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1.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  Dietary Patterns, Abdominal Visceral Adipose Tissue and Cardiometabolic Risk Factors in African Americans: the Jackson Heart Study 
Obesity (Silver Spring, Md.)  2013;21(3):10.1002/oby.20265.
Dietary behavior is an important lifestyle factor to impact an individual’s risk of developing cardiovascular disease (CVD). However, the influence of specific dietary factors on CVD risk for African Americans remains unclear. We conducted a cross-sectional study of 1775 participants from Jackson Heart Study (JHS) Exam 2 (between 2006 and 2009) who were free of hypertension, diabetes and CVD at the baseline (between 2001 and 2004). Dietary intakes were documented using a validated food-frequency questionnaire (FFQ) and dietary patterns were generated by factor analysis. Three major dietary patterns were identified: a “southern”, a “fast food” and a “prudent” pattern. After adjustment for age, sex, smoking and alcohol status, education level and physical activity, high “southern” pattern score was associated with an increased odds ratio (OR) for high abdominal visceral adipose tissue (VAT) (OR:1.80, 95%CI:1.1–3.0, p=0.02), hypertension (OR:1.42, 95%CI:1.1–1.9, p=0.02), diabetes (OR:2.03, 95%CI:1.1–3.9, p=0.03) and metabolic syndrome (OR:2.16, 95%CI:1.3–3.6, p=0.004). Similar associations were also observed in the “fast food” pattern (p ranges 0.03–0.0001). The “prudent” pattern was significantly associated, in a protective direction, with hypertension (OR 0.69, 95%CI 0.5–0.9, p=0.02). In conclusion, dietary patterns, especially the “southern” pattern, identified from a regional specific FFQ in this Deep South African Americans, are correlated with abdominal VAT and cardiometabolic risk factors.
PMCID: PMC3478414  PMID: 23592674
Jackson Heart Study; dietary patterns; cardiometabolic risk factors
9.  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
10.  Low density lipoprotein receptor related protein 1 variant interacts with saturated fatty acids in Puerto Ricans 
Obesity (Silver Spring, Md.)  2013;21(3):602-608.
Low density lipoprotein related receptor protein 1 (LRP1) is a multi-functional endocytic receptor that is highly expressed in adipocytes and the hypothalamus. Animal models and in vitro studies support a role for LRP1 in adipocyte metabolism and leptin signaling, but genetic polymorphisms have not been evaluated for obesity in people. We examined whether dietary fats (eg., saturated, polyunsaturated) modulated the association of LRP1 variants with anthropometric traits. We studied a population-based sample of Puerto Ricans (n=920, aged 45–74 y) living in the Boston area. In multivariable linear regression models, we dichotomized saturated fat intake and found significant interaction terms between total saturated fatty acids and LRP1 rs1799986 genotype for BMI (P=0.006) and hip (P=0.002). High intake of saturated fat was associated with higher BMI (P=0.001), waist (P=0.008) and hip (P=0.003) in minor allele carriers (CT+TT) compared to CC participants. Further analysis of dichotomized individual saturated fatty acids revealed that interactions were strongest for two individual longer chain fatty acids. High intake of palmitic acid (C16:0; P=0.0007) and high stearic acid intake (C18:0; P=0.005) were associated with higher BMI in T carriers. Interactions were not detected for polyunsaturated fatty acids. Gene-diet interactions at the LRP1 locus support the hypothesis that susceptibility to weight gain based on saturated fatty acids is modified by genotype and possibly by chain length. These results may facilitate the development of a panel of genetic candidates for use in optimizing dietary recommendations for obesity management.
PMCID: PMC3630241  PMID: 23404896
single nucleotide polymorphisms; saturated fatty acids; fatty acid chain length; Puerto Ricans
11.  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
12.  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
13.  Association between BDNF rs6265 and Obesity in the Boston Puerto Rican Health Study 
Journal of Obesity  2012;2012:102942.
