive Function in Elders Receiving Home Health Services 
The objective of this study was to examine the association between 25-hydroxyvitamin D, 25(OH)D, and cognitive function.
A cross-sectional investigation of 25(OH)D and cognition was completed in 377 black and 703 non-black (mainly Caucasian) elders (65–99 years) participating in the nutrition and memory in elders study. Participants underwent a comprehensive neuropsychological battery, and 25(OH)D concentrations were obtained.
More than 65% of elders had suboptimal 25(OH)D concentrations (≤20 ng/mL or ≤50 nmol/L). Approximately 18% were deficient in 25(OH)D (<10 ng/mL or <25 nmol/L). After adjusting for age, sex, race, body mass index, education, center, kidney function, seasonality, physical activity, and alcohol use, 25(OH)D was associated with better performance on trails A (β = –0.49, p < .03), trails B (β = –0.73, p < .02), digit symbol (β = 0.19, p < .001), matrix reasoning (β = 0.04, p < .02), and block design (β = 0.07, p < .04) tests. Associations remained after adjustment for homocysteine, apoE4 allele, plasma B vitamins, and multivitamin use (y/n). 25(OH)D concentrations >20 ng/mL were associated with better performance on tests of executive function, including trails A (80.5 vs 95, p < .05), trails B (205s vs 226s, p < .05), matrix reasoning (7.8 vs 7.0, p = .03), and digit symbol (31.5 vs 37, p < .01). There were no associations between 25(OH)D and memory tests. Factor analysis yielded factors for memory, executive function, and attention/processing speed. After adjustment, 25(OH)D was associated with the executive function (β = 0.01, p < 0.01) and attention/processing speed factors (β = 0.01, p = .03), but not the memory factor (β = –0.001, p = 0.65).
25(OH)D was positively associated with cognitive performance, particularly with measures of executive function in this elderly population.
PMCID: PMC2981461  PMID: 19377013
Cognitive function; Vitamin D; Elderly people; Dementia
11.  Validity of Estimated Dietary Eicosapentaenoic Acid and Docosahexaenoic Acid Intakes Determined by Interviewer-Administered Food Frequency Questionnaire Among Older Adults With Mild-to-Moderate Cognitive Impairment or Dementia 
American Journal of Epidemiology  2009;170(1):95-103.
Epidemiologic research is increasingly being focused on elderly persons, many of whom exhibit mild-to-moderate cognitive impairment. This presents a challenge for collection and interpretation of self-reported dietary data. There are few reports on the impact of cognitive function and dementia on the validity of self-reported dietary intakes. Using plasma phospholipid fatty acid profiles as a biomarker of intake, the authors assessed the validity of an interviewer-administered food frequency questionnaire (FFQ) to estimate intakes of 2 marine-based omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), among 273 community-dwelling adults aged ≥60 years participating in the Nutrition, Aging, and Memory in Elders Study (Boston, Massachusetts, 2002–2008). Age- and energy-adjusted Pearson correlation coefficients for correlations between dietary intakes and plasma phospholipids were consistent across categories of high and low cognitive function (r  = 0.48), based on Mini-Mental State Examination score, and were similar across clinically diagnosed categories of normal functioning (r  = 0.49), mild cognitive impairment (r  = 0.45), and dementia (r  = 0.52). The FFQ ranked 78% of subjects to within 1 quartile of their plasma phospholipid EPA + DHA quartile. This frequency was consistently high across all cognitive categories. With interviewer administration, this FFQ seems to be a valid method of assessing dietary EPA + DHA intake in older adults with mild-to-moderate cognitive impairment.
PMCID: PMC2733037  PMID: 19433614
aged; aged, 80 and over; dementia; epidemiologic methods; fatty acids, omega-3; mental recall; nutrition assessment; questionnaires
12.  Serum carotenoid and tocopherol concentrations vary by dietary pattern among African Americans 
Intakes and biochemical concentrations of carotenoids and tocopherols have been associated with chronic diseases.
To describe dietary patterns in Jackson Heart Study (JHS) participants and to determine if biochemical measurements of antioxidants differ across these.
Cross sectional analysis of data for 373 African American men and women (35–80 y), participating in the Diet and Physical Activity Sub-Study of the JHS.
