Lifestyle Moderates Genetic Risk of Venous Thromboembolism: The ARIC Study.

OBJECTIVE: Venous thromboembolism (VTE) is a common disease that has a genetic basis. Lifestyle factors contribute to risk, but it is unknown whether healthy lifestyle can mitigate the genetic risk. We studied whether greater adherence to the American Heart Association's cardiovascular health metric, Life's Simple 7 (LS7), is associated with lower incidence of VTE in individuals across categories of a genetic risk score (GRS) for VTE. Approach AND RESULTS: We followed 9026 White participants from the ARIC (Atherosclerosis Risk in Communities) Study, a prospective cohort enrolled in 1987 to 1989 until 2015. We tested the joint associations with VTE of a validated VTE GRS comprising 5 well-known gene variants and baseline LS7 categories. There were 466 incident VTE events over 22.8 years. Participants with an optimal LS7 score had a lower incidence of VTE (3.9%) than those with inadequate LS7 (5.7%). Compared with the high GRS and inadequate LS7 group (hazard ratio=1), those with high GRS and optimal LS7 indeed had a reduced hazard ratio of VTE: 0.65 (95% CI, 0.48-0.89). The group with low GRS and optimal LS7 had the lowest hazard ratio of VTE (0.39 [95% CI, 0.25-0.61]). Of the LS7 components, in all GRS groups, the factor most strongly protective for VTE was normal weight. CONCLUSIONS: Among people at low or high genetic risk for VTE, healthier lifestyle factors, particularly normal weight, were associated with a lower incidence of VTE. Further studies should determine the impact of lifestyle changes among patients at high genetic risk of VTE, such as in thrombophilic families.

Associations of Calcium, Vitamin D, and Dairy Product Intakes with Colorectal Cancer Risk among Older Women: The Iowa Women's Health Study.

Calcium and, to a lesser extent, dairy products are consistently modestly inversely associated with colorectal cancer (CRC). Dairy products may contain components other than calcium and fat, such as insulin-like growth factor-1, that may affect CRC risk. In the prospective Iowa Women's Health Study, calcium, dairy product, and vitamin D intakes were assessed using a semiquantitative food frequency questionnaire. To investigate dairy products independent of their calcium components, we estimated residuals from linear regression models of their associations with dietary calcium. Of the 35,221 55-69-year-old cancer-free women at baseline in 1986, 1,731 developed CRC during follow-up through 2012. For those in the highest relative to the lowest intake quintiles, the adjusted hazards ratios and 95% confidence intervals from multivariable Cox proportional hazards regression models for overall and distal CRC were 0.81 (0.67-0.98; Ptrend = 0.004) and 0.59 (0.44-0.80; Ptrend = 0.003), respectively, for total calcium; and 0.79 (0.66-0.94; Ptrend = 0.01) and 0.69 (0.53-0.90; Ptrend = 0.003) for total dairy products, respectively. The various dairy product residuals were not associated with CRC. These results support that, among women, calcium and dairy products may be inversely associated with CRC-perhaps primarily distal CRC-but suggest that the non-calcium, non-fat component of dairy products may not be associated with CRC.

Associations of calcium and dairy product intakes with all-cause, all-cancer, colorectal cancer and CHD mortality among older women in the Iowa Women's Health Study.

Ca and dairy product intakes may be inversely associated with all-cause and cause-specific mortality, and non-Ca components of dairy products, such as insulin-like growth factor-1, may be independently associated with mortality. We investigated associations of Ca and dairy product intakes with all-cause, all-cancer, colorectal cancer (CRC) and CHD mortality among 35 221 55- to 69-year-old women in the prospective Iowa Women's Health Study, who were cancer-free in 1986. We assessed diet using a Willett FFQ, and associations using multivariable Cox proportional hazards regression. We estimated residuals from linear regression models of dairy products with dietary Ca to investigate total and specific dairy products independent of their Ca content. Through 2012, 18 687 participants died, including 4665 from cancer (including 574 from CRC) and 3603 from CHD. For those in the highest relative to the lowest quintiles of intake, the multivariable-adjusted hazard ratios (HR) and 95 % CI for total Ca (dietary plus supplemental) were 0·88 (0·83, 0·93; P trend=0·001) for all-cause mortality, 0·91 (0·81, 1·02; P trend=0·34) for all-cancer mortality, 0·60 (0·43, 0·83; P trend=0·002) for CRC mortality and 0·73 (0·64, 0·83; P trend <0·0001) for CHD mortality. The corresponding HR for associations of whole milk, whole milk residuals, and low-/non-fat milk residuals with all-cause mortality were 1·20 (95 % CI 1·13, 1·27), 1·20 (95 % CI 1·13, 1·28) and 0·91 (95 % CI 0·86, 0·96), respectively. These results suggest that Ca may be associated with lower risk of all-cause, CRC and CHD mortality, and that non-Ca components of milk may be independently associated with mortality.