Brain-derived neurotrophic factor (BDNF) has been associated with regulation of body weight and appetite. The goal of this study was to examine the interactions of a functional variant (rs6265) in the BDNF gene with dietary intake for obesity traits in the Boston Puerto Rican Health Study. BDNF rs6265 was genotyped in 1147 Puerto Rican adults and examined for association with obesity-related traits. Men (n = 242) with the GG genotype had higher BMI (P = 0.009), waist circumference (P = 0.002), hip (P = 0.002), and weight (P = 0.03) than GA or AA carriers (n = 94). They had twice the risk of being overweight (BMI ≥ 25) relative to GA or AA carriers (OR = 2.08, CI = 1.02–4.23, and P = 0.043). Interactions between rs6265 and polyunsaturated fatty acids (PUFA) intake were associated with BMI, hip, and weight, and n-3 : n-6 PUFA ratio with waist circumference in men. In contrast, women (n = 595) with the GG genotype had significantly lower BMI (P = 0.009), hip (P = 0.029), and weight (P = 0.027) than GA or AA carriers (n = 216). Women with the GG genotype were 50% less likely to be overweight compared to GA or AA carriers (OR = 0.05, CI = 0.27–0.91, and P = 0.024). In summary, BDNF rs6265 is differentially associated with obesity risk by sex and interacts with PUFA intake influencing obesity traits in Boston Puerto Rican men.
PMCID: PMC3543800  PMID: 23326649
14.  Flavonoid intakes in the Baltimore Longitudinal Study of Aging 
Major sources of flavonoids were identified, and mean intakes over several decades were reported, among 1638 participants (mean age 62.1 +/− 16.0 y), of the Baltimore Longitudinal Study of Aging (BLSA). Dietary data were collected using 7-day diet records during three time periods (1980s, 1990s and 2000-present), and the USDA flavonoid, proanthocyanidin and isoflavone databases were used to estimate dietary flavonoid intakes. Dietary intake data were divided according to decade of visit. Foods were matched with appropriate foods in the USDA databases. Mixed dishes were disaggregated to individual foods and a similar procedure was followed. Total flavonoids and five sub-classes of flavonoids, including flavonols, flavones, flavanones, flavan-3-ols and anthocyanidins, were computed by summing appropriate compounds. The median intakes of flavonoids and the contributions of various foods to intakes were calculated by decade. Age and sex adjusted mean (SE) daily intakes of flavonoids increased from 250 (7.4) in the 1980s to 280 (9.9) mg in the 2000s. Top contributors of flavonoids were tea, apple/pear (and juices), citrus fruits (and juices), peaches, plums, grapes, nectarines (and juices) and chocolate. The data show an increase in the consumption of flavonoids over the three decades, which appears to be related to intake of fruit.
PMCID: PMC3251215  PMID: 22228923
Flavonoids; Antioxidants; Aging; Diet records; Database; Food data management; Food composition
15.  Gap Junctions and Connexin Hemichannels Underpin Haemostasis and Thrombosis 
Circulation  2012;125(20):2479-2491.
Connexins are a widespread family of membrane proteins that assemble into hexameric hemichannels, also known as connexons. Connexons regulate membrane permeability in individual cells or couple between adjacent cells to form gap junctions and thereby provide a pathway for regulated intercellular communication. We have now examined the role of connexins in platelets, blood cells that circulate in isolation, but upon tissue injury adhere to each other and the vessel wall to prevent blood loss and facilitate wound repair.
Methods and Results
We report the presence of connexins in platelets, notably connexin37, and that the formation of gap junctions within platelet thrombi is required for the control of clot retraction. Inhibition of connexin function modulated a range of platelet functional responses prior to platelet-platelet contact, and reduced laser induced thrombosis in vivo in mice. Deletion of the Cx37 gene (Gja4) in transgenic mice reduced platelet aggregation, fibrinogen binding, granule secretion and clot retraction indicating an important role for Cx37 hemichannels and gap junctions in platelet thrombus function.