Dietary intake was assessed with a region specific food frequency questionnaire. Patterns were defined by cluster analysis of food groups, as percent of energy intake.
Four dietary patterns were identified: 1) Fast food 2) Southern 3) Prudent and 4) Juice. Individuals in the Fast food pattern (n=153) had significantly lower serum concentrations of lutein plus zeaxanthin and beta cryptoxanthin; those in the Southern cluster (n=99) had significantly lower serum alpha carotene; and those in the Prudent (n=63) and Juice (n=58) clusters had significantly higher serum alpha carotene and beta cryptoxanthin (P < 0.05) relative to those in at least one other cluster (all P < 0.05). The Juice cluster also had higher serum alpha tocopherol concentrations relative to the Fast food cluster.
Diets high in fast food, snacks, soft drinks and meat were associated with relatively low concentrations of carotenoids and alpha tocopherol. This pattern contained the largest number of participants, and could contribute to the extensive health disparities seen in this region.
PMCID: PMC2659595  PMID: 19027404
food frequency questionnaire; Jackson Heart Study; dietary patterns; antioxidant biomarkers; African Americans
13.  Vitamin B6 Is Associated with Depressive Symptomatology in Massachusetts Elders 
We examined the cross-sectional relationship between dietary vitamin B6 and plasma pyridoxyl-5′-phosphate concentrations (PLP) with depressive symptomatology among a representative sample of 618 elderly Caribbean Hispanics, and a neighborhood based comparison group of 251 non-Hispanic white (NHW) older adults in Massachusetts.
Depressive symptomatology was assessed with the Center for Epidemiologic Studies Depression Scale (CES-D). 41% of Hispanics and 22.6% of NHWs had CES-D scores greater than 16, indicating depressive caseness. Dietary intake was calculated from a semi-quantitative food frequency questionnaire (FFQ) designed for this population.
PLP was significantly associated with CES-D score and depressive caseness in the total sample and in non-supplement users. Deficient levels of plasma PLP (plasma PLP < 20 nmol/L) approximately doubled the likelihood of depressive caseness. Total intake (diet + supplement) of vitamin B6 was not associated with these outcomes. However, dietary vitamin B6 was significantly associated with CES-D score and depressive caseness.
Longitudinal studies are needed to clarify the direction of causality between vitamin B6 and depressive symptoms.
PMCID: PMC2572855  PMID: 18838531
14.  Assessing the Health Impact of Phosphorus in the Food Supply: Issues and Considerations123 
Advances in Nutrition  2014;5(1):104-113.
The Western dietary pattern of intake common to many Americans is high in fat, refined carbohydrates, sodium, and phosphorus, all of which are associated with processed food consumption and higher risk of life-threatening chronic diseases. In this review, we focus on the available information on current phosphorus intake with this Western dietary pattern, and new knowledge of how the disruption of phosphorus homeostasis can occur when intake of phosphorus far exceeds nutrient needs and calcium intake is limited. Elevation of extracellular phosphorus, even when phosphorus intake is seemingly modest, but excessive relative to need and calcium intake, may disrupt the endocrine regulation of phosphorus balance in healthy individuals, as it is known to do in renal disease. This elevation in serum phosphate, whether episodic or chronically sustained, may trigger the secretion of regulatory hormones, whose actions can damage tissue, leading to the development of cardiovascular disease, renal impairment, and bone loss. Therefore, we assessed the health impact of excess phosphorus intake in the context of specific issues that reflect changes over time in the U.S. food supply and patterns of intake. Important issues include food processing and food preferences, the need to evaluate phosphorus intake in relation to calcium intake and phosphorus bioavailability, the accuracy of various approaches used to assess phosphorus intake, and the difficulties encountered in evaluating the relations of phosphorus intake to chronic disease markers or incident disease.
PMCID: PMC3884091  PMID: 24425729
15.  Determinants of self-rated health and the role of acculturation: Implications for health inequalities 
Ethnicity & health  2013;18(6):10.1080/13557858.2013.771147.
