Plasminogen activator inhibitor-1 is associated with leukocyte telomere length in American Indians: findings from the Strong Heart Family Study.

Essentials Plasminogen activator inhibitor-1 (PAI-1) advanced cellular senescence in experiment studies. No population study exists on the association between PAI-1 and biological aging in American Indians. We found cross-sectional and longitudinal associations between higher PAI-1 and shorter telomere length. Our findings suggest a pathway linking PAI-1 with biological aging beyond metabolic factors. SUMMARY: Background Plasminogen activator inhibitor-1 (PAI-1) promotes cellular aging both in vitro and in vivo. Telomere length is a marker of biological aging. Objectives To examine the cross-sectional and longitudinal associations between plasma PAI-1 and leukocyte telomere length in a large-scale epidemiological study of American Indians. Methods We measured leukocyte telomere length (LTL) and plasma PAI-1 in 2560 American Indians who were free of overt cardiovascular disease (CVD) and participated in the Strong Heart Family Study (SHFS) clinical examination in 2001-2003. LTL and PAI-1 were repeatedly measured in 475 participants who attended SHFS clinical visits in both 2001-2003 and 1998-1999. A generalized estimating equation model was used to examine the cross-sectional and longitudinal associations between PAI-1 and LTL, adjusting for known risk factors. Results A higher level of plasma PAI-1 was negatively associated with shorter age-adjusted LTL (ß = -0.023; 95% CI, -0.034 to -0.013). This association was attenuated (ß = -0.015; 95% CI, -0.029 to -0.002) after adjustments for demographics, study site, lifestyle (smoking, drinking and physical activity) and metabolic factors (obesity, blood pressure, fasting glucose, insulin, lipids and kidney function). Further adjustment for hsCRP did not change this association (ß = -0.015; 95% CI, -0.029 to -0.001). Longitudinal analysis revealed that change in plasma PAI-1 was also inversely associated with change in LTL after adjusting for demographics, follow-up years, lifestyle factors, changes in metabolic factors, baseline levels of PAI-1 and LTL (ß = -0.0005; 95% CI, -0.0009 to -0.0001). Conclusions A higher level of plasma PAI-1 was associated with shorter LTL in American Indians. This finding may suggest a potential role of PAI-1 in biological aging among American Indians.

Cadmium body burden and increased blood pressure in middle-aged American Indians: the Strong Heart Study.

Cadmium (Cd) is an environmental pollutant that has been associated with cardiovascular disease in populations, but the relationship of Cd with hypertension has been inconsistent. We studied the association between urinary Cd concentrations, a measure of total body burden, and blood pressure in American Indians, a US population with above national average Cd burden. Urinary Cd was measured using inductively coupled plasma mass spectrometry, and adjusted for urinary creatinine concentration. Among 3714 middle-aged American Indian participants of the Strong Heart Study (mean age 56 years, 41% male, 67% ever-smokers, 23% taking antihypertensive medications), urinary Cd ranged from 0.01 to 78.48 µg g-1 creatinine (geometric mean=0.94 µg g-1) and it was correlated with smoking pack-year among ever-smokers (r2=0.16, P<0.0001). Participants who were smokers were on average light-smokers (mean 10.8 pack-years), and urinary Cd was similarly elevated in light- and never-smokers (geometric means of 0.88 µg g-1 creatinine for both categories). Log-transformed urinary Cd was significantly associated with higher systolic blood pressure in models adjusted for age, sex, geographic area, body mass index, smoking (ever vs never, and cumulative pack-years) and kidney function (mean blood pressure difference by lnCd concentration (ß)=1.64, P=0.002). These associations were present among light- and never-smokers (ß=2.03, P=0.002, n=2627), although not significant among never-smokers (ß=1.22, P=0.18, n=1260). Cd was also associated with diastolic blood pressure among light- and never-smokers (ß=0.94, P=0.004). These findings suggest that there is a relationship between Cd body burden and increased blood pressure in American Indians, a population with increased cardiovascular disease risk.

