Genome-wide association study of vitamin B6, vitamin B12, folate, and homocysteine blood concentrations.

The B vitamins are components of one-carbon metabolism (OCM) that contribute to DNA synthesis and methylation. Homocysteine, a by-product of OCM, has been associated with coronary heart disease, stroke and neurological disease. To investigate genetic factors that affect circulating vitamin B6, vitamin B12, folate and homocysteine, a genome-wide association analysis was conducted in the InCHIANTI (N = 1175), SardiNIA (N = 1115), and BLSA (N = 640) studies. The top loci were replicated in an independent sample of 687 participants in the Progetto Nutrizione study. Polymorphisms in the ALPL gene (rs4654748, p = 8.30 x 10(-18)) were associated with vitamin B6 and FUT2 (rs602662, [corrected] p = 2.83 x 10(-20)) with vitamin B12 serum levels. The association of MTHFR, a gene consistently associated with homocysteine, was confirmed in this meta-analysis. The ALPL gene likely influences the catabolism of vitamin B6 while FUT2 interferes with absorption of vitamin B12. These findings highlight mechanisms that affect vitamin B6, vitamin B12 and homocysteine serum levels.

Common variation in the beta-carotene 15,15'-monooxygenase 1 gene affects circulating levels of carotenoids: a genome-wide association study.

Low plasma levels of carotenoids and tocopherols are associated with increased risk of chronic disease and disability. Because dietary intake of these lipid-soluble antioxidant vitamins is only poorly correlated with plasma levels, we hypothesized that circulating carotenoids (vitamin A-related compounds) and tocopherols (vitamin E-related compounds) are affected by common genetic variation. By conducting a genome-wide association study in a sample of Italians (n = 1190), we identified novel common variants associated with circulating carotenoid levels and known lipid variants associated with alpha-tocopherol levels. Effects were replicated in the Women's Health and Aging Study (n = 615) and in the alpha-Tocopherol, beta-Carotene Cancer Prevention (ATBC) study (n = 2136). In meta-analyses including all three studies, the G allele at rs6564851, near the beta-carotene 15,15'-monooxygenase 1 (BCMO1) gene, was associated with higher beta-carotene (p = 1.6 x 10(-24)) and alpha-carotene (p = 0.0001) levels and lower lycopene (0.003), zeaxanthin (p = 1.3 x 10(-5)), and lutein (p = 7.3 x 10(-15)) levels, with effect sizes ranging from 0.10-0.28 SDs per allele. Interestingly, this genetic variant had no significant effect on plasma retinol (p > 0.05). The SNP rs12272004, in linkage disequilibrium with the S19W variant in the APOA5 gene, was associated with alpha-tocopherol (meta-analysis p = 7.8 x 10(-10)) levels, and this association was substantially weaker when we adjusted for triglyceride levels (p = 0.002). Our findings might shed light on the controversial relationship between lipid-soluble anti-oxidant nutrients and human health.

A genome-wide association study identifies protein quantitative trait loci (pQTLs).

There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts - cis effects, and elsewhere in the genome - trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (p = 1.8x10(-57)), CCL4L1 (p = 3.9x10(-21)), IL18 (p = 6.8x10(-13)), LPA (p = 4.4x10(-10)), GGT1 (p = 1.5x10(-7)), SHBG (p = 3.1x10(-7)), CRP (p = 6.4x10(-6)) and IL1RN (p = 7.3x10(-6)) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA), variation in gene copy number (CCL4L1) and altered transcription (GGT1). We identified one novel trans effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha) levels (p = 6.8x10(-40)), but this finding was not present when TNF-alpha was measured using a different assay , or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in cis locations. The identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving our understanding of disease pathways.

Common lipid-altering gene variants are associated with therapeutic intervention thresholds of lipid levels in older people.