Effects of smoking on the genetic risk of obesity: the population architecture using genomics and epidemiology study.

BACKGROUND: Although smoking behavior is known to affect body mass index (BMI), the potential for smoking to influence genetic associations with BMI is largely unexplored. METHODS: As part of the 'Population Architecture using Genomics and Epidemiology (PAGE)' Consortium, we investigated interaction between genetic risk factors associated with BMI and smoking for 10 single nucleotide polymorphisms (SNPs) previously identified in genome-wide association studies. We included 6 studies with a total of 56,466 subjects (16,750 African Americans (AA) and 39,716 European Americans (EA)). We assessed effect modification by testing an interaction term for each SNP and smoking (current vs. former/never) in the linear regression and by stratified analyses. RESULTS: We did not observe strong evidence for interactions and only observed two interactions with p-values <0.1: for rs6548238/TMEM18, the risk allele (C) was associated with BMI only among AA females who were former/never smokers (ß = 0.018, p = 0.002), vs. current smokers (ß = 0.001, p = 0.95, p(interaction) = 0.10). For rs9939609/FTO, the A allele was more strongly associated with BMI among current smoker EA females (ß = 0.017, p = 3.5 x 10(-5)), vs. former/never smokers (ß = 0.006, p = 0.05, p(interaction) = 0.08). CONCLUSIONS: These analyses provide limited evidence that smoking status may modify genetic effects of previously identified genetic risk factors for BMI. Larger studies are needed to follow up our results. CLINICAL TRIAL REGISTRATION: NCT00000611.

Prediction of venous thromboembolism incidence in the general adult population using two published genetic risk scores.

INTRODUCTION: Most strategies for prevention of venous thromboembolism focus on preventing recurrent events. Yet, primary prevention might be possible through approaches targeting the whole population or high-risk patients. To inform possible prevention strategies, population-based information on the ability of genetic risk scores to identify risk of incident venous thromboembolism is needed. MATERIALS AND METHODS: We used proportional hazards regression to relate two published genetic risk scores (273-variants versus 5-variants) with venous thromboembolism incidence in the Atherosclerosis Risk in Communities Study (ARIC) cohort (n = 11,292), aged 45-64 at baseline, drawn from 4 US communities. RESULTS: Over a median of 28 years, ARIC identified 788 incident venous thromboembolism events. Incidence rates rose more than two-fold across quartiles of the 273-variant genetic risk score: 1.7, 2.7, 3.4 and 4.0 per 1,000 person-years. For White participants, age, sex, and ancestry-adjusted hazard ratios (95% confidence intervals) across quartiles were strong [1 (reference), 1.30 (0.99,1.70), 1.85 (1.43,2.40), and 2.58 (2.04,3.28)] but weaker for Black participants [1, 1.05 (0.63,1.75), 1.37 (0.84,2.22), and 1.32 (0.80,2.20)]. The 5-variant genetic risk score showed a less steep gradient, with hazard ratios in Whites of 1, 1.17 (0.89,1.54), 1.48 (1.14,1.92), and 2.18 (1.71,2.79). Models including the 273-variant genetic risk score plus lifestyle and clinical factors had a c-statistic of 0.67. CONCLUSIONS: In the general population, middle-aged adults in the highest quartile of either genetic risk score studied have approximately two-fold higher risk of an incident venous thromboembolism compared with the lowest quartile. The genetic risk scores show a weaker association with venous thromboembolism for Black people.