Continuous Combined Estrogen Plus Progestin and Endometrial Cancer: The Women's Health Initiative Randomized Trial.

BACKGROUND: While progestin addition to estrogen mitigates endometrial cancer risk, the magnitude of the effect on incidence, specific endometrial cancer histologies, and endometrial cancer mortality remains unsettled. These issues were assessed by analyses after extended follow-up of the Women's Health Initiative (WHI) randomized clinical trial evaluating continuous combined estrogen plus progestin use. METHODS: The WHI enrolled 16 608 postmenopausal women into a randomly assigned, double-blind, placebo-controlled trial. Women age 50 to 79 years with intact uteri with normal endometrial biopsy at entry were randomly assigned to once-daily 0.625 mg conjugated equine estrogen plus 2.5mg medroxyprogesterone acetate (n = 8506) as a single pill or matching placebo (n = 8102). Follow-up beyond the original trial completion date required reconsent, obtained from 12 788 (83%) of surviving participants. Analyses were by intent-to-treat. All statistical tests were two-sided. RESULTS: After 5.6 years' median intervention and 13 years' median cumulative follow-up, there were fewer endometrial cancers in the combined hormone therapy compared with the placebo group (66 vs 95 case patients, yearly incidence, 0.06% vs 0.10%; hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.48 to 0.89, P = .007). While there were somewhat fewer endometrial cancers during intervention (25 vs 30, respectively; HR = 0.77, 95% CI = 0.45 to 1.31), the difference became statistically significant postintervention (41 vs 65, respectively; HR = 0.59, 95% CI = 0.40 to 0.88, P = .008), but hazard ratios did not differ between phases (P difference = .46). There was a statistically nonsignificant reduction in deaths from endometrial cancer in the estrogen plus progestin group (5 vs 11 deaths, HR = 0.42, 95% CI = 0.15 to 1.22). CONCLUSION: In postmenopausal women, continuous combined estrogen plus progestin decreases endometrial cancer incidence.

The impact of birth weight on cardiovascular disease risk in the Women's Health Initiative.

BACKGROUND AND AIMS: Cardiovascular disease (CVD) is among the leading causes of morbidity and mortality worldwide. Traditional risk factors predict 75-80% of an individual's risk of incident CVD. However, the role of early life experiences in future disease risk is gaining attention. The Barker hypothesis proposes fetal origins of adult disease, with consistent evidence demonstrating the deleterious consequences of birth weight outside the normal range. In this study, we investigate the role of birth weight in CVD risk prediction. METHODS AND RESULTS: The Women's Health Initiative (WHI) represents a large national cohort of post-menopausal women with 63,815 participants included in this analysis. Univariable proportional hazards regression analyses evaluated the association of 4 self-reported birth weight categories against 3 CVD outcome definitions, which included indicators of coronary heart disease, ischemic stroke, coronary revascularization, carotid artery disease and peripheral arterial disease. The role of birth weight was also evaluated for prediction of CVD events in the presence of traditional risk factors using 3 existing CVD risk prediction equations: one body mass index (BMI)-based and two laboratory-based models. Low birth weight (LBW) (<6 lbs.) was significantly associated with all CVD outcome definitions in univariable analyses (HR = 1.086, p = 0.009). LBW was a significant covariate in the BMI-based model (HR = 1.128, p < 0.0001) but not in the lipid-based models. CONCLUSION: LBW (<6 lbs.) is independently associated with CVD outcomes in the WHI cohort. This finding supports the role of the prenatal and postnatal environment in contributing to the development of adult chronic disease.

Sex differences in obesity prevalence and cardiometabolic factors among Western Alaska Native people.