Together, these data demonstrate that platelet gap junctions and hemichannels underpin the control of haemostasis and thrombosis and represent potential therapeutic targets.
PMCID: PMC3378664  PMID: 22528526
Connexin37; Gap junction; Haemostasis; Platelets; Thrombosis
16.  Health benefits of cereal fibre: a review of clinical trials 
Nutrition research reviews  2011;24(1):118-131.
Cereal fibre and whole-grain intakes have been consistently associated in the epidemiological literature with reduced mortality and risk of chronic disease including obesity, CVD and type 2 diabetes. The present review focuses on intervention trials with three primary aims: (1) understanding the mechanisms through which fibre consumption improves health (for example, examination of intermediate endpoints reflecting improved lipid, glucose and energy metabolism); (2) close evaluation of qualitative factors which modify fibre’s effectiveness including physiochemical properties (for example, solubility, fermentability and viscosity), fibre extract molecular weight, fibre particle size and botanical structure of the fibre source grain; and (3) identification of areas in which additional research is needed. The first two aims typify the goals of nutrition research, in that improved understanding of the specific factors which determine fibre’s health benefits has critical implications for dietary recommendations as well as improving understanding of physiological mechanisms. The third aim acknowledges the substantial gap between recommended and actual fibre intakes in many developed countries including the USA and the UK. In recognition of this deficit in total fibre intake, food manufacturing processes increasingly utilise fibre extracts and concentrates as food additives. However, whether fibre extracts provide similar health benefits to the fibre supplied in the constituents of whole grain is largely unexplored. The relative benefits of fibre extracts compared with whole-grain fibre sources therefore represent a critical area in which additional research is needed.
PMCID: PMC3145818  PMID: 21320383
Dietary fibre; Whole grains; Clinical trials; Cereal fibre
17.  Traffic Exposure in a Population with High Prevalence Type 2 Diabetes - Do Medications Influence Concentrations of C-Reactive Protein? 
Type 2 Diabetes (T2D) and particulate air pollution are associated with inflammatory dysregulation. We assessed the modifying effects of diabetes medications on the association of C-reactive protein (CRP), a marker of inflammation, and traffic exposure in adults with T2D (n=379). CRP concentrations were significantly positively associated with residence ≤100 m of a roadway, >100m and ≤200m of a roadway and increased traffic density for individuals using insulin. For individuals using oral hypoglycemic medications (OHAs), CRP was significantly negatively associated with residence >100 m - ≤200 m of a roadway and multiple roadway exposure in an interaction model. Among people with diabetes, individuals on insulin appear to be most vulnerable to the effects of traffic exposure. Disease severity among insulin users may promote the pro-inflammatory response to traffic exposure, though diabetes medications may also modify the response. Possible anti-inflammatory effects of OHAs with traffic exposure merit further evaluation.
PMCID: PMC3412137  PMID: 21292365
Residential traffic exposure; C-reactive protein; Type 2 diabetes; Traffic proximity; Traffic density; Puerto Rican; Inflammation
18.  Depression and Glycemic Intake in the Homebound Elderly 
Journal of affective disorders  2011;132(1-2):94-98.
Depression is associated with an increase in the incidence of type 2 diabetes, but the mechanism is unclear. We aimed to study the relationship between depression and glycemic intake in the elderly, and examine whether antidepressant use modified this relationship.
Design, Setting and Participants
We evaluated 976 homebound elders in a cross-sectional study. Depressed was defined by having a Center for Epidemiological Studies Depression (CES-D) score ≥ 16. Antidepressant use was documented. Glycemic index (GI), Glycemic load (GL), and fasting blood insulin levels were measured.
