Background

Vitamin D is crucial for maintaining musculoskeletal health. Recently, vitamin D insufficiency has been linked to a number of extraskeletal disorders, including diabetes, cancer, and cardiovascular disease. Determinants of circulating 25-hydroxyvitamin D (25-OH D) include sun exposure and dietary intake, but its high heritability suggests that genetic determinants may also play a role.

Methods

We performed a genome-wide association study of 25-OH D among ∼30,000 individuals of European descent from 15 cohorts. Five cohorts were designated as discovery cohorts (n=16,125), five as in silico replication cohorts (n=9,366), and five as de novo replication cohorts (n=8,378). Association results were combined using z-score-weighted meta-analysis. Vitamin D insufficiency was defined as 25-OH D <75 nmol/L or <50 nmol/L.

Findings

Variants at three loci reached genome-wide significance in the discovery cohorts, and were confirmed in the replication cohorts: 4p12 (overall P=1.9 × 10-109 for rs2282679, in GC); 11q12 (P=2.1 × 10-27 for rs12785878, near DHCR7); 11p15 (P=3.3 × 10-20 for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (P=6.0 × 10-10 for rs6013897). A genotype score was constructed using the three confirmed variants. Those in the top quartile of genotype scores had 2- to 2.5-fold elevated odds of vitamin D insufficiency (P≤1 × 10-26).

Interpretation

Variants near genes involved in cholesterol synthesis (DHCR7), hydroxylation (CYP2R1, CYP24A1), and vitamin D transport (GC) influence vitamin D status. Genetic variation at these loci identifies individuals of European descent who have substantially elevated risk of vitamin D insufficiency.

Background

Atrial fibrillation (AF) is common and is an important cause of cardiovascular morbidity and mortality. Vitamin D is an emerging risk factor in cardiovascular disease, and vitamin D status is modifiable. Thus, we sought to investigate whether vitamin D status predisposed to the development of AF in a community-based sample.

Methods

We evaluated the relation between vitamin D status and development of AF in 2,930 participants of the Framingham Heart Study, Massachusetts, United States, without prevalent AF. The mean age was 65±11 years and 56% were women. Vitamin D status was assessed by measuring 25-hydroxyvitamin D (25[OH]D) concentrations. Multivariable Cox regression models were adjusted for AF risk factors and season.

Results

During a mean follow up of 9.9 years, 425 participants (15%) developed AF. In Cox proportional hazards models, 25(OH)D was not associated with development of AF, with a multivariable-adjusted hazard ratio of 0.99 per SD increment in 25(OH)D levels (95% confidence interval [CI], 0.88 to 1.10; p=0.81). Also, no relation was found in models including 25(OH)D as a dichotomous variable (above and below the cohort-specific 20th percentile; p=0.59).

Conclusion

In our community-based sample, vitamin D status was not related to incident AF. Our data suggest that vitamin D deficiency does not promote the development of AF in the ambulatory setting.

Aims:

Salt sensitivity, a trait characterized by a pressor blood pressure (BP) response to increased dietary salt intake, has been associated with higher rates of cardiovascular target organ damage and cardiovascular disease events. Recent experimental studies have highlighted the potential role of the natriuretic peptides and aldosterone in mediating salt sensitivity.

Methods and Results:

We evaluated 1575 non-hypertensive Framingham Offspring cohort participants (mean age 55±9 years, 58% women) who underwent routine measurements of circulating aldosterone and N-terminal proatrial natriuretic peptide (NT-ANP) and assessment of dietary sodium intake. Participants were categorized as potentially ‘salt-sensitive’ if their serum aldosterone was >sex-specific median but plasma NT-ANP was ≤sex-specific median value. Dietary sodium intake was categorized as lower versus higher (dichotomized at the sex-specific median). We used multivariable linear regression to relate presence of salt sensitivity (as defined above) to longitudinal changes (Δ) in systolic and diastolic BP on follow-up (median 4 years). Participants who were ‘salt-sensitive’ (N=437) experienced significantly greater increases in BP (Δ systolic, +4.4 and +2.3 mmHg; Δ diastolic, +1.9 and −0.3 mmHg; on a higher versus lower sodium diet, respectively) as compared to the other participants (Δ systolic, +2.8 and +1.0 mmHg; Δ diastolic, +0.5 and −0.2 mmHg; on higher versus lower sodium diet, respectively; p=0.033 and p=0.0127 for differences between groups in Δ systolic and Δ diastolic BP, respectively).