Changes in insulin resistance and cardiovascular risk during adolescence: establishment of differential risk in males and females.

BACKGROUND: Developmental changes in insulin resistance and cardiovascular risk were studied in youths 11 to 19 years of age. METHODS AND RESULTS: A cohort was randomly selected after blood pressure screening of Minneapolis, Minn, school children. Studies were done 3 times on this cohort and once on their siblings (996 observations on 507 individuals from 363 families). Insulin sensitivity was determined by euglycemic clamp. Body mass index and waist circumference increased similarly in both sexes from ages 11 to 19 years. Body fat decreased in males and increased in females (P<0.001). Lean body mass increased at a steeper rate in males (P<0.0001). Insulin resistance was lower in males at 11 years but increased steadily to 19 years (P=0.003); in contrast, it did not increase in females. Thus, despite being less insulin resistant at 11 years and decreasing in fatness during puberty, males became more insulin resistant than females by 19 years of age. Triglycerides increased in males and high-density lipoprotein cholesterol decreased, whereas the opposite pattern was seen in females, which resulted in higher triglycerides and lower high-density lipoprotein cholesterol in males at 19 years. No gender difference in low-density lipoprotein or total cholesterol was seen. Systolic blood pressure increased in both sexes but at a greater rate in boys (P=0.03). CONCLUSIONS: During the transition from late childhood through adolescence, insulin resistance in males increased in association with increased triglycerides and decreased high-density lipoprotein cholesterol, despite a concurrent reduction in body fatness, whereas the opposite occurred in females. These gender-related developmental changes in insulin resistance, which were independent from changes in fatness, total cholesterol, and low-density lipoprotein cholesterol, are consistent with an early role for insulin resistance in the increased cardiovascular risk found in males.

Reasons for Differences in the Incidence of Venous Thromboembolism in Black Versus White Americans.

INTRODUCTION: Venous thromboembolism incidence rates are 30%-100% higher in US blacks than whites. We examined the degree to which differences in the frequencies of socioeconomic, lifestyle, medical risk factors, and genetic variants explain the excess venous thromboembolism risk in blacks and whether some risk factors are more strongly associated with venous thromboembolism in blacks compared with whites. METHODS: We measured venous thromboembolism risk factors in black and white participants of the Atherosclerosis Risk in Communities study in 1987-1989 and followed them prospectively through 2015 for venous thromboembolism incidence. RESULTS: Over a mean of 22 years, we identified 332 venous thromboembolisms in blacks and 578 in whites, yielding 65% higher crude incidence rates per 1000 person-years in blacks. The age and sex-adjusted hazard ratio (95% confidence interval) of venous thromboembolism for blacks compared with whites was 2.04 (1.76, 2.37) for follow-up >10 years and was attenuated to 1.14 (0.89, 1.46) when adjusted for baseline confounders or mediators of the race association, which tended to be more common in blacks. For example, adjustment for just baseline weight, family income, and concentration of plasma factor VIII reduced the regression coefficient for race by 75%. There were no significant (P <0.05) 2-way multiplicative interactions of race with any risk factor, except with a 5-single nucleotide polymorphism (5-SNP) genetic risk score (a weaker venous thromboembolism risk factor in blacks) and with hospitalization for heart failure (a stronger venous thromboembolism risk factor in blacks). CONCLUSION: The higher incidence rate of venous thromboembolism in blacks than whites was mostly explained by blacks having higher frequencies of venous thromboembolism risk factors.

Flavonoid intake and cardiovascular disease mortality: a prospective study in postmenopausal women.

