Search

BACKGROUNDLeft ventricular hypertrophy (LVH) and dyslipidemia are strong, independent predictors for cardiovascular disease, but their relationship is less well studied. A longitudinal lipidomic profiling of left ventricular mass (LVM) and LVH is still lacking.METHODSUsing liquid chromatography-mass spectrometry (LC-MS), we repeatedly measured 1,542 lipids from 1,755 unique American Indians attending 2 exams (mean, 5 years apart). Cross-sectional associations of individual lipid species with LVM index (LVMI) were examined by generalized estimating equation (GEE), followed by replication in an independent biracial cohort (65% White, 35% Black). Baseline plasma lipids associated with LVH risk beyond traditional risk factors were identified by logistic GEE model in American Indians. Longitudinal associations between changes in lipids and changes in LVMI were examined by GEE, adjusting for baseline lipids, baseline LVMI, and covariates.RESULTSMultiple lipid species were significantly associated with LVMI or the risk of LVH in American Indians. Some lipids were confirmed in Black and White individuals. Moreover, some LVH-related lipids were inversely associated with risk of coronary heart disease (CHD). Longitudinal changes in several lipid species were significantly associated with changes in LVMI.CONCLUSIONAltered fasting plasma lipidome and its longitudinal change over time were significantly associated with LVMI and risk for LVH in American Indians. Our results offer insight into the role of individual lipid species in LV remodeling and risk of LVH, independent of known risk factors.FUNDINGThis study was supported by the NIH grant (R01DK107532). The Strong Heart Study has been funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute, NIH, Department of Health and Human Services, under contract nos. 75N92019D00027, 75N92019D00028, 75N92019D00029, and 75N92019D00030.

At high levels, inorganic arsenic exposure is linked to peripheral arterial disease (PAD) and cardiovascular disease. To our knowledge, no prior study has evaluated the association between low-to-moderate arsenic exposure and incident PAD by ankle brachial index (ABI). We evaluated this relationship in the Strong Heart Study, a large population-based cohort study of American Indian communities. A total of 2,977 and 2,966 PAD-free participants who were aged 45-74 years in 1989-1991 were reexamined in 1993-1995 and 1997-1999, respectively, for incident PAD defined as either ABI <0.9 or ABI >1.4. A total of 286 and 206 incident PAD cases were identified for ABI <0.9 and ABI >1.4, respectively. The sum of inorganic and methylated urinary arsenic species (∑As) at baseline was used as a biomarker of long-term exposure. Comparing the highest tertile of ∑As with the lowest, the adjusted hazard ratios were 0.57 (95% confidence interval (CI): 0.32, 1.01) for ABI <0.9 and 2.24 (95% CI: 1.01, 4.32) for ABI >1.4. Increased arsenic methylation (as percent dimethylarsinate) was associated with a 2-fold increased risk of ABI >1.4 (hazard ratio = 2.04, 95% CI: 1.02, 3.41). Long-term low-to-moderate ∑As and increased arsenic methylation were associated with ABI >1.4 but not with ABI <0.9. Further studies are needed to clarify whether diabetes and enhanced arsenic metabolism increase susceptibility to the vasculotoxic effects of arsenic exposure., (© The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Although saturated fatty acids (FAs) have been linked to cardiovascular mortality, it is not clear whether this outcome is attributable solely to their effects on low-density lipoprotein cholesterol (LDL-C) or whether other risk factors are also associated with FAs. The Western Alaskan Native population, with its rapidly changing lifestyles, shift in diet from unsaturated to saturated fatty acids and dramatic increase in cardiovascular disease (CVD), presents an opportunity to elucidate any associations between specific FAs and known CVD risk factors., Objective: We tested the hypothesis that the specific FAs previously identified as related to CVD mortality are also associated with individual CVD risk factors., Methods: In this community-based, cross-sectional study, relative proportions of FAs in plasma and red blood cell membranes were compared with CVD risk factors in a sample of 758 men and women aged ≥35 years. Linear regression analyses were used to analyze relations between specific FAs and CVD risk factors (LDL-C, high-density lipoprotein cholesterol, triglycerides, C-reactive protein, systolic blood pressure, diastolic blood pressure, heart rate, body mass index, fasting glucose and fasting insulin, 2-hour glucose and 2-hour insulin)., Results: The specific saturated FAs previously identified as related to CVD mortality, the palmitic and myristic acids, were adversely associated with most CVD risk factors, whereas unsaturated linoleic acid (18:2n-6) and the marine n-3 FAs were not associated or were beneficially associated with CVD risk factors., Conclusions: The results suggest that CVD risk factors are more extensively affected by individual FAs than hitherto recognized, and that risk for CVD, MI and stroke can be reduced by reducing the intake of palmitate, myristic acid and simple carbohydrates and improved by greater intake of linoleic acid and marine n-3 FAs.

Background and Objectives: CKD disproportionally affects American Indians, who similar to other populations, show genetic susceptibility to kidney outcomes. Recent studies have identified several loci associated with kidney traits, but their relevance in American Indians is unknown., Design, Setting, Participants, & Measurements: This study used data from a large, family-based genetic study of American Indians (the Strong Heart Family Study), which includes 94 multigenerational families enrolled from communities located in Oklahoma, the Dakotas, and Arizona. Individuals were recruited from the Strong Heart Study, a population-based study of cardiovascular disease in American Indians. This study selected 25 single nucleotide polymorphisms in 23 loci identified from recently published kidney-related genome-wide association studies in individuals of European ancestry to evaluate their associations with kidney function (estimated GFR; individuals 18 years or older, up to 3282 individuals) and albuminuria (urinary albumin to creatinine ratio; n=3552) in the Strong Heart Family Study. This study also examined the association of single nucleotide polymorphisms in the APOL1 region with estimated GFR in 1121 Strong Heart Family Study participants. GFR was estimated using the abbreviated Modification of Diet in Renal Disease Equation. Additive genetic models adjusted for age and sex were used., Results: This study identified significant associations of single nucleotide polymorphisms with estimated GFR in or nearby PRKAG2, SLC6A13, UBE2Q2, PIP5K1B, and WDR72 (P<2.1 × 10(-3) to account for multiple testing). Single nucleotide polymorphisms in these loci explained 2.2% of the estimated GFR total variance and 2.9% of its heritability. An intronic variant of BCAS3 was significantly associated with urinary albumin to creatinine ratio. APOL1 single nucleotide polymorphisms were not associated with estimated GFR in a single variant test or haplotype analyses, and the at-risk variants identified in individuals with African ancestry were not detected in DNA sequencing of American Indians., Conclusion: This study extends the genetic associations of loci affecting kidney function to American Indians, a population at high risk of kidney disease, and provides additional support for a potential biologic relevance of these loci across ancestries.