BACKGROUND AND AIMS: Obesity is associated with increased risks of cardiovascular disease, type 2 diabetes, and other chronic diseases. Prevalence estimates for metabolic disorders are well documented in many populations, but Alaska Native groups are understudied. The Western Alaska Tribal Collaborative for Health Study combines data from three Alaska Native study cohorts to assess differences in obesity prevalence and associations with cardiometabolic risk factors by sex. METHODS AND RESULTS: Analyses were based upon a sample of 3985 adult Yup'ik and Inupiat participants with a mean age of 40 years. Prevalence of obesity and metabolic risk factors was assessed according to nationally recognized guidelines. Regression analysis was used to evaluate the association between obesity and cardiometabolic risk factors, including lipids, blood pressure and glucose. The prevalence of obesity (BMI ≥ 30) was significantly higher in women (40%) than men (20%). Only 18.6% of men had a waist circumference (WC) > 102 cm, while 58% of women had a WC > 88 cm (p < 0.001). Women had higher mean HDL-C and triglyceride levels compared to men, while systolic and diastolic blood pressure, LDL-C, and glucose means were higher in men than in women. In multivariate analyses, BMI and WC were significantly associated with all of the cardiometabolic risk factors, although these associations were more pronounced in men than women. CONCLUSION: The high prevalence of obesity and central adiposity among AN women is an important public health concern. Differences in associations between obesity and cardiometabolic risk factors by sex warrants further investigation to develop effective intervention programs.

Serum uric acid does not predict incident metabolic syndrome in a population with high prevalence of obesity.

AIM: To evaluate whether uric acid (UA) predicts 4-yr incidence of metabolic syndrome (MetS) in non-diabetic participants of the Strong Heart Study (SHS) cohort. METHODS AND RESULTS: In this population-based prospective study we analyzed 1499 American Indians (890 women), without diabetes or MetS, controlled during the 4th SHS exam and re-examined 4 years later during the 5th SHS exam. Participants were divided into sex-specific tertiles of UA and the first two tertiles (group N) were compared with the third tertile (group H). Body mass index (BMI = 28.3 ± 7 vs. 31.1 ± 7 kg/m(2)), fat-free mass (FFM = 52.0 ± 14 vs. 54.9 ± 11 kg), waist-to-hip ratio, HOMA-IR (3.66 vs. 4.26), BP and indices of inflammation were significantly higher in group H than in group N (all p < 0.001). Incident MetS at the time of the 5th exam was more frequent in group H than group N (35 vs. 28%, OR 1.44 (95% CI = 1.10-1.91; p < 0.01). This association was still significant (OR = 1.13, p = 0.04) independently of family relatedness, sex, history of hypertension, HOMA-IR, central adiposity and renal function, but disappeared when fat-free mass was included in the model. CONCLUSIONS: In the SHS, UA levels are associated to parameters of insulin resistance and to indices of inflammation. UA levels, however, do not predict incident MetS independently of the initial obesity-related increased FFM.

Ethnic differences in the relationship between birth weight and type 2 diabetes mellitus in postmenopausal women.

AIM: The objective of this study is to examine the relationship between self-reported birth weight and the adult occurrence of type 2 diabetes mellitus in a large multi-ethnic population of women. METHODS: Baseline data from the Women's Health Initiative Observational Study [n=75,993] was used to examine the association between participant birth weight category and prevalent type 2 diabetes mellitus. Models were adjusted for age, ethnicity, body mass index and other pertinent risk factors. Sub-analyses were performed stratifying by ethnicity. RESULTS: There was a strong inverse association between birth weight and type 2 diabetes mellitus with a birth weight of <6 pounds (lbs) (OR: 1.16, 95% CI: 1.01, 1.33) significantly associated with an increased risk of type 2 diabetes mellitus and a birth weight of ≥10 lbs (OR: 0.72, 95% CI: 0.57, 0.92) associated with a decreased risk of type 2 diabetes mellitus compared to women who reported their birth weight between 7 and 8 lbs 15 ounces (oz). Stratifying by ethnicity, the inverse association between birth weight and type 2 diabetes mellitus was only apparent in White women, but not Black, Hispanic or Asian women. CONCLUSION: Lower birth weight was associated with increased T2D risk in American White and Black post-menopausal women.