Self-rated health (SRH) is an important indicator of overall health, predicting morbidity and mortality. This paper investigates what individuals incorporate into their self-assessments of health and how acculturation plays a part in this assessment. The relationship of acculturation to SRH and whether it moderates the association between indicators of health and SRH is also examined.
The paper is based on data from adults in the Boston Puerto Rican Health Study, living in the greater Boston area (n=1357) mean age 57.2 (SD=7.6). We used multiple regression analysis and testing for moderation effects.
The strongest predictors of poor self-rated health were the number of existing medical conditions, functional problems, allostatic load and depressive symptoms. Poor self-rated health was also associated with being female, fewer years of education, heavy alcohol use, smoking, poverty, and low emotional support. More acculturated Puerto Rican adults rated their health more positively, which corresponded to better indicators of physical and psychological health. Additionally, acculturation moderated the association between some indicators of morbidity (functional status and depressive symptoms) and self-rated health.
Self-assessments of overall health integrate diverse indicators, including psychological symptoms, functional status and objective health indicators such as chronic conditions and allostatic load. However, adults’ assessments of overall health differed by acculturation, which moderated the association between health indicators and SRH. The data suggest that when in poor health, those less acculturated may understate the severity of their health problems when rating their overall health, thus SRH might thus conceal disparities. Using SRH can have implications for assessing health disparities in this population.
PMCID: PMC3758374  PMID: 23425383
16.  Lead Exposure, B Vitamins, and Plasma Homocysteine in Men 55 Years of Age and Older: The VA Normative Aging Study 
Environmental Health Perspectives  2014;122(10):1066-1074.
Background: Lead (Pb) exposure may influence the plasma concentration of homocysteine, a one-carbon metabolite associated with cardiovascular and neurodegenerative diseases. Little is known about the associations between Pb and homocysteine over time, or the potential influence of dietary factors.
Objectives: We examined the longitudinal association of recent and cumulative Pb exposure with homocysteine concentrations and the potential modifying effect of dietary nutrients involved in one-carbon metabolism.
Methods: In a subcohort of the Veterans Affairs (VA) Normative Aging Study (1,056 men with 2,301 total observations between 1993 and 2011), we used mixed-effects models to estimate differences in repeated measures of total plasma homocysteine across concentrations of Pb in blood and tibia bone, assessing recent and cumulative Pb exposure, respectively. We also assessed effect modification by dietary intake and plasma concentrations of folate, vitamin B6, and vitamin B12.
Results: An interquartile range (IQR) increment in blood Pb (3 μg/dL) was associated with a 6.3% higher homocysteine concentration (95% CI: 4.8, 7.8%). An IQR increment in tibia bone Pb (14 μg/g) was associated with a 3.7% higher homocysteine (95% CI: 1.6, 5.6%), which was attenuated to 1.5% (95% CI: –0.5, 3.6%) after adjusting for blood Pb. For comparison, a 5-year increase in time from baseline was associated with a 5.7% increase in homocysteine (95% CI: 4.3, 7.1%). The association between blood Pb and homocysteine was significantly stronger among participants with estimated dietary intakes of vitamin B6 and folate below (vs. above) the study population medians, which were similar to the U.S. recommended dietary allowance intakes.
Conclusions: Pb exposure was positively associated with plasma homocysteine concentration. This association was stronger among men with below-median dietary intakes of vitamins B6 and folate. These findings suggest that increasing intake of folate and B6 might reduce Pb-associated increases in homocysteine, a risk factor for cardiovascular disease and neurodegeneration.
Citation: Bakulski KM, Park SK, Weisskopf MG, Tucker KL, Sparrow D, Spiro A III, Vokonas PS, Nie LH, Hu H, Weuve J. 2014. Lead exposure, B vitamins, and plasma homocysteine in men 55 years of age and older: the VA Normative Aging Study. Environ Health Perspect 122:1066–1074;
PMCID: PMC4181916  PMID: 24905780
17.  Genome-wide interaction of genotype by erythrocyte n-3 fatty acids contributes to phenotypic variance of diabetes-related traits 
BMC Genomics  2014;15(1):781.