Background: Cadmium has been associated with peripheral arterial disease (PAD) in cross-sectional studies, but prospective evidence is lacking. Our goal was to evaluate the association of urine cadmium concentrations with incident PAD in a large population-based cohort., Methods and Results: A prospective cohort study was performed with 2864 adult American Indians 45 to 74 years of age from Arizona, Oklahoma, and North and South Dakota who participated in the Strong Heart Study from 1989 to 1991 and were followed through 2 follow-up examination visits in 1993 to 1995 and 1997 to 1999. Participants were free of PAD, defined as an ankle brachial index <0.9 or >1.4 at baseline, and had complete baseline information on urine cadmium, potential confounders, and ankle brachial index determinations in the follow-up examinations. Urine cadmium was measured using inductively coupled plasma mass spectrometry and corrected for urinary dilution by normalization to urine creatinine. Multivariable-adjusted hazard ratios were computed using Cox-proportional hazards models for interval-censored data. A total of 470 cases of incident PAD, defined as an ankle brachial index <0.9 or >1.4, were identified. After adjustment for cardiovascular disease risk factors including smoking status and pack-years, the hazard ratio comparing the 80th to the 20th percentile of urine cadmium concentrations was 1.41 (1.05-1.81). The hazard ratio comparing the highest to the lowest tertile was 1.96 (1.32-2.81). The association persisted after excluding participants with ankle brachial index >1.4 only as well as in subgroups defined by sex and smoking status., Conclusions: Urine cadmium, a biomarker of long-term cadmium exposure, was independently associated with incident PAD, providing further support for cadmium as a cardiovascular disease risk factor.

Background: A significant proportion of the variability in carotid artery lumen diameter is attributable to genetic factors., Methods: Carotid ultrasonography and genotyping were performed in the 3300 American Indian participants in the Strong Heart Family Study (SHFS) to identify chromosomal regions harboring novel genes associated with inter-individual variation in carotid artery lumen diameter. Genome-wide linkage analysis was conducted using standard variance component linkage methods, implemented in SOLAR, based on multipoint identity-by-descent matrices., Results: Genome-wide linkage analysis revealed a significant evidence for linkage for a locus for left carotid artery diastolic and systolic lumen diameters in Arizona SHFS participants on chromosome 7 at 120 cM (lod = 4.85 and 3.77, respectively, after sex and age adjustment, and lod = 3.12 and 2.72, respectively, after adjustment for sex, age, height, weight, systolic and diastolic blood pressure, diabetes mellitus and current smoking). Other regions with suggestive evidence of linkage for left carotid artery diastolic and systolic lumen diameter were found on chromosome 12 at 153 cM (lod = 2.20 and 2.60, respectively, after sex and age adjustment, and lod = 2.44 and 2.16, respectively, after full covariate adjustment) in Oklahoma SHFS participants; suggestive linkage for right carotid artery diastolic and systolic lumen diameter was found on chromosome 9 at 154 cM (lod = 2.72 and 3.19, respectively after sex and age adjustment, and lod = 2.36 and 2.21, respectively, after full covariate adjustment) in Oklahoma SHFS participants., Conclusion: We found significant evidence for loci influencing carotid artery lumen diameter on chromosome 7q and suggestive linkage on chromosomes 12q and 9q., (© 2013. Published by Elsevier Ireland Ltd. All rights reserved.)

Aims/hypothesis: Type 2 diabetes is a chronic, heterogeneous disease and a major risk factor for cardiovascular diseases. The underlying mechanisms leading to progression to type 2 diabetes are not fully understood and genetic tools may help to identify important pathways of glycaemic deterioration., Methods: Using prospective data on American Indians from the Strong Heart Family Study, we identified 373 individuals defined as progressors (diabetes incident cases), 566 individuals with transitory impaired fasting glucose (IFG) and 1,011 controls (normal fasting glycaemia at all visits). We estimated the heritability (h(2)) of the traits and the evidence for association with 16 known variants identified in type 2 diabetes genome-wide association studies., Results: We noted high h(2) for diabetes progression (h(2) = 0.65 ± 0.16, p = 2.7 × 10(-6)) but little contribution of genetic factors to transitory IFG (h(2) = 0.09 ± 0.10, p = 0.19) for models adjusted for multiple risk factors. At least three variants (in WFS1, TSPAN8 and THADA) were nominally associated with diabetes progression in age- and sex-adjusted analyses with estimates showing the same direction of effects as reported in the discovery European ancestry studies., Conclusions/interpretation: Our findings do not exclude these loci for diabetes susceptibility in American Indians and suggest phenotypic heterogeneity of the IFG trait, which may have implications for genetic studies when diagnosis is based on a single time-point measure.

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., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ∼50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ∼2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10(-6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.

The delta-5 and delta-6 desaturases (D5D and D6D), encoded by fatty acid desaturase 1 (FADS1) and 2 (FADS2) genes, respectively, are rate-limiting enzymes in the metabolism of ω-3 and ω-6 fatty acids. The objective of this study was to identify genes influencing variation in estimated D5D and D6D activities in plasma and erythrocytes in Alaskan Eskimos (n = 761) participating in the genetics of coronary artery disease in Alaska Natives (GOCADAN) study. Desaturase activity was estimated by product: precursor ratio of polyunsaturated fatty acids. We found evidence of linkage for estimated erythrocyte D5D (eD5D) on chromosome 11q12-q13 (logarithm of odds score = 3.5). The confidence interval contains candidate genes FADS1, FADS2, 7-dehydrocholesterol reductase (DHCR7), and carnitine palmitoyl transferase 1A, liver (CPT1A). Measured genotype analysis found association between CPT1A, FADS1, and FADS2 single-nucleotide polymorphisms (SNPs) and estimated eD5D activity (p-values between 10(-28) and 10(-5)). A Bayesian quantitative trait nucleotide analysis showed that rs3019594 in CPT1A, rs174541 in FADS1, and rs174568 in FADS2 had posterior probabilities > 0.8, thereby demonstrating significant statistical support for a functional effect on eD5D activity. Highly significant associations of FADS1, FADS2, and CPT1A transcripts with their respective SNPs (p-values between 10(-75) and 10(-7)) in Mexican Americans of the San Antonio Family Heart Study corroborated our results. These findings strongly suggest a functional role for FADS1, FADS2, and CPT1A SNPs in the variation in eD5D activity.