BACKGROUND: Dietary flavonoids may have beneficial cardiovascular effects in human populations, but epidemiologic study results have not been conclusive. OBJECTIVE: We used flavonoid food composition data from 3 recently available US Department of Agriculture databases to improve estimates of dietary flavonoid intake and to evaluate the association between flavonoid intake and cardiovascular disease (CVD) mortality. DESIGN: Study participants were 34 489 postmenopausal women in the Iowa Women's Health Study who were free of CVD and had complete food-frequency questionnaire information at baseline. Intakes of total flavonoids and 7 subclasses were categorized into quintiles, and food sources were grouped into frequency categories. Proportional hazards rate ratios (RR) were computed for CVD, coronary heart disease (CHD), stroke, and total mortality after 16 y of follow-up. RESULTS: After multivariate adjustment, significant inverse associations were observed between anthocyanidins and CHD, CVD, and total mortality [RR (95% CI) for any versus no intake: 0.88 (0.78, 0.99), 0.91 (0.83, 0.99), and 0.90 (0.86, 0.95)]; between flavanones and CHD [RR for highest quintile versus lowest: 0.78 (0.65, 0.94)]; and between flavones and total mortality [RR for highest quintile versus lowest: 0.88 (0.82, 0.96)]. No association was found between flavonoid intake and stroke mortality. Individual flavonoid-rich foods associated with significant mortality reduction included bran (added to foods; associated with stroke and CVD); apples or pears or both and red wine (associated with CHD and CVD); grapefruit (associated with CHD); strawberries (associated with CVD); and chocolate (associated with CVD). CONCLUSION: Dietary intakes of flavanones, anthocyanidins, and certain foods rich in flavonoids were associated with reduced risk of death due to CHD, CVD, and all causes.

Pancreatic cancer incidence in relation to female reproductive factors: Iowa Women's Health Study.

OBJECTIVE: Motivated by inconsistent literature, we evaluated the association between incident pancreatic cancer and reproductive characteristics. DESIGN: The Iowa Women's Health Study is a large prospective population-based cohort followed from 1986 to 2003. Reproductive information was self-reported. PARTICIPANTS: The study population comprised 37,459 women aged 55-69 years at baseline. Over 18 years, 228 incident pancreatic cancers were identified. RESULTS: In a multivariate-adjusted model there were no associations between incident pancreatic cancer and age at first birth, number of births, age at menarche, or use of hormones. There was a statistically significant inverse association between age at menopause and pancreatic cancer incidence. Compared to menopause less than 45 years, the hazard ratio of pancreatic cancer was 0.61 (95% CI, 0.40-0.94) for menopause at 45-49 years, 0.75 (95% CI, 0.51-1.09) for 50-54 years, and 0.35 (95% CI, 0.18-0.68) for menopause at 55 years or more (P trend=0.005). This association held after restricting the cohort to never smokers. The associations between pancreatic cancer and ages at natural and surgical menopause followed similar patterns. In a parallel fashion, risk of pancreatic cancer was decreased for women with intact ovaries compared to those who had oophorectomy: hazard ratio was 0.70 (95% CI, 0.50-0.99). CONCLUSIONS: Our results indicate that older age at menopause is associated with reduced pancreatic cancer risk, but further research is warranted.

Relation of C-reactive protein to insulin resistance and cardiovascular risk factors in youth.

OBJECTIVE: Insulin resistance and C-reactive protein (CRP) levels are strongly correlated in adults. This study explored the relationship in youth. RESEARCH DESIGN AND METHODS: Associations between CRP levels, cardiovascular risk, and insulin resistance measured by the euglycemic clamp were investigated in 342 healthy Minneapolis youth. RESULTS: There was no difference in mean CRP levels among boys (n = 189, CRP 1.10 +/- 0.46 mg/l) and girls (n = 153, CRP 1.16 +/- 0.63 mg/l; P = 0.32). There was also no difference between CRP and Tanner stage. CRP, adjusted for BMI, was significantly greater in black subjects compared with white subjects (P = 0.03). CRP was strongly related to adiposity in both girls and boys. CRP levels were related to fasting insulin levels (r = 0.16, P = 0.003) but this association was not significant after adjustment for BMI (r = 0.07, P = 0.21). Similarly, M, the euglycemic clamp measurement of insulin sensitivity, was significantly related to CRP levels (r = -0.13, P = 0.02) but not when M was normalized to lean body mass (M(lbm)) (r = -0.10, P = 0.09). There was a significant inverse correlation between M(lbm) and CRP quartiles, which disappeared after adjustment for BMI. There was no significant association between CRP levels and lipids, blood pressure, physical activity, or left ventricular mass. CONCLUSIONS: In contrast to adult subjects, after adjustment for adiposity, CRP levels in children age 10-16 years were not significantly associated with insulin resistance or with other factors comprising the metabolic syndrome. This is consistent with the concept that insulin resistance may precede the development of CRP elevation in the evolution of the metabolic syndrome.