Little is known about the interplay between n-3 fatty acids and genetic variants for diabetes-related traits at the genome-wide level. The present study aimed to examine variance contributions of genotype by environment (GxE) interactions for different erythrocyte n-3 fatty acids and genetic variants for diabetes-related traits at the genome-wide level in a non-Hispanic white population living in the U.S.A. (n = 820). A tool for Genome-wide Complex Trait Analysis (GCTA) was used to estimate the genome-wide GxE variance contribution of four diabetes-related traits: HOMA-Insulin Resistance (HOMA-IR), fasting plasma insulin, glucose and adiponectin. A GxE genome-wide association study (GWAS) was conducted to further elucidate the GCTA results. Replication was conducted in the participants of the Boston Puerto Rican Health Study (BPRHS) without diabetes (n = 716).
In GOLDN, docosapentaenoic acid (DPA) contributed the most significant GxE variance to the total phenotypic variance of both HOMA-IR (26.5%, P-nominal = 0.034) and fasting insulin (24.3%, P-nominal = 0.042). The ratio of arachidonic acid to eicosapentaenoic acid + docosahexaenoic acid contributed the most significant GxE variance to the total variance of fasting glucose (27.0%, P-nominal = 0.023). GxE variance of the arachidonic acid/eicosapentaenoic acid ratio showed a marginally significant contribution to the adiponectin variance (16.0%, P-nominal = 0.058). None of the GCTA results were significant after Bonferroni correction (P < 0.001). For each trait, the GxE GWAS identified a far larger number of significant single-nucleotide polymorphisms (P-interaction ≤ 10E-5) for the significant E factor (significant GxE variance contributor) than a control E factor (non-significant GxE variance contributor). In the BPRHS, DPA contributed a marginally significant GxE variance to the phenotypic variance of HOMA-IR (12.9%, P-nominal = 0.068) and fasting insulin (18.0%, P-nominal = 0.033).
Erythrocyte n-3 fatty acids contributed a significant GxE variance to diabetes-related traits at the genome-wide level.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-781) contains supplementary material, which is available to authorized users.
PMCID: PMC4168207  PMID: 25213455
18.  Modulation by Dietary Fat and Carbohydrate of IRS1 Association With Type 2 Diabetes Traits in Two Populations of Different Ancestries 
Diabetes Care  2013;36(9):2621-2627.
Insulin receptor substrate 1 (IRS1) is central to insulin signaling pathways. This study aimed to examine the association of IRS1 variants with insulin resistance (IR) and related phenotypes, as well as potential modification by diet.
Two IRS1 variants (rs7578326 and rs2943641) identified by genome-wide association studies as related to type 2 diabetes were tested for their associations with IR and related traits and interaction with diet in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study (n = 820) and the Boston Puerto Rican Health Study (BPRHS) (n = 844).
Meta-analysis indicated that rs7578326 G-allele carriers and rs2943641 T-allele carriers had a lower risk of IR, type 2 diabetes, and metabolic syndrome (MetS). Significant interactions on IR and MetS were found for these two variants and their haplotypes with diet. In GOLDN, rs7578326 G-allele carriers and rs2943641 T-allele carriers and their haplotype G-T carriers had a significantly lower risk of IR and MetS than noncarriers only when the dietary saturated fatty acid-to-carbohydrate ratio was low (≤0.24). In both GOLDN (P = 0.0008) and BPRHS (P = 0.011), rs7578326 G-allele carriers had a lower risk of MetS than noncarriers only when dietary monounsaturated fatty acids were lower than the median intake of each population.
IRS1 variants are associated with IR and related traits and are modulated by diet in two populations of different ancestries. These findings suggest that IRS1 variants have important functions in various metabolic disorders and that dietary factors could modify these associations.
PMCID: PMC3747864  PMID: 23596181
19.  Strategies to Optimize the Impact of Nutritional Surveys and Epidemiological Studies12 
Advances in Nutrition  2013;4(5):545-547.