Objectives: To determine if heart rate (HR) is associated with desaturation indexes as HR is associated with arrhythmia and sudden death., Study Design: A community based cross-sectional study of 1214 Alaskan Inuit., Methods: Data of FA concentrations from plasma and red blood cell membranes from those ≥35 years of age (n = 819) were compared to basal HR at the time of examination. Multiple linear regression with backward stepwise selection was employed to analyze the effect of the desaturase indexes on HR, after adjustment for relevant covariates., Results: The Δ(5) desaturase index (Δ(5)-DI) measured in serum has recently been associated with a protective role for cardiovascular disease. This index measured here in plasma and red blood cells showed a negative correlation with HR. The plasma stearoyl-CoA-desaturase (SCD) index, previously determined to be related to cardiovascular disease (CVD) mortality, on the other hand, was positively associated with HR, while the Δ(6) desaturase index (Δ(6)-DI) had no significant effect on HR., Conclusion: Endogenous FA desaturation is associated with HR and thereby, in the case of SCD, possibly with arrhythmia and sudden death, which would at least partially explain the previously observed association between cardiovascular mortality and desaturase activity.

Variation in anthropometric measurements due to sexual dimorphism can be the result of genotype by sex interactions (G×S). The purpose of this study was to examine the sex-specific genetic architecture in anthropometric measurements in Alaskan Eskimos from the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study. Maximum likelihood-based variance components decomposition methods, implemented in SOLAR, were used for G×S analyses. Anthropometric measurements included BMI, waist circumference (WC), waist/height ratio, percent body fat (%BF), and subscapular and triceps skinfolds. Except for WC, mean values of all phenotypes were significantly different in men and women (P < 0.05). All anthropometric measures were significantly heritable (P < 0.001). In a preliminary analysis not allowing for G×S interaction, evidence of linkage was detected between markers D19S414 and D19S220 on chromosome 19 for WC (logarithm of odds (lod) = 3.5), %BF (lod = 1.7), BMI (lod = 2.4), waist/height ratio (lod = 2.5), subscapular (lod = 2.1), and triceps skinfolds (lod = 1.9). In subsequent analyses which allowed for G×S interaction, linkage was again found between these traits and the same two markers on chromosome 19 with significantly improved lod scores for: WC (lod = 4.5), %BF (lod = 3.8), BMI (lod = 3.5), waist/height ratio (lod = 3.2), subscapular (lod = 3.0), and triceps skinfolds (lod = 2.9). These results support the evidence of a G×S interaction in the expression of genetic effects resulting in sexual dimorphism in anthropometric phenotypes and identify the chromosome 19q12-13 region as important for adiposity-related traits in Alaskan Eskimos.

Objectives: To examine sex-specific associations of nutritional factors with prevalent hypertension (HTN) and systolic blood pressure (SBP) in Alaska Natives. Diet is known to affect SBP, a major risk factor for cardiovascular disease., Study Design: Cross-sectional analysis of participants without diabetes in the Genetics of Coronary Artery Disease in Alaska Natives study., Methods: Macronutrients such as fat, carbohydrate and protein and micronutrients such as sodium were investigated. HTN was defined as SBP≥140 mmHg, diastolic blood pressure≥90 mmHg and/or taking anti-HTN medication. Analyses were stratified by sex and covariates included age, body mass index (BMI), energy intake, smoking and physical activity., Results: Mean age was 42 years for men (n=456) and women (n=602). Men with HTN (n=106) compared to men without HTN consumed a higher proportion of calories from total (p=0.01), saturated (p<0.01) and trans fatty acid (p=0.03) fats. Women with HTN (n=99) compared to women without HTN consumed more total (p=0.03) and monounsaturated (p=0.04) fat, higher protein (p=0.02) and lower total (p<0.01) and simple (p<0.01) carbohydrates. After covariate adjustment, men not on anti-HTN medications (n=407) had significantly higher average SBP with increasing quartiles of trans fatty acid intake (p for linear trend=0.01) and sodium intake (p for linear trend=0.02). For women not on anti-HTN medications (n=528), after covariate adjustment, average SBP decreased with increasing quartiles of omega 3 fatty acid intake (p for linear trend <0.01)., Conclusions: Prospective evaluation of the sex-specific associations of nutritional factors with HTN and SBP on outcomes is needed along with novel interventions to lower the risk of cardiovascular disease.

The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10(-8)) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10(-8)). The top IBC association for SBP was rs2012318 (P= 6.4 × 10(-6)) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10(-6)) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.

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., (Copyright © 2009 Elsevier B.V. All rights reserved.)

Coronary heart disease (CHD) is the leading cause of mortality in African Americans. To identify common genetic polymorphisms associated with CHD and its risk factors (LDL- and HDL-cholesterol (LDL-C and HDL-C), hypertension, smoking, and type-2 diabetes) in individuals of African ancestry, we performed a genome-wide association study (GWAS) in 8,090 African Americans from five population-based cohorts. We replicated 17 loci previously associated with CHD or its risk factors in Caucasians. For five of these regions (CHD: CDKN2A/CDKN2B; HDL-C: FADS1-3, PLTP, LPL, and ABCA1), we could leverage the distinct linkage disequilibrium (LD) patterns in African Americans to identify DNA polymorphisms more strongly associated with the phenotypes than the previously reported index SNPs found in Caucasian populations. We also developed a new approach for association testing in admixed populations that uses allelic and local ancestry variation. Using this method, we discovered several loci that would have been missed using the basic allelic and global ancestry information only. Our conclusions suggest that no major loci uniquely explain the high prevalence of CHD in African Americans. Our project has developed resources and methods that address both admixture- and SNP-association to maximize power for genetic discovery in even larger African-American consortia., Competing Interests: JBM has a research grant from GSK and a consulting agreement with Interleukin Genetics, SLH reports being listed as co-inventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics. SLH reports having been paid as a consultant or speaker for the following companies: AstraZeneca Pharmaceuticals LP, BG Medicine, Merck & Co., Pfizer Takeda, Esperion, and Cleveland Heart Lab. SLH reports receiving research funds from Abbott, Liposcience, and Cleveland Heart Lab. WHWT reports receiving research grant support from Abbott Laboratories.

Objective: To compare fasting plasma glucose (FPG) and HbA(1c) in identifying and predicting type 2 diabetes in a population with high rates of diabetes., Research Design and Methods: Diabetes was defined as an FPG level ≥ 126 mg/dL or an HbA(1c) level ≥ 6.5%. Data collected from the baseline and second exams (1989-1995) of the Strong Heart Study were used. RESULTS For cases of diabetes identified by FPG ≥ 126 mg/dL, using HbA(1c) ≥ 6.5% at the initial and 4-year follow-up diabetes screenings (or in identifying incident cases in 4 years) among undiagnosed participants left 46% and 59% of cases of diabetes undetected, respectively, whereas for cases identified by HbA(1c) ≥ 6.5%, using FPG ≥ 126 mg/dL left 11% and 59% unidentified, respectively. Age, waist circumference, urinary albumin-to-creatinine ratio, and baseline FPG and HbA(1c) levels were common significant risk factors for incident diabetes defined by either FPG or HbA(1c); triglyceride levels were significant for diabetes defined by HbA(1c) alone, and blood pressure and sibling history of diabetes were significant for diabetes defined by FPG alone. Using both the baseline FPG and HbA(1c) in diabetes prediction identified more people at risk than using either measure alone. CONCLUSIONS Among undiagnosed participants, using HbA(1c) alone in initial diabetes screening identifies fewer cases of diabetes than FPG, and using either FPG or HbA(1c) alone cannot effectively identify diabetes in a 4-year periodic successive diabetes screening or incident cases of diabetes in 4 years. Using both criteria may identify more people at risk. The proposed models using the commonly available clinical measures can be applied to assessing the risk of incident diabetes using either criterion.