Depressed elders had slightly higher GI (Mean ± SD: 55.8 ± 3.8 vs. 55.1 ± 3.7, P = 0.003) and higher insulin levels (Median: 84.0 vs. 74.4 pmole/ml, P = 0.05) than non-depressed elders. Depressed elders receiving antidepressants, primarily selective serotonin reuptake inhibitors (SSRI), had lower GI (Mean ± SD: 55.1 ± 4.7 vs. 56.2 ± 3.4, P = 0.002) and GL (Median: 170.3 vs. 6826.3, P = 0.03) than those not taking antidepressants. After adjusting for potential confounding variables, GI remained positively associated with depression (β = + 0.65, SE = 0.28, P = 0.02); logarithm of GL was positively associated with depression (β = + 0.33, SE = 0.17, P = 0.05) and negatively associated with antidepressant use (β = − 0.54, SE = 0.18, P = 0.003).
Prospective studies are needed to examine whether high glycemic intake is a mediating factor between late life depression and the risk of type 2 diabetes.
PMCID: PMC3109136  PMID: 21396718
19.  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
20.  Metabolic syndrome in elderly living in marginal peri-urban communities in Quito, Ecuador 
Public health nutrition  2010;14(5):758-767.
The proportion of Latin American population > 60 y is expected to double during the next few decades. Metabolic syndrome (MetS) is associated with high morbidity and mortality worldwide. However, little is known about MetS in Latin America in general, and in Ecuador in particular.
To examine the prevalence of MetS and its association with blood micronutrient, homocysteine (tHcy) and CRP concentrations in elderly living in a low-income urban area.
We performed a cross-sectional study. MetS, using the International Diabetes Federation definition, dietary intake and plasma micronutrient, CRP and tHcy concentrations were assessed.
352 elderly (≥65 y)
Quito, Ecuador.
MetS was prevalent (40 %)—considerably more so among women (81%) than men (19%) (X2 = 32.6, P<0.0001). Further, 53 % of those without MetS exhibited two or more of its components. Micronutrient deficiencies were prevalent including those of vitamin C, zinc, B12, and folate. Vitamin C and E concentrations were inversely (OR= 0.78, CI = 0.71 – 0.86; OR= 0.16, CI =0.03 – 0.81, respectively), and CRP (OR=1.79, CI =1.04 – 3.06) was positively associated with MetS.
The co-existence of MetS with micronutrient deficiencies suggests that elderly Ecuadorians suffer from the double burden of diseases that is increasingly observed in less-developed countries. More research is needed to determine causal factors, but results presented suggest that these older adults would benefit from interventions to reduce the risk factors for MetS, in particular, higher consumption of micronutrient-rich foods.
PMCID: PMC3025090  PMID: 20955641
Elderly; metabolic syndrome; Ecuador; micronutrient deficiency; C-reactive protein
21.  Protective Effect of High Protein and Calcium Intake on the Risk of Hip Fracture in the Framingham Offspring Cohort 
Journal of Bone and Mineral Research  2010;25(12):2770-2776.
The effect of protein on bone is controversial, and calcium intake may modify protein's effect on bone. We evaluated associations of energy-adjusted tertiles of protein intake (ie, total, animal, plant, animal/plant ratio) with incident hip fracture and whether total calcium intake modified these associations in the Framingham Offspring Study. A total of 1752 men and 1972 women completed a baseline food frequency questionnaire (1991–1995 or 1995–1998) and were followed for hip fracture until 2005. Hazard ratios (HRs) were estimated using Cox proportional hazards regression adjusting for confounders. Baseline mean age was 55 years (SD 9.9 years, range 26 to 86 years). Forty-four hip fractures occurred over 12 years of follow-up. Owing to significant interaction between protein (total, animal, animal/plant ratio) and calcium intake (p interaction range = .03 to .04), stratified results are presented. Among those with calcium intakes less than 800 mg/day, the highest tertile (T3) of animal protein intake had 2.8 times the risk of hip fracture [HR = 2.84, 95% confidence interval (CI) 1.20–6.74, p = .02] versus the lowest tertile (T1, p trend = .02). In the 800 mg/day or more group, T3 of animal protein had an 85% reduced hip fracture risk (HR = 0.15, 95% CI 0.02–0.92, p = .04) versus T1 (p trend = .04). Total protein intake and the animal/plant ratio were not significantly associated with hip fracture (p range = .12 to .65). Our results from middle-aged men and women show that higher animal protein intake coupled with calcium intake of 800 mg/day or more may protect against hip fracture, whereas the effect appears reversed for those with lower calcium intake. Calcium intake modifies the association of protein intake and the risk of hip fracture in this cohort and may explain the lack of concordance seen in previous studies. © 2010 American Society for Bone and Mineral Research.