The development of nutrition and health guidelines and policies requires reliable scientific information. Unfortunately, theoretical considerations and empirical evidence indicate that a large percentage of science-based claims rely on studies that fail to replicate. The session “Strategies to Optimize the Impact of Nutrition Surveys and Epidemiological Studies” focused on the elements of design, interpretation, and communication of nutritional surveys and epidemiological studies to enhance and encourage the production of reliable, objective evidence for use in developing dietary guidance for the public. The speakers called for more transparency of research, raw data, consistent data-staging techniques, and improved data analysis. New approaches to collecting data are urgently needed to increase the credibility and utility of findings from nutrition epidemiological studies. Such studies are critical for furthering our knowledge and understanding of the effects of diet on health.
PMCID: PMC3771144  PMID: 24038252
20.  The effects of ABCG5/G8 polymorphisms on HDL cholesterol concentrations depend on ABCA1 genetic variants in the Boston Puerto Rican Health Study 
Background and aims
ATP-binding cassette transporters G5/G8 (ABCG5/G8) are associated with HDL-C concentrations. To assess whether the effect of ABCG5/G8 genetic variants on HDL-C concentrations is dependent on ATP-binding cassette transporters A1 (ABCA1), we studied potential interactions between single nucleotide polymorphisms (SNPs) at ABCG5/G8 (i7892T>C, 5U145A>C, T54CA>G, T400KC>A) and ABCA1 (i27943G>A, i48168G>A, K219RG>A, i125970G>C, 3U8995A>G) genes with HDL-C concentrations.
Methods and Results
ABCG5/G8 and ABCA1 SNPs were genotyped in 788 subjects (228 men and 560 women) who participated in the Boston Puerto Rican Health Study. Biochemical measurements were determined by standard procedures. Genotyping was performed using TaqMan® assays according to routine laboratory protocols. Significant gene-gene interactions for HDL-C were found between ABCG8 (5U145A>C, T54CA>G, T400KC>A) SNPs and ABCA1_ i48168G>A genetic variant (P=0.009, P=0.042 and P=0.036, respectively), in which carriers of the 5U145C and 54C alleles, and homozygotes for the T400 allele at ABCG8 genetic variants displayed lower HDL-C concentrations than homozygotes for the 5U145A and T54 alleles, and heterozygotes for the 400K allele at ABCG8 SNPs, only if they were also homozygous for the minor allele (A) at the aforementioned ABCA1 SNP.
The gene-gene interactions reported in the present study support the hypothesis that the effect of ABCG5/G8 genetic variants on HDL-C concentrations is dependent on ABCA1 expression. Replication of these analyses to further populations, particularly with low HDL-C, is clearly warranted.
PMCID: PMC4038034  PMID: 19692220
ATP binding cassette transporters; HDL-cholesterol; gene-gene interaction; pathway; reverse cholesterol transport
Background and aims
Using a genetic predisposition score (GPS), integrating the additive associations of a set of single nucleotide polymorphisms (SNPs) with CHD, we examined the consequences of the joint presence of a high GPS and conventional risk factors (CRFs).
Methods and Results
We studied eleven SNPs at eight loci in 197 participants with prior CHD and 524 CHD-free subjects from the Boston Puerto Rican Health Study. Each polymorphism contributed 1 unit (high-risk allele homozygous), 0.5 units (heterozygous) and 0 units (low-risk allele homozygous) to the GPS. Odds ratio (OR) of CHD for those at high-risk because of GPS (>5) and simultaneous presence of CRFs were estimated, compared with subjects at low-risk, for both measurements. The mean score was higher in participants with prior CHD than those CHD-free (P=0.015), and the OR for CHD with a GPS>5 was 2.90 (P<0.001).The joint presence of a high GPS and each CRF was associated with higher risk of CHD. Compared to participants with high GPS, those with low GPS (≤5) were protected against CHD even if they were smokers (OR=0.44), heavy drinkers (OR=0.43), displayed low physical activity (OR=0.35), had hypertension (OR=0.52) or hyperlipidemia (OR=0.34) (P values ranging from 0.004 to 0.023).
A simple genetic score of eleven polymorphisms may identify those subjects at increased risk of CHD beyond conventional risk factors.
PMCID: PMC4031647  PMID: 19501493
genes; coronary heart disease; conventional risk factors; genetic predisposition score; single nucleotide polymorphism
22.  Circulating 25-Hydroxyvitamin D, IRS1 Variant rs2943641, and Insulin Resistance: Replication of a Gene–Nutrient Interaction in 4 Populations of Different Ancestries 
Clinical chemistry  2013;60(1):186-196.