Conclusion:

Our observational data suggest that higher circulating aldosterone and lower NT-ANP concentrations may be markers of salt sensitivity in the community. Additional studies are warranted to confirm these observations.

The ability to interpret epidemiologic observations is limited because of potential residual confounding by correlated dietary components. Dietary pattern analyses by factor analysis or partial least squares may overcome the limitation. To examine confounding by dietary pattern as well as standard risk factors and selected nutrients, the authors modeled the longitudinal association between alcohol consumption and 7-year risk of type 2 diabetes mellitus in 2,879 healthy adults enrolled in the Framingham Offspring Study (1991–2001) by Cox proportional hazard models. After adjustment for standard risk factors, consumers of ≥9.0 drinks/week had a significantly lower risk of type 2 diabetes mellitus compared with abstainers (hazard ratio = 0.47, 95% confidence interval (CI): 0.27, 0.81). Adjustment for selected nutrients had little effect on the hazard ratio, whereas adjustment for dietary pattern variables by factor analysis significantly shifted the hazard ratio away from null (hazard ratio = 0.33, 95% CI: 0.17, 0.64) by 40.0% (95% CI: 16.8, 57.0; P = 0.002). Dietary pattern variables by partial least squares showed similar results. Therefore, the observed inverse association, consistent with past studies, was confounded by dietary patterns, and this confounding was not captured by individual nutrient adjustment. The data suggest that alcohol intake, not dietary patterns associated with alcohol intake, is responsible for the observed inverse association with type 2 diabetes mellitus risk.

Objectives

We investigated whether eating behaviors were concordant among diverse sets of social ties.

Methods

We analyzed the socio-economic and demographic distribution of eating among 3,418 members of the Framingham Heart Study observed between 1991 and 2001. A data classification procedure simplified choices into seven non-overlapping patterns; these patterns were matched with information on social network ties. Correlation analysis examined eating associations between four types of peers (spouses, friends, brothers, sisters). Longitudinal multiple logistic regression was used to evaluate evidence for peer influences on eating.

Results

Of all peer types, spouses showed strongest concordances in eating patterns over time after adjusting for social contextual factors. Across all peers, the eating pattern most likely to be shared by socially connected individuals is “alcohol and snacks.” Models estimating one’s current eating pattern based on a peer’s prior eating provide supportive evidence of a social influence process.

Conclusions

Certain eating patterns may be socially transmissible across different kinds of relationships. These findings represent an important step in specifying the relevant social environment in the study of health behaviors to include eating.

Background

Higher plasma total homocysteine (tHcy) is an established risk factor for cardiovascular disease. The relation between tHcy and carotid artery intima-media thickness (IMT) at the internal carotid artery (ICA)/bulb-IMT and common carotid artery (CCA)-IMT has not been systematically examined. Since the ICA/bulb segment is more prone to plaque formation than the CCA segment, differential associations with tHcy at these sites might suggest mechanisms of tHcy action.

Methods

We examined the cross-sectional segment-specific relations of tHcy to ICA/bulb-IMT and CCA-IMT in 2,499 participants from the Framingham Offspring Study, free of cardiovascular disease.

Results

In multivariable linear regression analysis, ICA/bulb-IMT was significantly higher in the fourth tHcy quartile category compared to the other quartile categories, in both the age- and sex-adjusted and in the multivariable-adjusted model (P for trend <0.0001 and <0.01, respectively). We observed a significant age by tHcy interaction for ICA/bulb-IMT (P=0.03) and therefore stratified the analyses by median age (58 years). There was a significant positive trend between tHcy and ICA/bulb-IMT in individuals 58 years of age or older (P-trend <0.01), but not in the younger individuals (P-trend=0.24). For CCA-IMT, no significant trends were observed in any of the analyses.

Conclusions

The segment-specific association between elevated tHcy levels and ICA/bulb-IMT suggests an association between tHcy and plaque formation.

Background

Biomarkers of multiple pathophysiological pathways have been related to incident atrial fibrillation (AF), but their predictive ability remains controversial.