Introduction: As a result of rapid economic development in China, the lifestyles and dietary habits of its people have been changing, and the rates of obesity, diabetes, and other chronic conditions have increased substantially. We report the prevalence of type 2 diabetes and impaired fasting glucose (IFG) and the association between diabetes and overweight and obesity in Chinese adults. We also compare the results with those from the US National Health and Nutrition Examination Survey, 1999-2002., Methods: Data were from adults aged 20 years or older who participated in the China National Nutrition and Health Survey, 2002 (n = 47,729). Diabetes and IFG were defined by the American Diabetes Association 2009 criteria. We assessed the prevalence of diabetes, IFG, and overweight and obesity by sex, age, region of residence, and ethnicity., Results: The prevalence of diabetes and IFG in Chinese adults was 2.7% and 4.9%, respectively. The prevalence of diabetes increased with age and body mass index. Men and women had a similar prevalence of diabetes, but men had a significantly higher prevalence of IFG. The prevalence of diabetes among Chinese who lived in urban areas was 2 to 3 times higher than the prevalence among those who lived in rural areas (3.9% for urban areas and 6.1% for large cities vs 1.9% for rural areas), and the prevalence of IFG was 1.5 to 2 times higher (6.1% and 8.1% vs 4.2%, respectively). The prevalence of diabetes among Chinese women and young (20-39 y) and middle-aged (40-59 y) adults who lived in large cities was similar to the prevalence of diabetes in the US population., Conclusion: The prevalence of diabetes and IFG was much higher in urban than rural areas, particularly in the large cities of China. Prevention must be emphasized among adults to reduce the future social and economic burden of diabetes in China.

Objective: To identify genetic variation influencing serum bilirubin levels in American Indians, we performed genome-wide screening and association analyses in the Strong Heart Family Study. Bilirubin is an endogenous antioxidant that has demonstrated an inverse relationship with cardiovascular disease. Genetic variation within the promoter region of uridine diphosphate glucuronosyltransferase (UGT1A1) on chromosome 2q has been associated with elevated serum bilirubin levels in European populations. However, no study has investigated the UGT1A1 promoter in American Indians., Methods: Statistical analyses were carried out with 3,484 participants aged 14 to 93 years recruited from three geographic areas in the United States; Arizona, Oklahoma, and North and South Dakota., Results: Variance components linkage analysis detected a quantitative trait locus (QTL) for bilirubin on chromosome 2q in the combined centers (LOD = 6.61, P = 4.24 × 10⁻⁶) and in Oklahoma (LOD = 5.65, P = 4.57 24 × 10⁻⁵). Genetic association of the UGT1A1 promoter polymorphism was significant for all geographic locations. After adjustment using conditional linkage for UGT1A1 promoter variance, the linkage signal dropped to 1.10 in the combined sample and to 3.32 (P = 0.02) in Oklahoma, indicating this polymorphism is not completely responsible for the linkage signal in American Indians. We also detected suggestive linkage signals in the Dakotas on chromosome 10p12 (LOD = 2.18) and in the combined centers (LOD = 2.24) on chromosome 10q21., Conclusions: Replication of a serum bilirubin QTL on chromosome 2q in American Indians implicates UGT1A1 but further genotyping is warranted to identify additional causative polymorphisms. Evidence also supports a potential novel locus for bilirubin on chromosome 10., (© 2010 Wiley-Liss, Inc.)

In January 2009, the National Heart, Lung, and Blood Institute convened a 28-member multidisciplinary Working Group to update the recommendations of a 2004 National Heart, Lung, and Blood Institute Working Group focused on Guidelines to the Return of Genetic Research Results. Changes in the genetic and societal landscape over the intervening 5 years raise multiple questions and challenges. The group noted the complex issues arising from the fact that technological and bioinformatic progress has made it possible to obtain considerable information on individuals that would not have been possible a decade ago. Although unable to reach consensus on a number of issues, the working group produced 5 recommendations. The working group offers 2 recommendations addressing the criteria necessary to determine when genetic results should and may be returned to study participants, respectively. In addition, it suggests that a time limit be established to limit the duration of obligation of investigators to return genetic research results. The group recommends the creation of a central body, or bodies, to provide guidance on when genetic research results are associated with sufficient risk and have established clinical utility to justify their return to study participants. The final recommendation urges investigators to engage the broader community when dealing with identifiable communities to advise them on the return of aggregate and individual research results. Creation of an entity charged to provide guidance to institutional review boards, investigators, research institutions, and research sponsors would provide rigorous review of available data, promote standardization of study policies regarding return of genetic research results, and enable investigators and study participants to clarify and share expectations for the handling of this increasingly valuable information with appropriate respect for the rights and needs of participants.

Large studies of extended families usually collect valuable phenotypic data that may have scientific value for purposes other than testing genetic hypotheses if the families were not selected in a biased manner. These purposes include assessing population-based associations of diseases with risk factors/covariates and estimating population characteristics such as disease prevalence and incidence. Relatedness among participants however, violates the traditional assumption of independent observations in these classic analyses. The commonly used adjustment method for relatedness in population-based analyses is to use marginal models, in which clusters (families) are assumed to be independent (unrelated) with a simple and identical covariance (family) structure such as those called independent, exchangeable and unstructured covariance structures. However, using these simple covariance structures may not be optimally appropriate for outcomes collected from large extended families, and may under- or over-estimate the variances of estimators and thus lead to uncertainty in inferences. Moreover, the assumption that families are unrelated with an identical family structure in a marginal model may not be satisfied for family studies with large extended families. The aim of this paper is to propose models incorporating marginal models approaches with a covariance structure for assessing population-based associations of diseases with their risk factors/covariates and estimating population characteristics for epidemiological studies while adjusting for the complicated relatedness among outcomes (continuous/categorical, normally/non-normally distributed) collected from large extended families. We also discuss theoretical issues of the proposed models and show that the proposed models and covariance structure are appropriate for and capable of achieving the aim.