Cardiometabolic risk in overweight subjects with or without relative fat-free mass deficiency: the Strong Heart Study.

BACKGROUND AND AIM: Sarcopenia is a condition mainly due to loss of fat-free mass (FFM) in elderly individuals. RFFMD, however, is also frequent in obese subjects due to abnormal body composition. Objective of this study was to evaluate the impact of relative fat-free mass deficiency (RFFMD) on cardiometabolic (CM) risk in obese normoglycemic individuals. METHODS AND RESULTS: Overweight/obese American Indians from the Strong Heart Study population, without diabetes and with FBG ≤ 110 mg/dL and with GFR >60 mg/mL/1.73 m(2) were selected for this analysis (n = 742). RFFMD was defined on the basis of a multivariable equation previously reported. Fasting glucose and 2 h-OGTT were measured together with urine albumin/creatinine excretion, laboratory and anthropometric parameters. In addition to lower FFM and greater adipose mass, participants with RFFMD had higher body mass index, waist circumference, C-reactive protein, fibrinogen, insulin resistance and urinary albumin/creatinine than participants with normal FFM (all p < 0.001); they also had a greater prevalence of hypertension, impaired glucose tolerance (IGT) or OGTT-diabetes than participants with normal FFM (all p < 0.003) and a near 2-fold greater probability of significant proteinuria (p < 0.01). RFFMD was more frequent in women than in men: significant sex-RFFMD interactions were found for BMI and waist circumference (both p < 0.0001). CONCLUSIONS: RFFMD in overweight/obese normoglycemic individuals is associated with greater probability of hypertension, abnormalities of glucose tolerance and proteinuria. Assessment of RFFRMD might, therefore, help stratifying cardiometabolic risk among normoglycemic individuals with overweight/obesity.

Generalization of adiposity genetic loci to US Hispanic women.

BACKGROUND: Obesity is a public health concern. Yet the identification of adiposity-related genetic variants among United States (US) Hispanics, which is the largest US minority group, remains largely unknown. OBJECTIVE: To interrogate an a priori list of 47 (32 overall body mass and 15 central adiposity) index single-nucleotide polymorphisms (SNPs) previously studied in individuals of European descent among 3494 US Hispanic women in the Women's Health Initiative SNP Health Association Resource (WHI SHARe). DESIGN: Cross-sectional analysis of measured body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) were inverse normally transformed after adjusting for age, smoking, center and global ancestry. WC and WHR models were also adjusted for BMI. Genotyping was performed using the Affymetrix 6.0 array. In the absence of an a priori selected SNP, a proxy was selected (r(2)0.8 in CEU). RESULTS: Six BMI loci (TMEM18, NUDT3/HMGA1, FAIM2, FTO, MC4R and KCTD15) and two WC/WHR loci (VEGFA and ITPR2-SSPN) were nominally significant (P<0.05) at the index or proxy SNP in the corresponding BMI and WC/WHR models. To account for distinct linkage disequilibrium patterns in Hispanics and further assess generalization of genetic effects at each locus, we interrogated the evidence for association at the 47 surrounding loci within 1 Mb region of the index or proxy SNP. Three additional BMI loci (FANCL, TFAP2B and ETV5) and five WC/WHR loci (DNM3-PIGC, GRB14, ADAMTS9, LY86 and MSRA) displayed Bonferroni-corrected significant associations with BMI and WC/WHR. Conditional analyses of each index SNP (or its proxy) and the most significant SNP within the 1 Mb region supported the possible presence of index-independent signals at each of these eight loci as well as at KCTD15. CONCLUSION: This study provides evidence for the generalization of nine BMI and seven central adiposity loci in Hispanic women. This study expands the current knowledge of common adiposity-related genetic loci to Hispanic women.