Methods and Results

In 3120 Framingham cohort participants (mean age 58.4±9.7, 54% women), we related 10 biomarkers representing inflammation (C-reactive protein [CRP], fibrinogen), neurohormonal activation (B-type natriuretic peptide [BNP], N-terminal pro-atrial natriuretic peptide), oxidative stress (homocysteine), renin-angiotensin-aldosterone system (renin, aldosterone), thrombosis and endothelial function (D-dimer, plasminogen-activator inhibitor 1 [PAI-1]), and microvascular damage (urine albumin excretion, n=2673) with incident AF (n=209, 40% women) over a median follow-up of 9.7 years (range 0.05–12.8 years).

In multivariable-adjusted analyses, the biomarker panel was associated with incident AF (P<0.0001). In stepwise selection models (P<0.01 for entry and retention), log-transformed BNP, hazard ratio [HR] per standard deviation 1.62 (95% confidence interval [CI] 1.41–1.85, P<0.0001), and CRP, HR 1.25 (95% CI 1.07–1.45, P=0.004), were chosen.

The addition of BNP to variables recently combined in a risk score for AF increased the C-statistic from 0.78 (95%CI 0.75–0.81 to 0.80 (95% CI 0.78–0.83), and showed an integrated discrimination improvement of 0.03 (95% CI 0.02–0.04, P<0.0001) with 34.9% relative improvement in reclassification analysis. The combined analysis of BNP and CRP did not appreciably improve risk prediction over the model incorporating BNP in addition to the risk factors.

Conclusions

BNP is a predictor of incident AF and improves risk stratification based on well-established clinical risk factors. Whether knowledge of BNP concentrations may be used to target individuals at risk of AF for more intensive monitoring or primary prevention needs further investigation.

Background

Several biological pathways are activated in ventricular remodeling and in overt heart failure (HF). There are no data, however, on the incremental utility of a parsimonious set of biomarkers (reflecting pathways implicated in HF) for predicting HF risk in the community.

Methods and Results

We related a multi-biomarker panel to the incidence of a first HF event in 2754 Framingham Heart Study participants (mean age 58 years; 54% women), who were free of HF and underwent routine assays for 6 biomarkers (c-reactive protein, plasminogen activator inhibitor-1, homocysteine, aldosterone-to-renin ratio, b-type natriuretic peptide [BNP] and urinary albumin-to-creatinine ratio [UACR]). We estimated model c-statistic, calibration and net reclassification improvement (NRI) to assess the incremental predictive usefulness of biomarkers. We also related biomarkers to incidence of non-ischemic HF in participants without prevalent coronary heart disease.

On follow-up (mean 9.4 years), 95 first HF events occurred (54 in men). In multivariable-adjusted models, the biomarker panel was significantly related to HF risk (p=0.00005). Upon backwards elimination, BNP and UACR emerged as key biomarkers predicting HF risk: hazards ratio (HR; confidence interval [CI]) per standard deviation increment in log-marker were 1.52 (1.24-1.87) and 1.35 (1.11-1.66), respectively. BNP and UACR significantly improved the model c-statistic (CI) from 0.84 (0.80-0.88) in standard models to 0.86 (0.83-0.90), enhanced risk reclassification (NRI = 0.13; p=0.002), and were also independently associated with non-ischemic HF risk.

Conclusion

Using a multimarker strategy, we identified BNP and UACR as key risk factors for new-onset HF with incremental predictive utility over standard risk factors.

In vitro data suggest protective roles for vitamins K and D in inflammation. To examine associations between vitamins K and D and inflammation in vivo, we used multiple linear regression analyses, adjusted for age, sex, body mass index, triglyceride concentrations, use of aspirin, lipid lowering and hormone replacement medications, season, and menopausal status. Participants were from the Framingham Offspring Study (n=1381; mean age 59 years; 52% women). Vitamin K status, measured by plasma phylloquinone and phylloquinone intake, was inversely associated with circulating inflammatory markers as a group, and with several individual inflammatory biomarkers (p< 0.01). Percent undercarboxylated osteocalcin, a functional measure of vitamin K status, was not associated with overall inflammation, but was associated with C-reactive protein (p<0.01). Although plasma 25-hydroxyvitamin D was inversely associated with urinary isoprostanes, an oxidative stress indicator (p<0.01), overall associations between vitamin D status and inflammation were inconsistent. The observation that high vitamin K status was associated with lower concentrations of inflammatory markers suggests that a protective role for vitamin K in inflammation merits further investigation.