Heart rate (HR) has been identified as a risk factor for cardiovascular disease (CVD), yet little is known regarding genetic factors influencing this phenotype. Previous research in American Indians (AIs) from the Strong Heart Family Study (SHFS) identified a significant quantitative trait locus (QTL) for HR on chromosome 9p21. Genetic association on HR was conducted in the SHFS. HR was measured from electrocardiogram (ECG) and echocardiograph (Echo) Doppler recordings. We examined 2248 single-nucleotide polymorphisms (SNPs) on chromosome 9p21 for association using a gene-centric statistical test. We replicated the aforementioned QTL [logarithm of odds (LOD) = 4.83; genome-wide P= 0.0003] on chromosome 9p21 in one SHFS population using joint linkage of ECG and Echo HR. After correcting for effective number of SNPs using a gene-centric test, six SNPs (rs7875153, rs7848524, rs4446809, rs10964759, rs1125488 and rs7853123) remained significant. We applied a novel bivariate association method, which was a joint test of association of a single locus to two traits using a standard additive genetic model. The SNP, rs7875153, provided the strongest evidence for association (P = 7.14 x 10(-6)). This SNP (rs7875153) is rare (minor allele frequency = 0.02) in AIs and is located within intron 9 of the gene KIAA1797. To support this association, we applied lymphocyte RNA expression data from the San Antonio Family Heart Study, a longitudinal study of CVD in Mexican Americans. Expression levels of KIAA1797 were significantly associated (P = 0.012) with HR. These findings in independent populations support that KIAA1797 genetic variation may be associated with HR but elucidation of a functional relationship requires additional study.

Objectives: Type 2 diabetes and the consumption of saturated fatty acids (FAs) are on the rise among Alaska Inuits. This analysis, based on a cross-sectional study, explores the possible associations of saturated FA content in red blood cells (RBCs) and parameters of glucose metabolism in a sample of Alaska Natives., Study Design and Methods: The sample included 343 women and 282 men aged 35-74. Statistical analyses explored the associations of selected RBC (myristic, palmitic and stearic acids) FAs with fasting glucose (plasma), fasting insulin (plasma), 2h glucose (2-hour glucose tolerance test), 2h insulin and homeostasis model assessment (HOMA) index. The models included sex and glucose metabolism status as fixed factors and age, body mass index (BMI), waist circumference, physical activity (METS) and FA content in RBCs as covariates. Measures of insulin, glucose and HOMA index were used as dependent variables., Results: Myristic acid was positively associated with fasting insulin (β=0.47, p<0.001), 2h insulin (β=0.53, p=0.02) and HOMA index (β=0.455, p<0.001). Palmitic acid was associated with 2h glucose (β=2.3×10(-2), p<0.001) and 2h insulin (β=5.6×10(-2), p=0.002) and stearic acid was associated with fasting glucose (β=4.8×10(-3), p=0.006)., Conclusions: These results strongly support the hypothesis that saturated fatty acids are associated with insulin resistance and glucose intolerance and that saturated fatty acids are significant risk factors for type 2 diabetes.

Objectives: To examine the relationship between depression and glycemic control in the Strong Heart Study (SHS), a longitudinal study of cardiovascular disease in American Indians., Methods: This cross-sectional analysis focused on the relationship between depression, diabetes and glycemic control among 2832 individuals aged > or =15 years. Depression was measured by the Center for Epidemiologic Studies of Depression Scale and diabetes by American Diabetes Association criteria. An ordered logit regression model was used to assess whether diabetes was related to level of depression (none, mild, moderate, severe). Multiple logistic regression was used to explore the relationship between A1c and severe depression in participants with diabetes., Results: Rates of depression were higher in men and women with diabetes when compared to those without diabetes, respectively (P<.05). For every 1-U increase in A1c, the odds of severe depression increased by 22% (OR 1.22, 95% CI: 1.05-1.42). Female sex (OR 2.97, 95% CI: 1.32-6.69) and body mass index (BMI) (OR 1.04, 95% CI: 1.00-1.08) also were significantly associated with increased risk for severe depression. Although BMI appears to be significantly associated with increased risk for severe depression, the magnitude of this effect was small., Conclusions: Individuals with diabetes have higher rates of depression than those without diabetes, consistent with other populations. There is a positive relationship between severity of depression and A1c levels; men and women with severe depression have higher A1c levels than those with moderate-to-no depression., (Copyright 2010. Published by Elsevier Inc.)

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.

Background: The National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe), a planned cross-cohort analysis of genetic variation in cardiovascular, pulmonary, hematologic, and sleep-related traits, comprises >40,000 participants representing 4 ethnic groups in 9 community-based cohorts. The goals of CARe include the discovery of new variants associated with traits using a candidate gene approach and the discovery of new variants using the genome-wide association mapping approach specifically in African Americans., Methods and Results: CARe has assembled DNA samples for >40,000 individuals self-identified as European American, African American, Hispanic, or Chinese American, with accompanying data on hundreds of phenotypes that have been standardized and deposited in the CARe Phenotype Database. All participants were genotyped for 7 single-nucleotide polymorphisms (SNPs) selected based on prior association evidence. We performed association analyses relating each of these SNPs to lipid traits, stratified by sex and ethnicity, and adjusted for age and age squared. In at least 2 of the ethnic groups, SNPs near CETP, LIPC, and LPL strongly replicated for association with high-density lipoprotein cholesterol concentrations, PCSK9 with low-density lipoprotein cholesterol levels, and LPL and APOA5 with serum triglycerides. Notably, some SNPs showed varying effect sizes and significance of association in different ethnic groups., Conclusions: The CARe Pilot Study validates the operational framework for phenotype collection, SNP genotyping, and analytic pipeline of the CARe project and validates the planned candidate gene study of approximately 2000 biological candidate loci in all participants and genome-wide association study in approximately 8000 African American participants. CARe will serve as a valuable resource for the scientific community.