AIMS: There are a large number of common genetic variants that have been robustly associated with low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglyceride concentrations. The majority of these have been identified or confirmed in recent genome-wide association studies, but few studies have assessed the combined effect of known lipid variants. We hypothesized that these variants would influence both the need for interventions and myocardial infarction (MI) outcomes. We aimed to estimate combined effects of proven SNPs on LDL, HDL, and triglyceride concentrations and MI history in a representative older population. METHODS AND RESULTS: In the InCHIANTI Study of Aging (age >or=65 years), we calculated individual dyslipidaemia risk allele counts for increased LDL (range 4-14, n = 594), reduced HDL (5-16, n = 635), and increased triglycerides (7-16, n = 611). Lipid levels were compared with ATPIII National Cholesterol Education Panel (NCEP) intervention guidelines. Individual variants and the APOE haplotype explained <2.1% of the variance in their respective lipid concentrations, with the exception of the CETP SNP rs1800775 and HDL levels (4.76%). Combined risk allele counts outperformed the largest single-SNP effects for LDL (explaining 7.1% of variance) and triglycerides (4.8%), but not HDL (3.4%). Risk alleles were divided as near as possible into quartiles. The 31% of respondents with 10 or more LDL increasing alleles were more likely to have LDL levels above the intervention threshold (OR 3.00, 95% CI 1.67-5.39, P = 2.5 x 10(-4)), compared with the 21% with 7 or less risk alleles. Similarly, the 35% with 13 or more triglyceride risk alleles were more likely to exceed NCEP intervention thresholds (OR 2.98, 95% CI 1.43-6.22, P = 0.004) compared with the 24% with 10 or less alleles. The number of individuals reporting an MI event was small (n = 67), but an event was more common in the 36% of respondents who had the highest combined risk allele score for all three lipids (OR 3.68, 95% CI 1.21-11.2, P = 0.021) compared with the lowest risk 22%. CONCLUSION: In a representative older population, the cumulative effects of proven LDL- and triglyceride-altering genetic variants increased the odds of crossing the lipid-level threshold for therapeutic intervention by approximately three-fold.

Frailty and the homeostatic network.

Trajectories of health and functioning with age show extreme variability among different individuals. In frail, older persons the decline in functional reserve is accelerated and compensatory mechanisms start failing, with high risk of homeostasis disruption and consequent negative health outcomes. Frailty is currently conceptualized as an age-related alteration in physiology and pathology that results into a typical constellation of signs and symptoms. Although current attempts to identify frail, older individuals for clinical purposes is based on measures of mobility and motor performance, candidate biological markers that may be specific of the frailty syndrome start to emerge in the literature. Different theories have been drawn to describe the interaction of aging process and loss of ability in performance. One of these hypothesis is based on the progressive dysregulation that occur with age in the homeostatic network and the less efficiency and efficacy in its vital mechanism that allows at all levels integration, from mitochondrial function to societal and community adaptations.

Predictivity of survival according to different equations for estimating renal function in community-dwelling elderly subjects.

BACKGROUND: Detection of subjects with early chronic kidney disease (CKD) is important because some will progress up to stage 5 CKD, and most are at high risk of cardiovascular morbidity and mortality. While validity and precision of estimated glomerular filtration rate (eGFR) equations in tracking true GFR have been repeatedly investigated, their prognostic performance for mortality has not been hitherto compared. This is especially relevant in an elderly population in whom the risk of death is far more common than progression. METHODS: We analysed data of participants in the InCHIANTI study, a community-based cohort study of older adults. Twenty-four-hour creatinine clearance (Ccr), Cockcroft-Gault (C-G) and Modification of Diet in Renal Disease (MDRD)-derived equations (six and four input variables) were calculated at enrolment (1998-2000), and all-cause mortality and cardiovascular mortality were prospectively ascertained by Cox regression over a 6-year follow-up. RESULTS: Of the 1270 participants, 942 (mean age 75 years) had complete data for this study. The mean renal function ranged from 77 ml/min/1.73 m(2) by Ccr to 64 ml/min/1.73 m(2) by C-G. Comparisons among equations using K/DOQI staging highlight relevant mismatches, with a prevalence of CKD ranging from 22% (MDRD-4) to 40% (C-G). Reduced renal function was a strong independent predictor of death. In a Cox model--adjusted for demographics, physical activity, comorbidities, proteinuria and inflammatory parameters-participants with Ccr 60-90 ml/min/1.73 m(2) and Ccr <60 ml/min/1.73 m(2) were, respectively, 1.70 (95% CI: 1.02-2.83) and 1.91 (95% CI: 1.11-3.29) times more likely to die over the follow-up compared to those with Ccr >90 ml/min/1.73 m(2). For the C-G, the group with values <60 ml/min/1.73 m(2) had a significant higher all-cause mortality compared to those with values >90 ml/min/1.73 m(2) (HR 2.59, 95% CI: 1.13-5.91). The classification based on the MDRD formulae did not provide any significant prognostic information. The adjusted risk of all-cause mortality followed a similar pattern when Ccr and estimating equations were introduced as continuous variables or dichotomized as higher or lower than 60 ml/min. C-G was the best prognostic indicator of cardiovascular mortality. Possibly, Ccr and C-G are better prognostic indicators than MDRD-derived equations because they incorporate a stronger effect of age. CONCLUSIONS: In a South-European elderly population, the prevalence of CKD is high and varies widely according to the method adopted to estimate GFR. Researchers and clinicians who want to capture the prognostic information on mortality related to kidney function should use the Ccr or C-G formula and not MDRD equations. These results highlight the importance of strategies for early detection and clinical management of CKD in elderly subjects.