A roundtable to discuss the measurement of folate status biomarkers in NHANES took place in July 2010. NHANES has measured serum folate since 1974 and red blood cell (RBC) folate since 1978 with the use of several different measurement procedures. Data on serum 5-methyltetrahydrofolate (5MTHF) and folic acid (FA) concentrations in persons aged ≥60 y are available in NHANES 1999–2002. The roundtable reviewed data that showed that folate concentrations from the Bio-Rad Quantaphase II procedure (Bio-Rad Laboratories, Hercules, CA; used in NHANES 1991–1994 and NHANES 1999–2006) were, on average, 29% lower for serum and 45% lower for RBC than were those from the microbiological assay (MA), which was used in NHANES 2007–2010. Roundtable experts agreed that these differences required a data adjustment for time-trend analyses. The roundtable reviewed the possible use of an isotope-dilution liquid chromatography–tandem mass spectrometry (LC-MS/MS) measurement procedure for future NHANES and agreed that the close agreement between the MA and LC-MS/MS results for serum folate supported conversion to the LC-MS/MS procedure. However, for RBC folate, the MA gave 25% higher concentrations than did the LC-MS/MS procedure. The roundtable agreed that the use of the LC-MS/MS procedure to measure RBC folate is premature at this time. The roundtable reviewed the reference materials available or under development at the National Institute of Standards and Technology and recognized the challenges related to, and the scientific need for, these materials. They noted the need for a commutability study for the available reference materials for serum 5MTHF and FA.

A roundtable to discuss the measurement of vitamin B-12 (cobalamin) status biomarkers in NHANES took place in July 2010. NHANES stopped measuring vitamin B-12–related biomarkers after 2006. The roundtable reviewed 3 biomarkers of vitamin B-12 status used in past NHANES—serum vitamin B-12, methylmalonic acid (MMA), and total homocysteine (tHcy)—and discussed the potential utility of measuring holotranscobalamin (holoTC) for future NHANES. The roundtable focused on public health considerations and the quality of the measurement procedures and reference methods and materials that past NHANES used or that are available for future NHANES. Roundtable members supported reinstating vitamin B-12 status measures in NHANES. They noted evolving concerns and uncertainties regarding whether subclinical (mild, asymptomatic) vitamin B-12 deficiency is a public health concern. They identified the need for evidence from clinical trials to address causal relations between subclinical vitamin B-12 deficiency and adverse health outcomes as well as appropriate cutoffs for interpreting vitamin B-12–related biomarkers. They agreed that problems with sensitivity and specificity of individual biomarkers underscore the need for including at least one biomarker of circulating vitamin B-12 (serum vitamin B-12 or holoTC) and one functional biomarker (MMA or tHcy) in NHANES. The inclusion of both serum vitamin B-12 and plasma MMA, which have been associated with cognitive dysfunction and anemia in NHANES and in other population-based studies, was preferable to provide continuity with past NHANES. Reliable measurement procedures are available, and National Institute of Standards and Technology reference materials are available or in development for serum vitamin B-12 and MMA.

Emerging technologies allow the high-throughput profiling of metabolic status from a blood specimen (metabolomics). We investigated whether metabolite profiles could predict the development of diabetes. Among 2,422 normoglycemic individuals followed for 12 years, 201 developed diabetes. Amino acids, amines, and other polar metabolites were profiled in baseline specimens using liquid chromatography-tandem mass spectrometry. Cases and controls were matched for age, body mass index and fasting glucose. Five branched-chain and aromatic amino acids had highly-significant associations with future diabetes: isoleucine, leucine, valine, tyrosine, and phenylalanine. A combination of three amino acids predicted future diabetes (>5-fold higher risk for individuals in top quartile). The results were replicated in an independent, prospective cohort. These findings underscore the potential importance of amino acid metabolism early in the pathogenesis of diabetes, and suggest that amino acid profiles could aid in diabetes risk assessment.

Background

Plasma total cholesterol is known to be decreasing while obesity is increasing, but information on recent population trends of high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) is sparse.

Methods

Plasma total cholesterol, HDL-C, and TG, measured by the same methods at the three most recently-completed examinations of Framingham Offspring Study participants (from 1991 to 2001), were compared in 1666 participants without prevalent cardiovascular disease, lipid or hormone replacement therapy (56% men; mean age, 53 and 60 years at first and last examination). Changes in age- and multivariable-adjusted mean lipid levels were related to changes in BMI.