Diabetes mellitus and subsite-specific colorectal cancer risks in the Iowa Women's Health Study.

OBJECTIVE: Controversy remains regarding the association between type 2 diabetes mellitus (DM) and colorectal cancer (CRC) risk. To clarify and extend the existing data, we prospectively evaluated the association between self-reported type 2 DM (onset at >30 years of age) and incident CRC, overall and by anatomic subsite, among postmenopausal women in the Iowa Women's Health Study (n = 35,230). METHODS: After 14 years of follow-up, a total of 870 incident CRC cases were identified through annual linkage to the Iowa Cancer Registry. DM was analyzed as reported at baseline and as a time-dependent variable using information obtained during follow-up. CRC risks were estimated using Cox proportional hazards regression models. RESULTS: After adjusting for age, body mass index and other potential confounding variables, the relative risk (RR) for women with DM versus women without DM was modestly increased at 1.4 [95% confidence interval (95% CI), 1.1-1.8]. By anatomic subsite, the RR for proximal colon cancer was statistically significantly increased (RR, 1.9; 95% CI, 1.3-2.6), whereas the RRs for distal colon (RR, 1.1; 95% CI, 0.6-1.8) and rectal cancer (RR, 0.8; 95% CI, 0.4-1.6) were not statistically different from unity. Analyses that included DM ascertained at baseline and follow-up yielded similar results. CONCLUSION: In this large, prospective study of postmenopausal women, the association between DM and incident CRC was found to be subsite specific. If confirmed by others, this finding implies that CRC prevention strategies among type 2 DM patients should include examination of the proximal colon.

Association between the insulin resistance of puberty and the insulin-like growth factor-I/growth hormone axis.

To test the hypothesis that the relative insulin resistance of puberty is associated with changes in IGF-I levels, we compared IGF-I, IGF binding protein-3 (IGFBP-3), and IGFBP-1 levels to insulin resistance [M(lbm), milligrams glucose used per kilogram of lean body mass (LBM) per minute] measured during euglycemic, hyperinsulinemic clamp studies in 342 children and adolescents. IGF-I levels rose and fell during the Tanner stages of puberty in a pattern that closely followed the rise and fall of insulin resistance. IGF-I levels were significantly related to M(lbm) in boys (P = 0.0006) and girls (P = 0.02). IGF-I was significantly related to fasting insulin levels only in girls (P = 0.006; boys, P = 0.26), and this relation was significantly influenced in girls by body fat (P = 0.007), with the strongest association between IGF-I and fasting insulin seen in thin girls. IGFBP-1 correlated negatively with insulin resistance in both boys (P = 0.0004) and girls (P = 0.04), whereas IGFBP-3 correlated positively with insulin resistance in boys (P = 0.0004) but not girls (P = 0.85). These data suggest that the GH/IGF-I axis is an important contributor to the insulin resistance of puberty.

Multiancestral analysis of inflammation-related genetic variants and C-reactive protein in the population architecture using genomics and epidemiology study.