Erythropoietin and polyneuropathy in older persons.

INTRODUCTION: Recent studies demonstrated that erythropoietin (EPO) have a number of non-erythropoietic effects including neuroprotection and vascular protection. MATERIALS: Using data from a representative sample of older persons, we tested the hypothesis that EPO levels are correlated with peripheral nerve parameters (NVC and CMAP) assessed by surface ENG and with clinically diagnosed polyneuropathy. We selected 972 participants (aged 60-98 years) with complete data for the analyses. RESULTS: We found a significant association between EPO and age-adjusted NCV and CMAP (for NCV: 0.57+/-0.26; p = 0.03 and for CMAP: 0.54+/-0.23; p = 0.02). In logistic regression models adjusting for age, sex and multiple potential confounders, higher EPO levels were associated with a significantly lower probability of having a clinical diagnosis of polyneuropathy (OR = 0.43; 95% CI: 0.22-0.84). DISCUSSION: These findings suggest that EPO is implicated in the pathogenesis of polyneuropathy in older persons. Whether low EPO is a risk factor for polyneuropathy should be tested in future longitudinal analyses.

Low plasma carotenoids and skeletal muscle strength decline over 6 years.

BACKGROUND: Higher intake of fruits and vegetables appears to protect against inflammation, poor physical performance, and disability, but its relationship with muscle strength is unclear. We examined the association between total plasma carotenoids, an indicator of fruit and vegetable intake, and changes in muscle strength over a 6-year follow-up in the participants aged 65 years and older in the InCHIANTI study, a population-based study in Tuscany, Italy. METHODS: Plasma carotenoids were measured at enrollment (1998-2000). Hip, knee, and grip strength were measured at enrollment and 6 years later (2004-2006) in 628 of the 948 participants evaluated at baseline. Poor muscle strength was defined as the lowest sex-specific quartile of hip, knee, and grip strength at enrollment. The main outcome was poor muscle strength at the 6-year follow-up visit among those participants originally in the upper three quartiles of strength at enrollment. RESULTS: Overall, 24.9% (110/441), 25.0% (111/444), and 24.9% (118/474) participants developed poor hip, knee, and grip strength, respectively. After adjusting for potential confounders, participants in the lowest versus the highest quartile of total plasma carotenoids at enrollment were at higher risk of developing poor hip (odds ratio [OR] = 3.01, 95% CI, 1.43-6.31, p =.004), knee (OR = 2.89, 95% CI, 1.38-6.02, p =.005), and grip (OR = 1.88, 95% CI, 0.93-3.56, p =.07) muscle strength at the 6-year follow-up visit. CONCLUSION: These findings suggest that older community-dwelling adults with lower plasma carotenoids levels, a marker of poor fruit and vegetable intake, are at a higher risk of decline in skeletal muscle strength over time.

Carotenoids as protection against disability in older persons.