Background and Aims: Although Eskimos were thought to be protected from cardiovascular disease (CVD), state health data show a large proportion of deaths from CVD, despite traditional lifestyles and high omega-3 fatty acid intake. This article explores CVD prevalence and its relation to risk factors in Alaska Eskimos., Methods and Results: A population-based cohort of 499 Alaska Eskimos > age 45 from the Norton Sound region was examined in 2000-2004 for CVD and associated risk factors as part of the Genetics of Coronary Artery Disease in Alaska Natives study. CVD and atherosclerosis were evaluated and adjudicated using standardized methods. Average age was 58 years; diabetes prevalence was low and high-density lipoprotein cholesterol (HDL-C) concentrations were high, but a large proportion smoked and had high pathogen burden. CVD was higher in men (12.6%) than in women (5.3%) (prevalence ratio 2.4, CI 1.3-4.4). Rates of stroke (6.1% in men, 1.8% in women) were similar to those for coronary heart disease (CHD) (6.1% men, 2.5% women). MI prevalence was low in both genders (1.9% and 0.7%). CVD was higher in men and in those >60 years. Hypertension, diabetes, high LDL-C, high apoB, and low HDL-C were all strong correlates (<.002) and albuminuria and CRP were also correlated with CVD (p<.05) after adjustment for age and gender. Carotid atherosclerosis was correlated with CVD (p=.0079) independent of other risk factors., Conclusion: These data show high CHD and stroke prevalence in Alaska Eskimos, despite low average LDL-C and high HDL-C. Hypertension and high LDL-C were independent correlates; identifying these risk factors early and treating to target is recommended.

Background: Alterations in plasma fatty acid distribution are linked to metabolic abnormalities related to type 2 diabetes and cardiovascular disease., Objective: The aim of this study was to investigate genetic factors influencing plasma fatty acid distribution in Alaskan Eskimos from the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study., Design: Fatty acids in plasma were measured by gas chromatography in 761 related individuals (>35 y of age)., Results: Quantitative genetic analyses showed that fatty acid distribution is significantly heritable (P < 0.001), with heritabilities ranging from 0.33 to 0.55. A genome-wide scan for plasma fatty acids identified a 20-cM region on chromosome 8 (p12-p21) with a quantitative trait locus for monounsaturated fatty acids (logarithm of odds score = 3.8). The same region had a quantitative trait locus for polyunsaturated fatty acids (logarithm of odds score = 2.6). We genotyped single nucleotide polymorphisms (SNPs) in candidate genes in 8p12-p21 and found a significant association between fatty acids and SNPs in apolipoprotein J (APOJ), lipoprotein lipase (LPL), macrophage scavenger receptor 1 (MSR1), and tumor necrosis factor receptor superfamily member 10b (TNFRSF10B). A Bayesian quantitative trait nucleotide analysis based on a measured genotype model showed that SNPs in LPL, TNFRSF10B, and APOJ had strong statistical evidence of a functional effect (posterior probability > or =75%) on plasma fatty acid distribution., Conclusions: The results indicate that there is strong genetic influence on plasma fatty acid distribution and that genetic variation in APOJ, LPL, and TNFRSF10B may play a role. The GOCADAN study was registered at www.clinicaltrials.gov as NCT00006192.

Background: Consumption of omega-3 fatty acids (FAs) is associated with a reduction in deaths from coronary heart disease, arrhythmia, and sudden death. Although these FAs were originally thought to be antiatherosclerotic, recent evidence suggests that their benefits are related to reducing risk for ventricular arrhythmia and that this may be mediated by a slowed heart rate (HR)., Methods: The study was conducted in Alaskan Eskimos participating in the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) Study, a population experiencing a dietary shift from unsaturated to saturated fats. We compared HR with red blood cell (RBC) FA content in 316 men and 391 women ages 35 to 74 years., Results: Multivariate linear regression analyses of individual FAs with HR as the dependent variable and specific FAs as covariates revealed negative associations between HR and docosahexaenoic acid (22:6n-3; P = .004) and eicosapentaenoic acid (20:5n-3; P = .009) and positive associations between HR and palmitoleic acid (16:1n-7; P = .021), eicosanoic acid (20:1n9; P = .007), and dihomo-gamma-linolenic acid (DGLA; 20:3n-6; P = .021). Factor analysis revealed that the omega-3 FAs were negatively associated with HR (P = .003), whereas a cluster of other, non-omega-3 unsaturated FAs (16:1, 20:1, and 20:3) was positively associated., Conclusions: Marine omega-3 FAs are associated with lower HR, whereas palmitoleic and DGLA, previously identified as associated with saturated FA consumption and directly related to cardiovascular mortality, are associated with higher HR. These relations may at least partially explain the relations between omega-3 FAs, ventricular arrhythmia, and sudden death., (Copyright 2010 Mosby, Inc. All rights reserved.)

Chronic kidney disease (CKD) is an important public health problem in American Indian populations. Recent research has identified associations of polymorphisms in the myosin heavy chain type II isoform A (MYH9) gene with hypertensive CKD in African-Americans. Whether these associations are also present among American Indian individuals is unknown. To evaluate the role of genetic polymorphisms in the MYH9 gene on kidney disease in American Indians, we genotyped 25 SNPs in the MYH9 gene region in 1,119 comparatively unrelated individuals. Four SNPs failed, and one SNP was monomorphic We inferred haplotypes using seven SNPs within the region of the previously described E haplotype using Phase v2.1. We studied the association between 20 MYH9 SNPs with kidney function (estimated glomerular filtration rate, eGFR) and CKD (eGFR\60 ml/min/1.73 m(2) or renal replacement therapy or kidney transplant) using age-, sex- and center-adjusted models and measured genotyped within the variance component models. MYH9 SNPs were not significantly associated with kidney traits in additive or recessive genetic adjusted models. MYH9 haplotypes were also not significantly associated with kidney outcomes. In conclusion, common variants in MYH9 polymorphisms may not confer an increased risk of CKD in American Indian populations. Identification of the actual functional genetic variation responsible for the associations seen in African-Americans will likely help to clarify the lack of replication of this gene in our population of American Indians.

Despite the tradition of a diet high in fish oils and abundant physical activity, coronary artery disease is increasing among Alaska Eskimos. Explanations for this observation include lifestyle changes. In this cross-sectional analysis, we evaluated dietary patterns of Alaska Eskimos and investigated the relations between these dietary patterns and known cardiovascular risk factors, including inflammatory markers. We used a principal component analysis with data from FFQ collected in 2000-2004 to determine dietary patterns of Alaska Eskimos. Four dietary patterns were identified: a traditional pattern, plus 3 patterns based on purchased food, one of which reflected healthy food choices. The traditional dietary pattern was associated with lower triglycerides (P < 0.001) and blood pressure (P = 0.04) and slightly higher LDL cholesterol (LDL-C) (P = 0.05). Whereas the healthy purchased diet was associated with a trend toward lower LDL-C (P = 0.09), the beverages and sweets diet was positively associated with LDL-C (P = 0.02). Diet pattern was not associated with inflammatory markers or pathogen burden. Our data show that the traditional diet is related to a better profile of cardiovascular disease risk factors and should be encouraged. Programs are needed to encourage the availability of healthy food choices for those not able to obtain traditional foods.