BACKGROUND: C-reactive protein (CRP) is a biomarker of inflammation. Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) associated with CRP concentrations and inflammation-related traits such as cardiovascular disease, type 2 diabetes mellitus, and obesity. We aimed to replicate previous CRP-SNP associations, assess whether these associations generalize to additional race/ethnicity groups, and evaluate inflammation-related SNPs for a potentially pleiotropic association with CRP. METHODS AND RESULTS: We selected and analyzed 16 CRP-associated and 250 inflammation-related GWAS SNPs among 40 473 African American, American Indian, Asian/Pacific Islander, European American, and Hispanic participants from 7 studies collaborating in the Population Architecture using Genomics and Epidemiology (PAGE) study. Fixed-effect meta-analyses combined study-specific race/ethnicity-stratified linear regression estimates to evaluate the association between each SNP and high-sensitivity CRP. Overall, 18 SNPs in 8 loci were significantly associated with CRP (Bonferroni-corrected P<3.1×10(-3) for replication, P<2.0×10(-4) for pleiotropy): Seven of these were specific to European Americans, while 9 additionally generalized to African Americans (1), Hispanics (5), or both (3); 1 SNP was seen only in African Americans and Hispanics. Two SNPs in the CELSR2/PSRC1/SORT1 locus showed a potentially novel association with CRP: rs599839 (P=2.0×10(-6)) and rs646776 (P=3.1×10(-5)). CONCLUSIONS: We replicated 16 SNP-CRP associations, 10 of which generalized to African Americans and/or Hispanics. We also identified potentially novel pleiotropic associations with CRP for two SNPs previously associated with coronary artery disease and/or low-density lipoprotein-cholesterol. These findings demonstrate the benefit of evaluating genotype-phenotype associations in multiple race/ethnicity groups and looking for pleiotropic relationships among SNPs previously associated with related phenotypes.

Predicting cardiovascular risk in young adulthood from the metabolic syndrome, its component risk factors, and a cluster score in childhood.

OBJECTIVE: The value of metabolic syndrome (MetS) in childhood and adolescence and its stability into young adulthood have been questioned. This study compared the MetS in late childhood (mean age 13) versus a cluster score of the MetS components as predictors of young adult (mean age 22) cardiovascular risk. METHODS: Anthropometrics, blood pressure, lipid profile, and insulin resistance (insulin clamp) were obtained in 265 individuals at mean ages 13 and 22. The MetS was defined dichotomously by current pediatric and adult criteria. The MetS cluster score used the average of deviates of the MetS components standardized to their means and standard deviations at mean age 13. RESULTS: The MetS was rarely present at mean age 13 and did not predict MetS at mean age 22 but identified individuals who continued to have adverse levels of risk factors at mean age 22. In contrast to the standard MetS definition, the MetS cluster score tracked strongly and at mean age 22 was significantly higher in the individuals with MetS at mean age 13 (0.78 ± 0.71) than those without MetS at mean age 13 (0.09 ± 0.70, p <0.0001). CONCLUSIONS: Although the MetS at mean age 13, using the conventional definition, is not a reliable method for predicting the MetS at mean age 22, it does predict adverse levels of cardiovascular risk factors. A cluster score, using the MetS components as continuous variables, is more reliable in predicting young adult risk from late childhood.

Obesity modifies the relations between serum markers of dairy fats and inflammation and oxidative stress among adolescents.

Pentadecanoic acid (15:0) and heptadecanoic acid (17:0), the dairy-specific saturated fatty acids have been inversely, while inflammation and oxidative stress have been positively related to the risk of cardiovascular disease (CVD). Both fatty acid metabolism and inflammation and oxidative stress may be influenced by adiposity. In the current cross-sectional analyses among adolescents (mean age 15 years), we determined whether overweight status modified the associations between dairy fatty acids (pentadecanoic acid (15:0) and heptadecanoic acid (17:0)) represented in serum phospholipids (PL) and markers of inflammation and oxidative stress. Six biomarkers for inflammation and oxidative stress were analyzed, including circulating adiponectin, C-reactive protein (CRP), cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), and urinary 15-keto-dihydro-PGF2α (15-keto) and 8-iso-PGF2α (F2-iso). Generalized linear regression analyses, adjusted for age, gender, race, tanner score, total energy intake and physical activity, revealed that PL dairy fatty acids were inversely associated with CRP, F2-iso and 15-keto in overweight, but not in normal weight adolescents (all P(interaction) < 0.05). However, higher level of PL dairy fatty acids was associated with lower IL-6 among all adolescents. Further adjustment for dietary intake of calcium, vitamin D, protein, total flavonoids, and ω-3 fatty acids did not materially change the findings. Dairy-specific saturated fats, i.e., 15:0 and 17:0 fatty acids, may contribute to the potential health benefits of dairy products, especially for overweight adolescents.

Fruit and vegetable consumption and its relation to markers of inflammation and oxidative stress in adolescents.