The purpose was to examine the relationship of total plasma carotenoids, an indicator of fruit and vegetable intake, with walking speed and severe walking disability in older adults. Nine hundred twenty-eight men and women aged 65 to 102 years from the Invecchiare in Chianti (Aging in the Chianti Area [InCHIANTI]) study, a population-based cohort in Tuscany, Italy, were studied. Plasma carotenoids were measured at enrollment (1998-2000), and walking speed over 4 meters and 400 meters distance were assessed at enrollment and 6 years later (2004-2006). At enrollment, 85 of 928 (9.2%) participants had severe walking disability (defined as being unable to walk or having a walking speed at the 4-meter walking test < 0.4 m/sec). After adjusting for potential confounders, participants with high total plasma carotenoids were significantly less likely to have prevalent severe walking disability (odds ration [OR] 0.59, 95% confidence interval [CI] 0.38-0.90, p = 0.01) and had higher walking speed over 4 meters (beta = 0.024, standard error [SE] = 0.011, p = 0.03) and over 400 meters (beta = 0.019, SE = 0.010, p = 0.04). Of 621 participants without severe walking disability at enrollment who were seen 6 years later, 68 (11.0%) developed severe walking disability. After adjusting for potential confounders, higher total plasma carotenoids were associated with a significantly lower risk of developing severe walking disability (OR 0.51, 95% CI 0.30-0.86, p = 0.01) and were associated with a less steep decline in 4-meter walking speed over a 6-year follow-up (n = 579; beta = 0.026, SE = 0.012, p = 0.03) and with lower incidence rates of being unable to successfully complete the 400-meter walking test at the 6-year follow-up visit (beta = -0.054, SE = 0.03, p = 0.04). High plasma carotenoids concentrations may be protective against the decline in walking speed and the development of severe walking disability in older adults.

Low total plasma carotenoids are independent predictors of mortality among older persons: the InCHIANTI study.

BACKGROUND: Plasma carotenoids are considered a valid biological marker for fruit and vegetable dietary intake. Recent studies show that low carotenoid levels are associated with a high risk of inflammation, cancer, and cardiovascular disease. AIM OF THE STUDY: To determine whether low plasma carotenoids are associated with increased mortality among older adults. METHODS: Longitudinal study among 1,043 adults, 65 years and older, in the InCHIANTI study, a population-based cohort of adults living in the community in the Tuscany region, Italy. RESULTS: Mean total carotenoid concentration was 1.80 micromol/l. During eight years of follow-up, 310 (29.7%) of participants died. Eight-year survival was lower in the lowest compared with the highest tertile of total serum carotenoids (P < 0.0001 by Mantel-Haenszel chi-square). In a multivariate Cox proportional hazards model adjusted for age, education, smoking, body mass index, energy intake, and chronic diseases, adults in the highest tertile of plasma carotenoids at enrollment had lower mortality compared to those in the lowest tertile (Hazards Ratio obtained by considering carotenoids level as an ordinal variable 0.81, 95%; CI 0.65-0.99; P for trend = 0.046). CONCLUSIONS: Low plasma carotenoids are an independent risk factor for mortality among older adults living in the community.

A common variant of the p16(INK4a) genetic region is associated with physical function in older people.

p16(INK4a) is active in cell senescence, ageing and tumor suppression. Deletion of the small p16(INK4a)/ARF/p15(INK4b) region occurs in many cancers. We screened 25 common polymorphisms across the region and three related genes for associations with physical functioning in older people. In an initial sample of 938 (aged 65-80 years) from the EPIC study (Norfolk, UK), the rs2811712 SNP minor allele (located between the shared p16(INK4a)/ARF locus and p15(INK4b)) was associated with reduced physical impairment. This association remained after testing an additional 1319 EPIC-Norfolk samples (p-value=0.013, total n=2257), and on independent replication in the InCHIANTI study (n=709, p=0.015), and at one-sided significance in Iowa-EPESE (n=419, p=0.079). Overall (n=3372), the prevalence of severely limited physical function was 15.0% in common homozygotes and 7.0% in rare homozygotes (per minor allele odds ratio=1.48, 95% CI: 1.17-1.88, p=0.001, adjusted for age, sex and study). This estimate was similar excluding screening set 1 (OR=1.45, 95% CI: 1.09-1.92, p=0.010, n=2434). These findings require further replication, but provide the first direct evidence that the p16(INK4a)/ARF/p15(INK4b) genetic region and the senescence machinery are active in physical ageing in heterogeneous human populations. The mechanism involved may be via greater cellular restorative activity and reduced stem cell senescence.