Associations of either insulin receptor substrate 1 (IRS1) variants or circulating 25-hydroxyvitamin D [25(OH)D] with type 2 diabetes (T2D) and insulin resistance (IR) are inconsistent. This study sought to determine whether circulating 25(OH)D modulates the association of a potentially functional variant at IRS1 (rs2943641) with insulin resistance.
Interaction between IRS1 rs2943641 and circulating 25(OH)D on homeostasis model assessment for IR (HOMA-IR) was examined in the Boston Puerto Rican Health Study (BPRHS) (n = 1144). Replication was performed in the African-American (n = 1126), non-Hispanic white (n = 1967), and Hispanic (n = 1241) populations of the Multi-Ethnic Study of Atherosclerosis (MESA) with genotypes of 3 IRS1 variants, rs2972144, rs1515104, and rs2673142, which are tag single nucleotide polymorphisms (SNPs) and in strong linkage disequilibrium with rs2943641.
Higher circulating 25(OH)D was associated with lower risk of T2D and IR in BPRHS women homozygous for minor allele rs2943641T. Consistently, in each of 3 MESA populations, HOMA-IR and insulin decreased more evidently with higher circulating 25(OH)D in women of the rs2943641TT genotype than in carriers of the major allele (rs2943641C). Metaanalysis indicated significant and consistent interactions between circulating 25(OH)D and IRS1 variants on HOMA-IR (log transformed) [pooled β = −0.008, 95% CI: −0.016 to −0.001, P interaction = 0.004] and insulin (log transformed) (pooled β = −0.006, 95% CI: −0.011 to −0.002, P interaction = 0.023) in 3065 women of the 4 populations.
Participants with different genotypes of IRS1 rs2943641 exhibit differential benefit from high circulating 25(OH)D for the reduction of insulin resistance and T2D risk. This gene–nutrient interaction, which appears to be limited to women, warrants further examination in randomized controlled trials of vitamin D supplementation.
PMCID: PMC4026060  PMID: 24255076
23.  Estudio Parto: postpartum diabetes prevention program for hispanic women with abnormal glucose tolerance in pregnancy: a randomised controlled trial – study protocol 
Diabetes and obesity have reached epidemic proportions in the U.S. with rates consistently higher among Hispanics as compared to non-Hispanic whites. Among Hispanic women diagnosed with gestational diabetes mellitus (GDM), 50% will go on to develop type 2 diabetes within 5 years of the index pregnancy. Although randomised controlled trials among adults with impaired glucose tolerance have shown that diet and physical activity reduce the risk of type 2 diabetes, such programs have not been tested in high-risk postpartum women. The overall goal of this randomised controlled trial is to test the efficacy of a culturally and linguistically modified, individually-tailored lifestyle intervention to reduce risk factors for type 2 diabetes and cardiovascular disease among postpartum Hispanic women with a history of abnormal glucose tolerance during pregnancy.
Hispanic pregnant women who screen positive for GDM will be recruited and randomly assigned to a Lifestyle Intervention (n = 150) or a Health & Wellness (control) Intervention (n = 150). Multimodal contacts (i.e., in-person, telephone, and mailed materials) will be used to deliver the intervention from late pregnancy (29 weeks gestation) to 12 months postpartum. Targets of the intervention are to achieve Institute of Medicine Guidelines for postpartum weight loss; American Congress of Obstetrician and Gynecologist guidelines for physical activity; and American Diabetes Association guidelines for diet. The intervention draws from Social Cognitive Theory and the Transtheoretical Model and addresses the specific cultural and environmental challenges faced by low-income Hispanic women. Assessments will be conducted at enrollment, and at 6-weeks, 6-months, and 12-months postpartum by trained bicultural and bilingual personnel blinded to the intervention arm. Efficacy will be assessed via postpartum weight loss and biomarkers of insulin resistance and cardiovascular risk. Changes in physical activity and diet will be measured via 7-day actigraph data and three unannounced 24-hour dietary recalls at each assessment time period.