Results

Over the three examinations, comparing earliest to most recent exam, HDL-C was significantly increased (multivariable-adjusted means, 44.4 and 46.6 mg/dL in men; 56.9 and 60.1 mg/dL in women; P for trend, <0.0001 in both sexes), whereas TG levels were decreased (144.5 and 134.1 mg/dL in men; 122.3 and 112.3 mg/dL in women; P for trend, 0.0041 in men, <0.0001 in women). Over the same time interval, BMI increased (27.8 and 28.5 kg/m2 in men; 27.0 and 27.6 kg/m2 in women; P for trend <0.0001 in men, 0.0011 in women). There was an inverse relation between changes in BMI and magnitude of dyslipidemia, i.e. individuals with least increase in BMI had most favorable changes in HDL-C and TG.

Conclusions

During a 10-year period of recent exams in the Framingham Heart Study there has been a decrease in dyslipidemia with an increase in HDL-C and decrease in TG despite an overall increase in BMI.

OBJECTIVE

Because vitamin D deficiency is associated with a variety of chronic diseases, understanding the characteristics that promote vitamin D deficiency in otherwise healthy adults could have important clinical implications. Few studies relating vitamin D deficiency to obesity have included direct measures of adiposity. Furthermore, the degree to which vitamin D is associated with metabolic traits after adjusting for adiposity measures is unclear.

RESEARCH DESIGN AND METHODS

We investigated the relations of serum 25-hydroxyvitamin D (25[OH]D) concentrations with indexes of cardiometabolic risk in 3,890 nondiabetic individuals; 1,882 had subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes measured by multidetector computed tomography (CT).

RESULTS

In multivariable-adjusted regression models, 25(OH)D was inversely associated with winter season, waist circumference, and serum insulin (P < 0.005 for all). In models further adjusted for CT measures, 25(OH)D was inversely related to SAT (−1.1 ng/ml per SD increment in SAT, P = 0.016) and VAT (−2.3 ng/ml per SD, P < 0.0001). The association of 25(OH)D with insulin resistance measures became nonsignificant after adjustment for VAT. Higher adiposity volumes were correlated with lower 25(OH)D across different categories of BMI, including in lean individuals (BMI <25 kg/m2). The prevalence of vitamin D deficiency (25[OH]D <20 ng/ml) was threefold higher in those with high SAT and high VAT than in those with low SAT and low VAT (P < 0.0001).

CONCLUSIONS

Vitamin D status is strongly associated with variation in subcutaneous and especially visceral adiposity. The mechanisms by which adiposity promotes vitamin D deficiency warrant further study.

OBJECTIVE— The purpose of this study was to assess the relationship between lifestyle factors and abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in a community-based setting.

RESEARCH DESIGN AND METHODS— Cross-sectional associations between lifestyle factors (dietary quality, physical activity, smoking, and alcohol consumption) and SAT and VAT volumes were examined in 2,926 Framingham Heart Study participants (48.6% women, aged 50 ± 10 years).

RESULTS— Diets consistent with the 2005 Dietary Guidelines Adherence Index and greater physical activity were inversely associated with SAT and VAT (P < 0.0001–0.002). In men, former smoking was associated with higher SAT (2,743 ± 56 cm3) compared with current smokers (2,629 ± 88 cm3) or those who never smoked (2,538 ± 44 cm3; P = 0.02). Both former and current smoking was associated with higher VAT (P = 0.03 [women]; P = 0.005 [men]). Women with high amounts of alcohol intake (>7 drinks/week) had lower SAT (2,869 ± 106 cm3) than those who consumed less alcohol (3,184 ± 44 cm3, P = 0.006); significant differences in VAT were not observed (P = 0.18). In men, high amounts of alcohol intake (>14 drinks/week) were associated with higher VAT (2,272 ± 59 cm3) compared with intake of ≤14 drinks/week (2,139 ± 25 cm3, P = 0.04), whereas SAT did not differ (P = 0.91). An increasing number of healthy lifestyle factors were associated with lower SAT and VAT volumes (all P < 0.003).

CONCLUSIONS— Adherence to recommended dietary guidelines and physical activity are associated with lower SAT and VAT volumes. However, both smoking and high alcohol intake are differentially associated with VAT volumes. Further research to uncover the putative mechanisms is warranted.