PMCID: PMC3179277  PMID: 20662074
22.  Urinary 8-Hydroxy-2-deoxyguanosine and Cognitive Function in Puerto Rican Adults 
American Journal of Epidemiology  2010;172(3):271-278.
DNA oxidative stress has been suggested as an important pathogenic mechanism in cognitive impairment and dementia. With baseline data collected from 2004 to 2008, the authors examined whether urinary 8-hydroxy-2-deoxyguanosine (8-OHdG), a biomarker of global DNA oxidation, was associated with cognitive function in a sample of 1,003 Puerto Rican adults, aged 45–75 years, living in Boston, Massachusetts, and the surrounding area. Cognitive function was measured by using a battery of 7 tests: the Mini-Mental State Examination, word list learning, digit span, clock drawing and figure copying, Stroop, and verbal fluency tests. The primary outcome was a global cognitive score, averaging standardized scores across all cognitive tests. A higher 8-OHdG concentration was significantly associated with lower global cognitive scores, after adjustment for age, education, status of the gene for apolipoprotein E (APOE), and other covariates (Ptrend = 0.01). The difference in the global score, comparing participants in the 2 extreme 8-OHdG quartiles, was −0.11 (95% confidence interval: −0.20, −0.02), which was equivalent to accelerating cognitive aging by about 4 years, as observed in this population. Prospective studies are needed to elucidate whether elevated urinary 8-OHdG concentrations can predict the rate of cognitive decline and incident dementia.
PMCID: PMC3026653  PMID: 20621990
biological markers; DNA damage; Hispanic Americans; neurobehavioral manifestations; oxidative stress
23.  Allostatic load is associated with chronic conditions in the Boston Puerto Rican Health Study 
Social science & medicine (1982)  2010;70(12):1988-1996.
Puerto Ricans living in the United States mainland present multiple disparities in prevalence of chronic diseases, relative to other racial and ethnic groups. Allostatic load (AL), or the cumulative wear and tear of physiological responses to stressors such as major life events, social and environmental burden, has been proposed as a possible mechanism for the inequalities observed in minority groups, but has not been studied in Puerto Ricans. The aim of this study was to determine the association of AL to six chronic diseases (abdominal obesity, hypertension, diabetes, and self-reported cardiovascular disease (CVD), arthritis and cancer) in Puerto Ricans, and to contrast AL to metabolic syndrome (MetS). Participants of the Boston Puerto Rican Health Study (n=1,116, ages 45–75 years) underwent a home-based interview, where questionnaires were completed and biological samples collected. A summary definition of AL was constructed using clinically-defined cutoffs and medication use for 10 physiological parameters in different body systems. Logistic regression models were run to determine associations between AL score and disease status, controlling for age, sex, smoking, alcohol use, physical activity, total fat intake and energy intake. Parallel models were also run with MetS score replacing AL. We found that increasing categories of AL score were significantly associated with abdominal obesity, hypertension, diabetes and self-reported cardiovascular disease (CVD) and arthritis, but not with self-reported cancer. The strength of associations of AL with all conditions, except diabetes and cancer, was similar to or larger than those of MetS score. In conclusion, Puerto Rican older adults experienced physiological dysregulation that was associated with increased odds of chronic conditions. AL was more strongly associated with most conditions, compared to MetS, suggesting that this cumulative measure may be a better predictor of disease. These results have prospective research implications for Puerto Ricans and other ethnic groups.
PMCID: PMC2907654  PMID: 20381934
allostatic load; health disparities; Puerto Ricans; chronic diseases; metabolic syndrome; USA
24.  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
25.  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

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