High interleukin-6 plasma levels are associated with low HDL-C levels in community-dwelling older adults: the InChianti study.

BACKGROUND: Low levels of high density lipoprotein cholesterol (HDL-C) are associated with increased incidence of coronary heart disease (CHD). A better understanding of the mechanisms leading to low HDL-C and CHD is essential for planning treatment strategies. Clinical studies have demonstrated that cytokines might affect both concentration and composition of plasma lipoproteins, including HDLs. METHODS: We investigated the possible association between low HDL-C levels, defined as < or =10th gender specific percentile, and circulating markers of inflammation (IL-1beta, TNF-alpha, IL-6, IL-10, IL-18, and CRP) in a population of 1044 community dwelling older Italian subjects from the InChianti study. RESULTS: Using logistic regression analysis we demonstrated that IL-6 levels (III versus I tertile, OR: 2.10; 1.10-3.75), TG (III versus I tertile OR: 27.45; 8.47-88.93), fasting insulin (III versus I tertile OR: 2.84; 1.50-5.42), and age (OR: 1.038; 1.002-1.075) were associated with low HDL-C independent of smoking, BMI, waist circumference, hypertension, diabetes, physical activity, alcohol intake, oral hypoglycaemics, CRP, IL-18, and TNF-alpha levels. The adjusted attributable risk of low HDL-C in the exposed group (III tertile of IL-6) was 54%. CONCLUSIONS: The present study provides the epidemiological evidence that besides triglycerides, fasting insulin, and age, IL-6 is one of the main correlates of low HDL-C levels in older individuals.

An interleukin-18 polymorphism is associated with reduced serum concentrations and better physical functioning in older people.

BACKGROUND: The proinflammatory cytokine interleukin-18 (IL-18) is associated with major disabling conditions, although whether as byproduct or driver is unclear. The role of common variation in the IL-18 gene on serum concentrations and functioning in old age is unknown. METHODS: We used 1671 participants aged 65-80 years from two studies: the InCHIANTI study and wave 6 of the Iowa-Established Populations for Epidemiological Study of the Elderly (EPESE). We tested three common polymorphisms against IL-18 concentration and measures of functioning. RESULTS: In the InCHIANTI study, a 1 standard deviation increase in serum IL-18 concentrations was associated with an increased chance of being in the 20% of slowest walkers (odds ratio 1.45; 95% confidence interval, 1.17-1.80; p =.0007) and 20% of those with poorest function based on the Short Physical Performance Battery Score (odds ratio 1.52; 95% confidence interval, 1.22-1.89; p =.00016) in age sex adjusted logistic regression models. There was no association with Activities of Daily Living (p =.26) or Mini-Mental State Examination score (p =.66). The C allele of the IL-18 polymorphism rs5744256 reduced serum concentrations of IL-18 by 39 pmol/mL per allele (p =.00001). The rs5744256 single nucleotide polymorphism was also associated with shorter walk times in InCHIANTI (n = 662, p =.016) and Iowa-EPESE (n = 995, p =.026). In pooled ranked models rs5744256 was also associated with higher SPPB scores (n = 1671, p =.019). Instead of adjusting for confounders in the IL-18 walk time association, we used rs5744256 in a Mendelian randomization analysis: The association remained in instrumental variable models (p =.021). CONCLUSION: IL-18 concentrations are associated with physical function in 65- to 80-year-olds. A polymorphism in the IL-18 gene alters IL-18 concentrations and is associated with an improvement in walk speed. IL-18 may play an active role in age-related functional impairment, but these findings need independent replication.

Magnesium and muscle performance in older persons: the InCHIANTI study.