Background

Arterial stiffness increases with age and contributes to the pathogenesis of systolic hypertension and cardiovascular disease in the elderly. Knowledge about pathophysiological processes that determine arterial stiffness may help guide therapeutic approaches.

Methods and Results

We related seven circulating biomarkers, representing distinct biological pathways (C-reactive protein [CRP], aldosterone-to-renin ratio [ARR], N-terminal pro–atrial natriuretic peptide and B-type natriuretic peptide, plasminogen activator inhibitor [PAI]-1, fibrinogen, homocysteine) to 5 vascular function measures (central pulse pressure, carotid-femoral pulse wave velocity, mean arterial pressure, forward pressure wave amplitude [all measures of conduit artery stiffness], and augmented pressure, an indicator of wave reflection) in 2,000 Framingham Offspring Study participants (mean age 61 years, 55% women). Tonometry measures were obtained on average three years after biomarkers were measured. In multivariable linear regression models adjusting for covariates, the biomarker panel was significantly associated with all 5 vascular measures (p<0.003 for all). Upon backwards elimination, the ARR was positively associated with each stiffness measure (p≤0.002 for all). In addition, CRP was positively related to augmented pressure (p=0.0003), whereas PAI-1 was positively associated with mean arterial pressure (p=0.003), central pulse pressure (p=0.001) and forward pressure wave (p=0.01).

Conclusions

Our cross-sectional data on a community-based sample suggest a distinctive pattern of positive associations of biomarkers of renin-angiotensin-aldosterone system activation with pan-arterial vascular stiffness, PAI-1 with central vascular stiffness indices, and of CRP with wave reflection. These observations support the notion of differential influences of biological pathways on vascular stiffness measures.

Background

Hyperhomocysteinemia may be a modifiable risk factor for the prevention of arteriosclerotic outcomes in chronic kidney disease (CKD). Few clinical trials of homocysteine lowering have been conducted in persons with CKD prior to reaching end-stage renal disease. Kidney transplant recipients are considered individuals with CKD.

Objectives

To describe the baseline characteristics of renal transplant recipients (RTRs) enrolled in a clinical trial of homocyteine lowering with a standard multivitamin containing high doses of folic acid, vitamins B6 and B12 aimed at reducing arteriosclerotic outcomes. Factors considered were level of kidney function, total homocysteine (tHcy) concentrations, and the prevalence of diabetes and previous cardiovascular disease (CVD).

Study Design

Cross sectional survey within a randomized controlled trial (RCT) cohort.

Setting and Participants

Participants were recruited from kidney transplant clinics in the U.S., Canada, and Brazil. Eligible participants had elevated levels of homocysteine (≥12.0 μmol/L in men and ≥11.0 μmol/L in women) and kidney function measured by Cockroft Gault estimated creatinine clearance of 30 mL/min or greater.

Results

Among 4,110 randomized participants 38.9% had diabetes, and 19.5% had previous CVD. Mean (± standard deviation) tHcy concentrations were 17.1 ± 6.3 μmol/L, while the mean (± standard deviation) creatinine clearance was 66.4 ± 23.2 mL/min. Approximately 90% of the trial cohort had an estimated glomerular filtration rate (eGFR) consistent with stage 2-3 CKD (i.e., eGFR 30-89 mL/min).

Limitations

Analysis is based on cross-sectional data from a RCT, self-report of co-morbid illnesses, and level of kidney function was estimated.

Conclusions

A large population of stable RTRs who are at high risk for the development of CVD (both de novo and recurrent) has been recruited into FAVORIT and are likely to experience a sufficient number of events to address the primary hypothesis of the trial.

OBJECTIVE—Vitamin K has a potentially beneficial role in insulin resistance, but evidence is limited in humans. We tested the hypothesis that vitamin K supplementation for 36 months will improve insulin resistance in older men and women.

RESEARCH DESIGN AND METHODS—This was an ancillary study of a 36-month, randomized, double-blind, controlled trial designed to assess the impact of supplementation with 500 μg/day phylloquinone on bone loss. Study participants were older nondiabetic men and women (n = 355; aged 60–80 years; 60% women). The primary outcome of this study was insulin resistance as measured by homeostasis model assessment (HOMA-IR) at 36 months. Fasting plasma insulin and glucose were examined as the secondary outcomes.