BACKGROUND: Fruits and vegetables, foods rich in flavonoids and antioxidants, have been associated with lower risk of stroke, coronary heart disease, and markers of inflammation and oxidative stress in adults. Markers of inflammation and oxidative stress are predictors of coronary heart disease risk; however, it is unknown whether these markers are related to dietary flavonoid and antioxidant intake in youth. OBJECTIVE: To determine whether greater intakes of fruit and vegetables, antioxidants, folate, and total flavonoids were inversely associated with markers of inflammation and oxidative stress in 285 adolescent boys and girls aged 13 to 17 years. DESIGN: In this cross-sectional study conducted between February 1996 and January 2000, diet was assessed by a 127-item food frequency questionnaire. Height and weight measurements were obtained and a fasting blood sample drawn. Spearman partial correlation analyses evaluated the relation of intakes of fruit and vegetables, antioxidants, folate, and flavonoids with markers of inflammation (C-reactive protein, interleukin-6, tumor necrosis factor-alpha, and 15-keto-dihydro-PGF(2alpha) metabolite and oxidative stress (urinary 8-iso prostaglandin F(2alpha), an F(2)-isoprostane), adjusting for age, sex, race, Tanner stage, energy intake, and body mass index. RESULTS: Urinary F(2)-isoprostane was inversely correlated with intakes of total fruit and vegetables, vitamin C, beta carotene, and flavonoids. Serum C-reactive protein was significantly inversely associated with intakes of fruit (r=-0.19; P=0.004), vitamin C (r=-0.13, P=0.03), and folate (r=-0.18; P=0.004). Serum interleukin-6 was inversely associated with intakes of legumes, vegetables, beta carotene, and vitamin C. Serum tumor necrosis factor-alpha was inversely associated with beta carotene (r=-0.14, P=0.02) and luteolin (r=-0.15, P=0.02). CONCLUSION: Study results show that the beneficial effects of fruit and vegetable intake on markers of inflammation and oxidative stress are already present by early adolescence and provide support for the Dietary Guidelines for Americans "to consume five or more servings per day" of fruits and vegetables to promote beneficial cardiovascular health.

Measurement of insulin sensitivity in children: comparison between the euglycemic-hyperinsulinemic clamp and surrogate measures.

OBJECTIVE: In this study we compared fasting insulin and measures of insulin sensitivity (M) based on fasting insulin and glucose (i.e., homeostasis model assessment [HOMA], quantitative insulin sensitivity check index [QUICKI], and fasting glucose-to-insulin ratio [FGIR]) or triglycerides to the insulin clamp in a cohort of children/adolescents. RESEARCH DESIGN AND METHODS: The subjects were Minneapolis fifth- to eighth-grade students. Euglycemic-hyperinsulinemic clamps were performed on 323 adolescents at mean age 13 and were repeated on 300 of these subjects at mean age 15. Insulin sensitivity was determined by glucose uptake (milligrams per kilogram per minute) adjusted for lean body mass (M(LBM)) and steady-state insulin (M(LBM)/ln SSI). Comparisons were made for the whole cohort and by body size (BMI < 85th percentile vs. BMI > or = 85th percentile). Receiver operating characteristic (ROC) curves were used to test whether specific fasting insulin cut points separated true-positive from false-positive approximations of insulin resistance. RESULTS: Fasting insulin was significantly correlated with HOMA (r = 0.99), QUICKI (r = 0.79), FGIR (r = -0.62), and (ln fasting insulin + ln triglycerides) (r = 0.88). Correlations of the surrogates with M(LBM) were significantly lower than those with M for the total cohort and > or = 85th percentile group. In general, correlations in the > or = 85th percentile group were higher than those in the < 85th percentile group. Correlations with M(LBM) and M(LBM)/ln SSI decreased in the total cohort and > or = 85th percentile group from age 13 to 15. ROC curves showed only a modest capability to separate true- from false-positive values. CONCLUSIONS: Surrogate measures are only modestly correlated with the clamp measures of insulin sensitivity and do not offer any advantage over fasting insulin. In general, lower correlations are seen with M(LBM) than with M and with thinner than with heavier individuals.