BACKGROUND: The role of magnesium in maintaining muscle integrity and function in older adults is largely unknown. OBJECTIVE: We aimed to investigate the relation between serum magnesium concentrations and muscle performance in older subjects. DESIGN: Data are from the baseline examination conducted between September 1998 and March 2000 of the InCHIANTI (aging in the Chianti area) study, a prospective epidemiologic survey of risk factors for late-life disability. From among 1453 randomly selected community residents completing a home interview, 1138 men (46%) and women (aged 66.7 +/- 15.2 y; x +/- SD) with complete data on muscle performance and serum magnesium who were not severely cognitively compromised and had no evidence of kidney disease or hypercalcemia were included in the analysis. Muscle performance was evaluated by grip strength, lower-leg muscle power, knee extension torque, and ankle extension isometric strength and was normalized for age and body mass index (BMI) within each sex. RESULTS: After adjustment for age, sex, BMI, laboratory variables, presence of chronic diseases, muscle area, muscle density, and physical activity level, serum magnesium concentrations were significantly associated with indexes of muscle performance, including grip strength (beta = 2.0 +/- 0.5, P = 0.0002), lower-leg muscle power (beta = 8.8 +/- 2.7, P = 0.001), knee extension torque (beta = 31.2 +/- 7.9, P < 0.0001), and ankle extension strength (beta = 3.8 +/- 0.5, P < 0.0001). CONCLUSIONS: The serum magnesium concentration is an independent correlate of muscle performance in older persons. Whether magnesium supplementation improves muscle function remains to be shown.

Effects of the diabetes linked TCF7L2 polymorphism in a representative older population.

BACKGROUND: A polymorphism in the transcription factor 7-like 2 (TCF7L2) gene has been found to be associated with type 2 diabetes in case-control studies. We aimed to estimate associations of the marker rs7903146 (C/T) polymorphism with fasting glucose, lipids, diabetes prevalence and complications in an older general population. METHODS: In total, 944 subjects aged > or = 65 years from the population representative InCHIANTI study were enrolled in this study. Those with fasting blood glucose of > or = 7 mmol/l or physician diagnosis were considered diabetic. Cut-off points for impaired fasting glucose (IFG) were > or = 5.6 mmol/l to < 7 mmol/l. RESULTS: In the general population sample, minor (T) allele carriers of rs7903146 had higher fasting blood glucose (FBG) (p = 0.028) but lower fasting insulin (p = 0.030) and HOMA2b scores (p = 0.001), suggesting poorer beta-cell function. T allele carriers also had smaller waist circumference (p = 0.009), lower triglyceride levels (p = 0.006), and higher high-density lipoprotein cholesterol (p = 0.008). The prevalence of diabetes or IFG was 32.4% in TT carriers and 23.3% in CC carriers; adjusted OR = 1.67 (95% confidence interval 1.05 to 2.65, p = 0.031). Within the diabetic and IFG groups, fewer T allele carriers had metabolic syndrome features (p = 0.047) or had experienced a myocardial infarction (p = 0.037). Conversely, T allele carriers with diabetes had poorer renal function (reduced 24-hour creatinine clearance, p = 0.013), and possibly more retinopathy (p = 0.067). Physician-diagnosed dementia was more common in the T carriers (in diabetes p = 0.05, with IFG p = 0.024). CONCLUSION: The TCF7L2 rs7903146 polymorphism is associated with lower insulin levels, smaller waist circumference, and lower risk lipid profiles in the general elderly population. Patients with diabetes who are carriers of the minor allele are less likely to have metabolic-syndrome features, but may experience more microvascular complications, although the number of cases was small. If replicated, these findings may have implications for developing treatment approaches tailored by genotype.

A proinflammatory state is associated with hyperhomocysteinemia in the elderly.

BACKGROUND: The mechanism by which high circulating homocysteine concentrations are a risk factor for atherothrombosis is incompletely understood. A proinflammatory state is related to atherosclerosis, and recent studies suggest that acute phase reactants correlate with circulating concentrations of homocysteine. OBJECTIVE: We determined whether high concentrations of inflammatory markers are associated with hyperhomocysteinemia independently of dietary vitamin intakes, vitamin concentrations, and cardiovascular disease risk factors in a large, representative sample of the general population. DESIGN: Five hundred eighty-six men and 734 women were randomly selected from the inhabitants of 2 small towns near Florence, Italy. RESULTS: After adjustment for multiple potential confounders, interleukin 1 receptor antagonist (IL-1ra) and interleukin 6 (IL-6) concentrations were significantly (P < 0.001) associated with plasma homocysteine concentrations in older (>65 y) populations. Compared with participants in the lowest IL-6 tertile, those in the highest tertile had a higher risk of having homocysteine concentrations that were high (>30 micromol/L; odds ratio: 2.6; 95% CI: 1.1, 5.6; P = 0.024) or in the intermediate range 15-30 micromol/L (odds ratio: 1.6; 95% CI: 1.2, 2.2; P = 0.0014). Sedentary state, intakes of vitamin B-6 and folic acid, and serum folate, vitamin B-12, vitamin B-6, and alpha-tocopherol concentrations were significant independent correlates of homocysteine. CONCLUSIONS: High circulating concentrations of IL-1ra and IL-6 are independent correlates of hyperhomocysteinemia and may explain, at least in part, the association between homocysteine and atherosclerosis.