RESULTS—The effect of 36-month vitamin K supplementation on HOMA-IR differed by sex (sex × treatment interaction P = 0.02). HOMA-IR was statistically significantly lower at the 36-month visit among men in the supplement group versus the men in the control group (P = 0.01) after adjustment for baseline HOMA-IR, BMI, and body weight change. There were no statistically significant differences in outcome measures between intervention groups in women.

CONCLUSIONS—Vitamin K supplementation for 36 months at doses attainable in the diet may reduce progression of insulin resistance in older men.

Vitamin E supplementation has been suggested to improve immune response in the aged in part by altering cytokine production. However, there is not a consensus regarding the effect of supplemental vitamin E on cytokine production in humans. There is evidence that baseline immune health can affect immune response to supplemental vitamin E in the elderly. Thus, the effect of vitamin E on cytokines may depend on their pre-supplementation cytokine response. Using data from a vitamin E intervention in elderly nursing home residents, we examined if the effect of vitamin E on ex vivo cytokine production of IL-1β, IL-6, TNF-α, and IFN-γ depended on baseline cytokine production. . We observed that the effect of vitamin E supplementation on cytokine production depended on pre-supplementation production of the respective cytokines. The interactions between vitamin E and baseline cytokine production were not explained covariates known to impact cytokine production. Our results offer evidence that baseline cytokine production should be considered in studies that examine the effect of supplemental vitamin E on immune and inflammatory responses. Our results could have implications in designing clinical trials to determine the impact of vitamin E on conditions in which cytokines are implicated such as infections and atherosclerotic disease.

Objective

To evaluate the relation between plasma homocysteine (tHcy) and brain MRI in a community-based sample.

Background

Elevated tHcy levels have been associated with an increased risk of dementia and stroke, but it is uncertain if the mediating mechanisms are predominantly cellular, vascular or both.

Design

Our sample comprised 1965 Framingham Offspring participants (1050 women; age 62±9 yrs) who were free of clinical stroke, dementia, or other neurological disease affecting brain MRI and who had at least one measurement of plasma tHcy (1991-2001) and a brain MRI (1999-2002). We used multivariable regressions to relate initial (1991-95) and concurrent (1998-2001) plasma tHcy concentrations to total cerebral brain volume (TCBV) and lobar volumes as measures of neuronal loss and atrophy; and to the presence or absence of silent brain infarcts (SBI) and extensive white matter hyperintensity (log-WMH ≥1 SD above the age-adjusted mean) as separate measures of vascular injury.

Results

Mean TCBV was 78%. 218 participants had SBI; 250 had extensive WMH. Participants with a plasma tHcy level in the highest age-, sex-specific quartile had a smaller TCBV (-0.37% and -0.48%; p=0.01 and <0.001 respectively), compared to participants with lower levels. Initial tHcy levels were associated with an increased prevalence of SBI (RR: 1.5; 95% CI: 1.1-2.1; p=0.02) and concurrent tHcy levels with smaller frontal and temporal lobar volumes (-0.14% and -0.10%; p=0.001 and 0.04 respectively). Prevalence of extensive WMH did not differ according to initial or concurrent plasma tHcy levels (RR: both 1.0, 95% CIs: 0.7-1.4 and 0.8-1.4, respectively).

Conclusion

Higher plasma tHcy levels are associated with smaller brain volumes and presence of silent infarcts on MRI, even in healthy, middle-aged adults. Thus, both cellular and vascular mechanisms may underlie the association of plasma tHcy with brain aging, as reflected by the effects on subclinical as well as overt disease.

Background

Zinc plays an important role in immune function. The association between serum zinc and pneumonia in the elderly has not been studied.

Objective

To determine if serum zinc concentrations in nursing home elderly are associated with incidence and duration of pneumonia, total and duration of antibiotic use, and pneumonia-associated and overall deaths.

Design

This observational study was conducted in residents from 33 nursing homes in Boston, MA, who participated in a one-year randomized, double-blind, and placebo controlled vitamin E supplementation trial; all were given daily doses of ½ RDA of essential vitamins and minerals including zinc. Participants with baseline (N=578) or final (N=420) serum zinc concentrations were categorized as having low (<70 μg/dL) or normal (≥70 μg/dL) serum zinc concentrations. Outcome measures included incidence and number of days with pneumonia, number of new antibiotic prescriptions, days of antibiotic use, death due to pneumonia, and, all-cause mortality.