Dietary patterns and their association with cardiovascular risk factors in a population undergoing lifestyle changes: The Strong Heart Study.

BACKGROUND AND AIMS: Rates of cardiovascular disease (CVD) are disproportionately high in American Indians (AI), and changes in lifestyle may be responsible. It is not known whether diverse dietary patterns exist in this population and whether the patterns are associated with CVD risk factors. This article describes the relationships between dietary patterns and CVD risk factors in this high-risk population. METHODS AND RESULTS: Nutrition data were collected via food frequency questionnaire from 3438 Strong Heart Study (SHS) participants, ≥ age 15 y. All participants were members of 94 extended families. The final sample consisted of 3172 men and women. Diet patterns were ascertained using factor analysis with the principal component factoring method. We derived four predominant dietary patterns: Western, traditional AI/Mexican, healthy, and unhealthy. Participants following the Western pattern had higher LDL cholesterol (LDL-C) (p < 0.001), slightly higher systolic blood pressure (BP) (p < 0.001), lower HDL cholesterol (HDL-C) (p < 0.001), and slightly lower homeostasis model assessment estimates of insulin resistance (HOMA-IR) in the lowest vs. highest deciles of adherence to this pattern (p < 0.001). The traditional diet was associated with higher HDL-C (p < 0.001), but higher body mass index (BMI) (p < 0.001) and HOMA-IR (p < 0.001). Followers of the healthy pattern had lower systolic BP, LDL-C, BMI, and HOMA-IR in increasing deciles (p < 0.001). The unhealthy pattern was associated with higher LDL-C. CONCLUSIONS: Dietary patterns reflect the changing lifestyle of AI and several of the patterns are associated with CVD risk factors. Evolving methods of food preparation have made the traditional pattern less healthy.

Does cardiovascular phenotype explain the association between diabetes and incident heart failure? The Strong Heart Study.

BACKGROUND AND AIMS: Diabetes remains a predictor of incident heart failure (HF), independent of intercurrent myocardial infarction (MI) and concomitant risk factors. Initial cardiovascular (CV) characteristics, associated with incident heart failure (HF) might explain the association of diabetes with incident HF. METHODS AND RESULTS: Participants to the 2nd Strong Heart Study exam, without prevalent HF or coronary heart disease, or glomerular filtration rate <30 mL/min/1.73 m(2), were analyzed (n = 2757, 1777 women, 1278 diabetic). Cox regression of incident HF (follow-up 8.91 ± 2.76 years) included incident MI censored as a competing risk event. Acute MI occurred in 96 diabetic (7%) and 84 non-diabetic participants (6%, p = ns). HF occurred in 156 diabetic (12%) and in 68 non-diabetic participants (5%; OR = 2.89, p < 0.001). After accounting for competing MI and controlling for age, gender, BMI, systolic blood pressure, smoking habit, plasma cholesterol, antihypertensive treatment, heart rate, fibrinogen and C-reactive protein, incident HF was predicted by greater LV mass index, larger left atrium, lower systolic function, greater left atrial systolic force and urinary albumin/creatinine excretion. Risk of HF was reduced with more rapid LV relaxation and anti-hypertensive therapy. Diabetes increases hazard of HF by 66% (0.02 < p < 0.001). The effect of diabetes could be explained by the level of HbA1c. CONCLUSIONS: Incident HF occurs more frequently in diabetes, independent of intercurrent MI, abnormal LV geometry, subclinical systolic dysfunction and indicators of less rapid LV relaxation, and is influenced by poor metabolic control. Identification of CV phenotype at high-risk for HF in diabetes should be advised.

Relationship between diabetes risk and admixture in postmenopausal African-American and Hispanic-American women.