Studies have been inconsistent regarding whether lipoprotein particle subfraction measures are useful indicators of cardiovascular risk. The present study evaluated the relation between lipoprotein particle concentrations and size, analyzed using nuclear magnetic resonance spectroscopy and measures of carotid atherosclerosis in a population with high cardiovascular risk but little hyperlipidemia. In this cross-sectional, population-based sample of Alaska Eskimos >or=35 years old (n = 656), a greater carotid intimal medial thickness was associated with greater low-density lipoprotein (LDL) cholesterol (p = 0.03) and total LDL particle concentration (p = 0.04), independently of other traditional risk factors. The effects of LDL cholesterol and LDL particle concentration on intimal medial thickness were additive (p = 0.015). Carotid plaque was associated with greater levels of LDL cholesterol (p = 0.01), greater concentrations of large LDL particles (p = 0.003), and a reduction in the size of the very-low-density lipoprotein particles (p = 0.03). The effects of LDL cholesterol and large LDL particles on the plaque score were additive. In conclusion, the carotid intimal medial thickness was associated with greater LDL particle concentrations. The association was strongest in those with greater LDL cholesterol levels. Plaque was associated with greater concentrations of LDL cholesterol, large LDL particles, and smaller very-low-density lipoprotein particles. It might be beneficial to determine the lipoprotein subfractions in populations with little hyperlipidemia.

Hyperuricemia is associated with the metabolic syndrome, gout, renal and cardiovascular disease (CVD). American Indians have high rates of CVD and 25% of individuals in the strong heart family study (SHFS) have high serum uric acid levels. The aim of this study was to investigate the genetic determinants of serum uric acid variation in American Indian participants of the SHFS. A variance component decomposition approach (implemented in SOLAR) was used to conduct univariate genetic analyses in each of three study centers and the combined sample. Serum uric acid was adjusted for age, sex, age x sex, BMI, estimated glomerular filtration rate, alcohol intake, diabetic status and medications. Overall mean +/- SD serum uric acid for all individuals was 5.14 +/- 1.5 mg/dl. Serum uric acid was found to be significantly heritable (0.46 +/- 0.03 in all centers, and 0.39 +/- 0.07, 0.51 +/- 0.05, 0.44 +/- 0.06 in Arizona, Dakotas and Oklahoma, respectively). Multipoint linkage analysis showed significant evidence of linkage for serum uric acid on chromosome 11 in the Dakotas center [logarithm of odds score (LOD) = 3.02] and in the combined sample (LOD = 3.56) and on chromosome 1 (LOD = 3.51) in the combined sample. A strong positional candidate gene in the chromosome 11 region is solute carrier family22, member 12 (SLC22A12) that encodes a major uric acid transporter URAT1. These results show a significant genetic influence and a possible role for one or more genes on chromosomes 1 and 11 on the variation in serum uric acid in American Indian populations.

Background: Population studies have demonstrated an important role of social, behavioral, and environmental factors in blood pressure (BP) levels. Accounting for the genetic interaction of these factors may help to identify common BP susceptibility alleles., Methods and Results: We studied the interaction of additive genetic effects and behavioral (physical activity, smoking, alcohol use) and socioeconomic (education) factors on BP in approximately 3600 American Indian participants of the Strong Heart Family Study, using variance component models. The mean and SD of resting systolic and diastolic BPs were 123 + or - 17 and 76 + or - 11 mm Hg, respectively. We detected evidence for distinct genetic effects on diastolic BP among ever smokers compared with never smokers (P = 0.01). For alcohol intake, we observed significant genotype-by-environment interactions on diastolic (rhog = 0.10, P = 0.0003) and on systolic BPs (rhog = 0.59, P = 0.0008) among current drinkers compared with former or never drinkers. We also detected genotype-by-physical activity interactions on diastolic BP (rhog = 0.35, P = 0.0004). Finally, there was evidence for distinct genetic effects on diastolic BP among individuals with less than high school education compared with those with 12 or more years of education (rhog = 0.41, P = 0.02)., Conclusions: Our findings suggest that behavioral and socioeconomic factors can modify the genetic effects on BP phenotypes. Accounting for context dependent factors may help us to better understand the complexities of the gene effects on BP and other complex phenotypes with high levels of genetic heterogeneity.

American Indians have a higher prevalence of albuminuria than the general population, likely resulting from a combination of environmental and genetic risk factors. To localize gene regions influencing variation in urinary albumin-to-creatinine ratio, we performed a linkage analysis and explored gene-by-diabetes, -hypertension, and -obesity interactions in a large cohort of American Indian families. We recruited >3600 individuals from 13 American Indian tribes from three centers (Arizona, North and South Dakota, and Oklahoma). We performed multipoint variance component linkage analysis in each center as well as in the entire cohort after controlling for center effects. We used two modeling strategies: Model 1 incorporated age, gender, and interaction terms; model 2 also controlled for diabetes, BP, body mass index, HDL, LDL, triglycerides, and smoking status. We evaluated interactions with diabetes, hypertension, and obesity using additive, interaction-specific linkage and stratified analyses. Loci suggestive for linkage to urinary albumin-to-creatinine ratio included 1q, 6p, 9q, 18q, and 20p. Gene-by-diabetes interaction was present with a quantitative trait locus specific to the diabetic stratum in the Dakotas isolated on 18q21.2 to 21.3 using model 1 (logarithm of odds = 3.3). Gene-by-hypertension interaction was present with quantitative trait loci specific to the hypertensive stratum in the Dakotas on 7q21.11 using model 1 (logarithm of odds = 3.4) and 10q25.1 using model 2 (logarithm of odds = 3.3). These loci replicate findings from multiple other genome scans of kidney disease phenotypes with distinct populations and are worthy of further study.

Objective: To explore relationships between C-reactive protein (CRP), subclinical infection, insulin resistance, and metabolic syndrome., Research Design and Methods: Data from 1,174 Eskimos, aged >/=18 years, from the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study were analyzed; 40 participants with diabetes were eliminated. Baseline assessment included interviews, physical exam, and blood and urine sampling. Metabolic syndrome was assessed using Adult Treatment Panel III criteria. CRP and antibodies to common pathogens were measured., Results: Although CRP was related in univariate analyses to insulin resistance and metabolic syndrome, relations were attenuated or eliminated after adjustment for relevant covariates. CRP was not higher among those with impaired fasting glucose (IFG), and pathogen burden was not related to insulin resistance, metabolic syndrome, or IFG., Conclusions: Pathogen burden and inflammation do not seem to be related to insulin resistance, metabolic syndrome, or IFG in this population. The inflammatory process may reflect insulin resistance or its correlates but most likely is not causative.