Chlamydia pneumoniae seropositivity and cardiovascular risk factors: The InCHIANTI Study.

OBJECTIVES: To assess the prevalence of Chlamydia pneumoniae (CP) seropositivity and test the hypothesis that CP infection (CPI) is associated with cardiovascular (CV) risk factors and levels of inflammatory biomarkers. DESIGN: Cross-sectional survey. SETTING: Representative sample of the residents of Greve in Chianti and Bagno a Ripoli, two small towns located in the Chianti geographic area (Tuscany, Italy). PARTICIPANTS: A total of 1,304 (age-range: 20-103, 79% aged> or =65) participants of the InCHIANTI study. MEASUREMENTS: CP seropositivity was assessed using immunofluorescence. Previous CPI was defined as immunoglobulin (Ig) G > or =1/16 and <1/256, and recent CPI was defined as IgG > or =1/512 or IgM > or =1/16. Inflammatory markers included interleukin (IL)-6, soluble IL-6 receptor (sIL-6r), tumor necrosis factor-alpha (TNF-alpha), IL-1beta, IL-1 receptor antagonist (IL-1ra), iron, ferritin, and C-reactive protein (CRP). CV risk factors included smoking, body mass index (BMI), lipid profile, and hypertension. RESULTS: The prevalence of CP seropositivity was 75%, increased with age, and was higher in men than in women (P<.01). CPI was not associated with IL-1beta, IL-1ra, iron, ferritin, CRP, BMI, lipids, and smoking. After adjusting for age and sex, previous or recent CPI was associated with higher TNF-alpha (P<.01), IL-6 (P<.03), sIL-6R (P<.01), and hypertension (P<.02). In additional age and sex-adjusted models, the associations between CPI and TNF-alpha, IL-6, sIL-6r, and hypertension appeared to be mutually independent. CONCLUSION: CP seropositivity is highly prevalent in the older population and is a significant, independent correlate of hypertension and circulating levels of TNF-alpha, IL-6, and sIL-6r.

Anemia is associated with disability and decreased physical performance and muscle strength in the elderly.

OBJECTIVES: To examine the association between anemia and disability, physical performance, and muscle strength in older persons. DESIGN: Cross-sectional. SETTING: Community-dwelling older persons in the Chianti area in Italy. PARTICIPANTS: A total of 1,156 persons aged 65 and older participating in the InChianti Study ("Invecchiare in Chianti," i.e., Aging in the Chianti Area). MEASUREMENTS: Anemia was defined according to World Health Organization criteria as a hemoglobin concentration below 12 g/dL in women and below 13 g/dL in men. Disability in six basic and eight instrumental activities of daily living was assessed. Physical performance was assessed using the short physical performance battery (4-m walk, balance, and chair stands), which yields a summary performance score ranging from 0 to 12 (high). Muscle strength was determined using knee extensor and handgrip strength assessments. RESULTS: Overall, 11.1% of the men and 11.5% of the women had anemia. After adjustment for age, sex, body mass index, Mini-Mental State Examination score, creatinine level, and presence of various comorbid conditions, anemic persons had more disabilities (1.71 vs 1.04, P=.002) and poorer performance (8.8 vs 9.6, P=.003) than persons without anemia. Anemic persons also had significantly lower knee extensor strength (14.1 vs 15.2 kg, P=.02) and lower handgrip strength (25.3 vs 27.1 kg, P=.04) than persons without anemia. Further adjustment for inflammatory markers (interleukin-6, C-reactive protein, tumor necrosis factor-alpha) did not change these associations. CONCLUSION: Anemia is associated with disability, poorer physical performance, and lower muscle strength. Further research should explore whether treating anemia has a beneficial effect on the functional status of older persons.