AIMS/HYPOTHESIS: Type 2 diabetes is more prevalent in African-Americans (AFAs) and Hispanic-Americans (HAs) than in European-Americans. We assessed whether continental admixture was correlated with diabetes risk in these high-risk groups. METHODS: We estimated the proportion of sub-Saharan African (AFR), Amerindian (AMI) and European admixture using 92 ancestry-informative marker genotypes in 16,476 AFA and HA women from the Women's Health Initiative. Cox regression models were used to examine the association between admixture and diabetes risk, with and without accounting for socioeconomic status (SES) and adiposity measurements. RESULTS: AFR admixture was significantly associated with diabetes risk in AFA women when adjusting for entry age, neighbourhood SES and BMI or waist/hip ratio (WHR) (all p < 0.0001). In HA women, AMI admixture had significant associations with diabetes risk that remained significant after adjustment for SES and BMI (all p < 0.0005). In both AFAs and HAs, SES showed significant negative associations while BMI or WHR had significant positive associations with diabetes risk, with and without adjustment for genetic admixture. CONCLUSIONS/INTERPRETATION: In AFAs, admixture, SES and BMI/WHR each independently contribute to diabetes risk after accounting for each of the other factors; in HAs, admixture, SES and BMI each independently contribute to diabetes risk after accounting for each of the other factors, whereas admixture is not significantly associated with diabetes risk after accounting for SES and WHR. The findings emphasise the importance of considering both genetic and environmental causes in the aetiology of type 2 diabetes.

Coffee consumption and the incidence of type 2 diabetes in men and women with normal glucose tolerance: the Strong Heart Study.

BACKGROUND AND AIMS: It was reported that high coffee consumption was related to decreased diabetes risk. The aim of this study is to examine the association between coffee consumption and the incidence of type 2 diabetes in persons with normal glucose tolerance in a population with a high incidence and prevalence of diabetes. METHODS AND RESULTS: In a prospective cohort study, information about daily coffee consumption was collected at the baseline examination (1989-1992) in a population-based sample of American Indian men and women 45-74 years of age. Participants with normal glucose tolerance (N = 1141) at the baseline examination were followed for an average of 7.6 years. The incidence of diabetes was compared across the categories of daily coffee consumption. The hazard ratios of diabetes related to coffee consumption were calculated using Cox proportional hazards models, adjusted for potential confounders. Levels of coffee consumption were positively related to levels of current smoking and inversely related to body mass index, waist circumference, female gender, and hypertension. Compared to those who did not drink coffee, participants who drank 12 or more cups of coffee daily had 67% less risk of developing diabetes during the follow-up (hazard ratio: 0.33, 95% confidence interval: 0.13, 0.81). CONCLUSION: In this population, a high level of coffee consumption was associated with a reduced risk of deterioration of glucose metabolism over an average 7.6 years of follow-up. More work is needed to understand whether there is a plausible biological mechanism for this observation.

Pleiotropic effects on subclasses of HDL, adiposity, and glucose metabolism in adult Alaskan Eskimos.

The aim of this study was to analyze the heritability and the presence of pleiotropic effects on subfractions of high-density lipoproteins (HDLs) as measured by nuclear magnetic resonance (NMR), parameters for adiposity, and glucose metabolism in adult Alaskan Eskimos. The present family study included 1,214 adult Alaskan Eskimos (537 male/677 female). Body weight, height, circumferences, selected skinfolds, and blood pressure were measured in all participants. Blood samples were collected under fasting conditions for the isolation of plasma. Glucose, insulin, subclasses and size of lipoproteins, triglycerides, total, and HDL cholesterol and lipoprotein (a) were measured in plasma. HbA1c was measured in total blood. Univariate and bivariate quantitative genetic analyses were conducted between HDL subclasses and size and the anthropometric and biochemical measures using the variance decomposition approach. Variation in all the analyzed traits exhibits a significant genetic component. Heritabilities ranged between 0.18 +/- 0.11 for LDL(2) (intermediate) and 0.89 +/- 0.07 for small HDL. No common genetic effects were found on the HDL subclasses (small, intermediate, and large). Small HDL particles were genetically correlated with LDL particles and HbA1c. Negative genetic correlations were observed between intermediate and large HDL subfractions, HDL size and measures of adiposity, and LDL and parameters for glucose metabolism (HbA1, insulin). These observations confirm the presence of possible pleiotropic effects on HDL, adiposity, and cardiovascular risk factors and provide novel insight on the relationship between HDL subclasses, adiposity, and glucose regulation.