Hispanic women are the fastest growing minority group in the U.S. and have the highest rates of sedentary behavior and postpartum diabetes after a diagnosis of GDM. This randomised trial uses a high-reach, low-cost strategy that can readily be translated into clinical practice in underserved and minority populations.
Trial registration
PMCID: PMC3975296  PMID: 24606590
Lifestyle intervention; Randomised controlled trial; Healthy eating; Prevention; Diet; Latina; Physical activity; Postpartum; Pregnancy; Gestational diabetes mellitus; Transtheoretical model
24.  Air Pollution and Homocysteine: More Evidence that Oxidative Stress-related Genes Modify Effects of Particulate Air Pollution 
Epidemiology (Cambridge, Mass.)  2010;21(2):198-206.
Ambient particles are associated with cardiovascular events, and recently with total plasma homocysteine. High total plasma homocysteine is a risk for human health. However, the biological mechanisms are not fully understood. One of putative pathways is through oxidative stress. We aimed to examine whether associations of PM2.5 and black carbon with homocysteine were modified by genotypes including HFE H63D, C282Y, CAT (rs480575, rs1001179, rs2284367 and rs2300181), NQO1 (rs1800566), GSTP1 I105V, GSTM1, GSTT1(deletion vs non-deletion) and HMOX-1 (any short vs both long). We attempted to replicate identified genes in an analysis of heart rate variability, and in other outcomes reported in the literature.
Study subjects were 1000 white non-Hispanic men in the Boston area, participating in a cohort study of aging. PM2.5, black carbon, total plasma homocysteine and other covariates were measured at several points in time between 1995 and 2006. We fit mixed models to examine effect modification of genes on associations of pollution with total plasma homocysteine.
Interquartile range (IQR) increases in PM2.5 and black carbon (7-day moving averages) were associated with 1.5% (95% confidence interval = 0.2% to 2.8%) and 2.2% (0.6% to 3.9%) increases in total plasma homocysteine, respectively. GSTT1 and HFE C282Y modified effects of black carbon on total plasma homocysteine, and HFE C282Y and CAT (rs2300181) modified effects of PM2.5 on homocysteine. Several genotypes marginally modified effects of PM2.5 and black carbon on various endpoints. All genes with significant interactions with particulate air pollution had modest main effects on total plasma homocysteine.
Effects of PM2.5 and black carbon on various endpoints appeared to be mediated by genes related to oxidative stress pathways.
PMCID: PMC3939788  PMID: 20110814
25.  Mediterranean Diet, Healthy Eating Index-2005, and Cognitive Function in Middle-Aged and Older Puerto Rican Adults 
Adherence to a Mediterranean diet (MeD) has recently been shown to protect against cognitive decline and dementia. It remains unclear, however, whether such protection extends to differing ethnic groups and middle-aged individuals, and how it may compare with adherence to the USDA Dietary Guidelines for Americans 2005 (measured with Healthy Eating Index-2005, HEI-2005). This study examined associations between diet quality, as assessed by the MeD and HEI-2005, and cognitive performance in a sample of 1,269 Puerto Rican adults, aged 45–75 years, living in the Greater Boston area, Massachusetts. Dietary intake was assessed with a food-frequency questionnaire specifically designed for and validated with this population. Adherence to the MeD was assessed with a 0 to 9 point scale, and the HEI-2005 score was calculated with a maximum score of 100. Cognitive performance was measured with a battery of seven tests; the Mini Mental State Examination (MMSE) was used for global cognitive function. Greater adherence to the MeD was associated with higher MMSE score (P trend = 0.012) and lower likelihood (OR = 0.87 for each additional point, 95% CI, 0.80–0.94, P <0.001) of cognitive impairment, after adjustment for confounders. Similarly, individuals with higher HEI-2005 score had higher MMSE score (P trend = 0.011) and lower odds of cognitive impairment (OR = 0.86 for each 10 points, 95% CI, 0.74–0.99, P = 0.033). In conclusion, high adherence to either the MeD or the diet recommended by the USDA dietary guidelines may protect cognitive function in middle-aged and older adults.
PMCID: PMC3662236  PMID: 23351632
Mediterranean diet; Healthy Eating Index-2005; diet quality; Cognitive impairment

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