Results

Subjects with normal final serum zinc concentrations had lower pneumonia incidence, total antibiotic use (by almost 50%), and shorter duration of pneumonia and antibiotic use (by 3.9 and 2.6 days, respectively) (all p-values ≤0.004) relative to those with low zinc concentrations. Normal baseline serum zinc concentrations were associated with decreased all-cause mortality (p=0.049).

Conclusion

Normal serum zinc concentrations in nursing home elderly were associated with decreased incidence and duration of pneumonia, and decreased use and duration of antimicrobial therapy. Zinc supplementation to maintain normal serum zinc concentrations in the elderly may help reduce pneumonia incidence and associated morbidity.

Background

Historic reports on the treatment of pernicious anemia with folic acid suggest that high-level folic acid fortification delays the diagnosis of or exacerbates the effects of vitamin B-12 deficiency, which affects many seniors. This idea is controversial, however, because observational data are few and inconclusive. Furthermore, experimental investigation is unethical.

Objective

We examined the relations between serum folate and vitamin B-12 status relative to anemia, macrocytosis, and cognitive impairment (ie, Digit Symbol-Coding score <34) in senior participants in the 1999–2002 US National Health and Nutrition Examination Survey.

Design

The subjects had normal serum creatinine concentrations and reported no history of stroke, alcoholism, recent anemia therapy, or diseases of the liver, thyroid, or coronary arteries (n = 1459). We defined low vitamin B-12 status as a serum vitamin B-12 concentration <148 pmol/L or a serum methylmalonic acid concentration >210 nmol/L—the maximum of the reference range for serum vitamin B-12–replete participants with normal creatinine.

Results

After control for demographic characteristics, cancer, smoking, alcohol intake, serum ferritin, and serum creatinine, low versus normal vitamin B-12 status was associated with anemia [odds ratio (OR): 2.7; 95% CI: 1.7, 4.2], macrocytosis (OR: 1.8; 95% CI: 1.01, 3.3), and cognitive impairment (OR: 2.5; 95% CI: 1.6, 3.8). In the group with a low vitamin B-12 status, serum folate ≤59 nmol/L (80th percentile), as opposed to ≤59 nmol/L, was associated with anemia (OR: 3.1; 95% CI: 1.5, 6.6) and cognitive impairment (OR: 2.6; 95% CI: 1.1, 6.1). In the normal vitamin B-12 group, ORs relating high versus normal serum folate to these outcomes were <1.0 (Pinteraction <0.05), but significantly <1.0 only for cognitive impairment (0.4; 95% CI: 0.2, 0.9).

Conclusion

In seniors with low vitamin B-12 status, high serum folate was associated with anemia and cognitive impairment. When vitamin B-12 status was normal, however, high serum folate was associated with protection against cognitive impairment.

OBJECTIVE

Many genetic variants have been associated with glucose homeostasis and type 2 diabetes in genome-wide association studies. Zinc is an essential micronutrient that is important for β-cell function and glucose homeostasis. We tested the hypothesis that zinc intake could influence the glucose-raising effect of specific variants.

RESEARCH DESIGN AND METHODS

We conducted a 14-cohort meta-analysis to assess the interaction of 20 genetic variants known to be related to glycemic traits and zinc metabolism with dietary zinc intake (food sources) and a 5-cohort meta-analysis to assess the interaction with total zinc intake (food sources and supplements) on fasting glucose levels among individuals of European ancestry without diabetes.

RESULTS

We observed a significant association of total zinc intake with lower fasting glucose levels (β-coefficient ± SE per 1 mg/day of zinc intake: −0.0012 ± 0.0003 mmol/L, summary P value = 0.0003), while the association of dietary zinc intake was not significant. We identified a nominally significant interaction between total zinc intake and the SLC30A8 rs11558471 variant on fasting glucose levels (β-coefficient ± SE per A allele for 1 mg/day of greater total zinc intake: −0.0017 ± 0.0006 mmol/L, summary interaction P value = 0.005); this result suggests a stronger inverse association between total zinc intake and fasting glucose in individuals carrying the glucose-raising A allele compared with individuals who do not carry it. None of the other interaction tests were statistically significant.

CONCLUSIONS

Our results suggest that higher total zinc intake may attenuate the glucose-raising effect of the rs11558471 SLC30A8 (zinc transporter) variant. Our findings also support evidence for the association of higher total zinc intake with lower fasting glucose levels.