Genome-wide linkage scan for plasma high density lipoprotein cholesterol, apolipoprotein A-1 and triglyceride variation among American Indian populations: the Strong Heart Family Study.

BACKGROUND: Recent studies have identified chromosomal regions linked to variation in high density lipoprotein cholesterol (HDL-C), apolipoprotein A-1 (apo A-1) and triglyceride (TG), although results have been inconsistent and previous studies of American Indian populations are limited. OBJECTIVE: In an attempt to localise quantitative trait loci (QTLs) influencing HDL-C, apo A-1 and TG, we conducted genome-wide linkage scans of subjects of the Strong Heart Family Study. METHODS: We implemented analyses in 3484 men and women aged 18 years or older, at three study centres. RESULTS: With adjustment for age, sex and centre, we detected a QTL influencing both HDL-C (logarithm of odds (LOD) = 4.4, genome-wide p = 0.001) and apo A-1 (LOD = 3.2, genome-wide p = 0.020) nearest marker D6S289 at 6p23 in the Arizona sample. Another QTL influencing apo A-1 was found nearest marker D9S287 at 9q22.2 (LOD = 3.0, genome-wide p = 0.033) in the North and South Dakotas. We detected a QTL influencing TG nearest marker D15S153 at 15q22.31 (LOD = 4.5 in the overall sample and LOD = 3.8 in the Dakotas sample, genome-wide p = 0.0044) and when additionally adjusted for waist, current smoking, current alcohol, current oestrogen, lipid treatment, impaired fasting glucose, and diabetes, nearest marker D10S217 at 10q26.2 (LOD = 3.7, genome-wide p = 0.0058) in the Arizona population. CONCLUSIONS: The replication of QTLs in regions of the genome that harbour well known candidate genes suggest that chromosomes 6p, 9q and 15q warrant further investigation with fine mapping for causative polymorphisms in American Indians.

Metabolic syndrome and left ventricular hypertrophy in the prediction of cardiovascular events: the Strong Heart Study.

BACKGROUND AND AIMS: Metabolic syndrome (MetS) is associated with increased prevalence of echocardiographic LV hypertrophy (LVH), a potent predictor of cardiovascular (CV) outcome. Whether MetS increases risk of CV events independently of presence of LVH has never been investigated. It is also unclear whether LVH predicts CV risk both in the presence and absence of MetS. METHODS AND RESULTS: Participants in the 2nd Strong Heart Study examination without prevalent coronary heart disease, congestive heart failure or renal insufficiency (plasma creatinine >2.5mg/dL) were studied (n=2758; 1746 women). MetS was defined by WHO criteria. Echocardiographic LV hypertrophy was defined using population-specific cut-point value for LV mass index (>47.3g/m(2.7)). After controlling for age, sex, LDL-cholesterol, smoking, plasma creatinine, diabetes, hypertension and obesity, participants with MetS had greater probability of LVH than those without MetS (OR=1.55 [1.18-2.04], p<0.002). Adjusted hazard of composite fatal and non-fatal CV events was greater when LVH was present, in participants without (HR=2.03 [1.33-3.08]) or with MetS (HR=1.64 [1.31-2.04], both p<0.0001), with similar adjusted population attributable risk (12% and 14%). After adjustment for LVH, risk of incident CV events remained 1.47-fold greater in MetS (p<0.003), an effect, however, that was not confirmed when diabetic participants were excluded. CONCLUSION: LVH is a strong predictor of composite 8-year fatal and non-fatal CV events either in the presence or in the absence of MetS and accounts for a substantial portion of the high CV risk associated with MetS.