Is chronic inflammation a determinant of blood pressure in the elderly?

BACKGROUND: Previous studies have shown that a rise in blood pressure (BP) causes chronic inflammation of the endothelium which, in turn, may be responsible for further damage of endothelium and worsening of BP control. On the other hand, several metabolic abnormalities such as dyslipidemia, hyperinsulinemia/insulin-resistance, diabetes, and obesity causes inflammation followed by a later rise in arterial BP. We investigated the role of chronic inflammation in the modulation of BP independently of other traditional cardiovascular risk factors and atherosclerotic lesions. METHODS: A total of 537 aged subjects, selected from the whole population of the INCHIANTI cohort, were enrolled. All subjects underwent plasma insulin, glucose, interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-1 beta (IL-1 beta), interleukin-1 receptor antagonist (IL-1ra), C-reactive protein, and tumor necrosis factor-alpha (TNF-alpha) levels determination. The IL-6-174 C/G promoter polymorphism was also evaluated. RESULTS: After adjusting for age, sex, insulin resistance syndrome score, and severity of carotid atherosclerosis, serum IL-1 beta (P <.001), IL-1ra (P <.005) concentration and the insulin resistance syndrome score (P <.001) were the only predictors of diastolic BP. Indeed, age (P <.001), insulin resistance syndrome score (P =.05), IL-1 beta (P <.05), and severity of carotid atherosclerosis (P <.05) were the only significant predictor of systolic BP. CONCLUSION: These results suggest that chronic inflammation may play a role in the modulation of arterial BP.

Inflammatory markers and physical performance in older persons: the InCHIANTI study.

BACKGROUND: Some studies have proposed chronic inflammation as an underlying biological mechanism responsible for physical function decline in elderly people. The aim of this study is to evaluate the relationship between several inflammatory markers and physical performance in an older population. METHODS: This study is part of the "Invecchiare in Chianti" (InCHIANTI) study, a prospective population-based study of older people, aimed at identifying risk factors for late-life disability. The study sample consisted of 1020 participants aged 65 years and older living in the Chianti area of Italy. Physical performance was assessed using walking speed, the chair-stand test, and the standing balance test. Hand-grip strength was assessed using a hand-held dynamometer. Serum levels of C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor-alpha (TNF-alpha), IL-10, IL-1beta, IL-6sR, and IL-1RA were determined. Linear regression analyses were used to assess the multivariate relationship of inflammatory marker levels with physical performance, scored as a continuous variable from 0 to 3, and hand-grip strength after adjustment for demographics, chronic conditions, medication use, and other biological variables. RESULTS: CRP, IL-6, and IL1RA were significantly correlated with physical performance (r=-0.162, r=-0.251, and r=-0.127, respectively). Significant correlations with hand-grip strength were found for CRP and IL-6 (r=-0.081 and r=-0.089, respectively). After adjustment for covariates, high levels of IL-6 and IL-1RA continued to be strongly associated with worse physical performance (p<.001 and p=0.004, respectively). High levels of CRP (p<.001) and IL-6 (p<.001) were associated with low hand-grip strength. Mean adjusted physical performance scores ranged from 2.21 in the CRP<0.59 mg/dl group to 2.07 in the CRP>0.60 mg/dl group (p for trend=.004), and from 2.25 in the lowest IL-6 quartile to 2.08 in the highest IL-6 quartile (p for trend<.001). This trend was also reflected in mean adjusted hand-grip strength, with a range from 28.8 kg for the CRP<0.59 mg/dl group to 26.0 kg for the CRP>0.60 mg/dl group (p for trend=.001), and from 27.4 kg for the lowest IL-6 quartile to 25.1 kg for the highest IL-6 quartile (p for trend=.001). CONCLUSIONS: Inflammation, measured as high levels of IL-6, CRP, and IL-1RA, is significantly associated with poor physical performance and muscle strength in older persons. These data also support the biological face validity of physical performance measures. The assessment of inflammatory markers may represent a useful screening test and perhaps a potential target of intervention.