Sex-specific interaction between APOE genotype and carbohydrate intake affects plasma HDL-C levels: the Strong Heart Family Study.

Low plasma levels of high-density lipoprotein cholesterol (HDL-C) are identified as a risk factor for cardiovascular disease (CVD). Sexual dimorphism, however, is widely reported in both HDL-C and CVD, with the underlying explanations of these sexual differences not fully understood. HDL-C is a complex trait influenced by both genes and dietary factors. Here we examine evidence for a sex-specific effect of APOE and the macronutrient carbohydrate on HDL-C, triglycerides (TG) and apoprotein A-1 (ApoA-1) in a sample of 326 male and 423 female participants of the Strong Heart Family Study (SHFS). Using general estimating equations in SAS to account for kinship correlations, stratifying by sex, and adjusting for age, body mass index (BMI) and SHS center, we examine the relationship between APOE genotype and carbohydrate intake on circulating levels of HDL-C, TG, and ApoA-1 through a series of carbohydrate-by-sex interactions and stratified analyses. APOE-by-carbohydrate intake shows significant sex-specific effects. All males had similar decreases in HDL-C levels associated with increased carbohydrate intake. However, only those females with APOE-4 alleles showed significantly lower HDL-C levels as their percent of carbohydrate intake increased, while no association was noted between carbohydrate intake and HDL-C in those females without an APOE-4 allele. These findings demonstrate the importance of understanding sex differences in gene-by-nutrient interaction when examining the complex architecture of HDL-C variation.

Assessing the impact of different imputation methods on serial measures of renal function: the Strong Heart Study.

Missing data are a common problem in epidemiologic studies. This study had two aims: (a) to determine which method for imputing missing renal function data provides estimates closest to those made with complete data and (b) to determine which measure of renal function better estimates cardiovascular disease (CVD) risk. For these analyses, a subset of Strong Heart Study participants with complete data for renal function was identified. Data were randomly dropped from this complete set at three rates: 30, 45, and 60%. Five common techniques for handling missing data were compared: imputation using the mean, adjacent value (AV), single imputation, multiple imputation, and listwise deletion. Differences between the imputed sets and the complete set were determined for each method. Imputation methods were used to fill in missing values for serum creatinine (Scr) in one model and estimated glomerular filtration rate (eGFR) in another. For both Scr and eGFR, the AV method provided the most favorable results in predicting CVD risk, regardless of the rate of missing data.

Prevalence and persistence of antibodies to herpes viruses, Chlamydia pneumoniae and Helicobacter pylori in Alaskan Eskimos: the GOCADAN Study.

The prevalence and persistence of antibodies against cytomegalovirus (CMV), herpes simplex virus types 1 (HSV1) and 2 (HSV2), Helicobacter pylori and Chlamydia pneumoniae were determined in Alaskan Eskimos. The study included 610 individuals (mean age 43 +/- 15 years; 45% males) participating in the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study. Archived serum samples and those collected during the GOCADAN study were analysed for antibodies against the above pathogens by ELISA. The current prevalence of antibody seropositivity was 94% to CMV, 90% to HSV1, 38% to HSV2, 80% to H. pylori, and 42% to C. pneumoniae. The persistence of antibodies (in both archived and current samples) against CMV, HSV1 and H. pylori was high (83%, 84% and 67%, respectively) compared with those against HSV2 (26%) and C. pneumoniae (29%). Moreover, the seroconversion rates to these organisms were low. Most individuals acquired CMV, HSV1 and H. pylori antibodies by the age of 24 years (94%, 90% and 72%, respectively), and >50% carried HSV2 and C. pneumoniae antibodies by the age of 45 years. There were gender differences in antibody seropositivity rates. Over 70% of individuals had antibodies to at least three of the five pathogens tested. The study demonstrated the high prevalence and lifelong persistence of multiple antibodies, suggesting chronic infections among Alaskan Eskimos.