American Indians have a disproportionately high rate of kidney disease likely due to a combination of environmental and genetic factors. We performed a genome wide scan of estimated glomerular filtration rate in 3665 participants of the Strong Heart Family Study to localize genes influencing kidney disease risk factors. The participants were men and women from 13 American Indian tribes recruited from 3 centers located in Arizona, the Dakotas and Oklahoma. Multipoint variance component linkage analysis was performed for each center and on the entire cohort after controlling for center effects. Modeling strategies that incorporated age, gender and interaction terms (model 1) and another that also controlled for diabetes mellitus, systolic and diastolic blood pressure, body mass index, low density and high density lipoproteins, triglycerides and smoking status (model 2) were used. Significant evidence for linkage in the Arizona group was found on chromosome 12p12.2 at 39cM (nearest marker D12S310) using model 1. Additional loci with very suggestive evidence for linkage were detected at 1p36.31 for all groups using both models and at 2q33.3 and 9q34.2 for the Dakotas group each using model 1. No significant evidence for additive interaction with diabetes, hypertension or obesity was noted. This evidence for linkage of a quantitative trait locus influencing estimated glomerular filtration rate to a region of chromosome 12p in a large cohort of American Indians will be worth studying in more detail in the future.

Background: Body fat mass distribution and deposition are determined by multiple environmental and genetic factors. Obesity is associated with insulin resistance, hyperinsulinemia, and type 2 diabetes. We previously identified evidence for genotype-by-diabetes interaction on obesity traits in Strong Heart Family Study (SHFS) participants. To localize these genetic effects, we conducted genome-wide linkage scans of obesity traits in individuals with and without type 2 diabetes, and in the combined sample while modeling interaction with diabetes using maximum likelihood methods (SOLAR 2.1.4)., Methods: SHFS recruited American Indians from Arizona, North and South Dakota, and Oklahoma. Anthropometric measures and diabetes status were obtained during a clinic visit. Marker allele frequencies were derived using maximum likelihood methods estimated from all individuals and multipoint identity by descent sharing was estimated using Loki. We used variance component linkage analysis to localize quantitative trait loci (QTLs) influencing obesity traits. We tested for evidence of additive and QTL-specific genotype-by-diabetes interactions using the regions identified in the diabetes-stratified analyses., Results: Among 245 diabetic and 704 non-diabetic American Indian individuals, we detected significant additive gene-by-diabetes interaction for weight and BMI (P < 0.02). In analysis accounting for QTL-specific interaction (P < 0.001), we detected a QTL for weight on chromosome 1 at 242 cM (LOD = 3.7). This chromosome region harbors the adiponectin receptor 1 gene, which has been previously associated with obesity., Conclusion: These results suggest distinct genetic effects on body mass in individuals with diabetes compared to those without diabetes, and a possible role for one or more genes on chromosome 1 in the pathogenesis of obesity.

Objective: This study was designed to evaluate the relation between omega-3 fatty acid (FA) consumption and atherosclerosis., Background: The hypothesis that omega-3 FAs protect against atherosclerosis has not been tested with objective measures of atherosclerosis., Methods: A population-based sample of 1131 Alaskan Eskimos of age >or=18 underwent ultrasound assessment of carotid atherosclerosis. Those of age >35 (N=686) were included in the analysis. Diet was assessed by a food frequency questionnaire. Intimal-medial thickness (IMT) of the far wall of the distal common carotid arteries and plaque score (number of segments containing plaque) were assessed., Results: Mean consumption of total omega-3 FAs was 4.76 g/day in those without and 5.07 g/day in those with plaque. In models adjusting for relevant risk factors, presence and extent of plaque were unrelated to intake of C20-22 omega-3 FAs or total omega-3 FAs. In contrast, the odds of plaque rose significantly with quartiles of palmitic (p=0.02) and stearic acid intake (p=0.04). The extent of plaque (or plaque score) was also associated with a higher percentage intake of palmitic acid (p=0.01). IMT was negatively associated with grams of C20-22 omega-3 FAs (p=0.05), total omega-3 (p=0.05), palmitate (p=0.03), and stearate (p=0.03) consumed., Conclusions: Dietary intake of omega-3 FAs in a moderate-to-high range does not appear to be associated with reduced plaque, but is negatively associated with IMT. The presence and extent of carotid atherosclerosis among Eskimos is higher with increasing consumption of saturated FAs.

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.

Since 2000, the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study has been collecting information on cardiovascular disease (CVD) and its risk factors from 1,214 Alaska Natives of the Norton Sound region, a population with increasing rates of heart disease and stroke. Because smoking was reported in a large proportion of the participants, this analysis was undertaken to evaluate smoking patterns and their relation to other risk factors and to CVD. The relationships among smoking habits and demographic factors, body mass index, plasma fibrinogen, prevalent hypertension, and carotid plaque were evaluated. Eighty percent of participants had smoked 100+ cigarettes in their lifetime. Fifty-seven percent of women and 63% of men (p = .12) were current smokers: one in four smokers had quit. Current smokers (OR = 2.1; 95% CI = 1.1-3.8) and those who had quit <5 years ago (OR = 1.6; 95% CI = 1.1-2.2) were more likely than non-smokers to have carotid plaque. Pack-years smoked also were correlated with carotid plaque. The high prevalence of smoking and low rates of cessation in this population demonstrate an urgent need for smoking prevention and cessation programs among Alaskan Eskimos of the Norton Sound region and other Alaska Native groups.

Background: There have been no studies that use longitudinal data with more than 2 measurements and methods of longitudinal data analysis to identify risk factors for incident albuminuria over time more effectively., Study Design: Longitudinal study., Settings & Participants: A subgroup of participants in the Strong Heart Study, a population-based sample of American Indians, in central Arizona, Oklahoma, and North and South Dakota. Participants with diabetes without albuminuria were followed up for a mean of 4 years., Predictors: Age, sex, study center, high-density lipoprotein and low-density lipoprotein cholesterol levels, triglyceride level, body mass index, systolic blood pressure, use of antihypertensive medication, smoking, hemoglobin A(1c) level, fasting glucose level, type of diabetes therapy, diabetes duration, plasma creatinine level, and urinary albumin-creatinine ratio (UACR)., Outcomes & Measurements: Albuminuria was defined as UACR of 30 mg/g or greater. Urine creatinine and albumin were measured by using the picric acid method and a sensitive nephelometric technique, respectively., Results: Of 750 and 568 participants with diabetes without albuminuria and with normal plasma creatinine levels at the first and second examinations, 246 and 132 developed albuminuria by the second and third examinations, respectively. Incident albuminuria was predicted by baseline UACR, fasting glucose level, systolic blood pressure, plasma creatinine level, study center, current smoking, and use of angiotensin-converting enzyme inhibitors and antidiabetic medications. UACR of 10 to 30 mg/g increased the odds of developing albuminuria 2.7-fold compared with UACR less than 5 mg/g., Limitations: Single random morning urine specimen., Conclusions: Many risk factors identified for incident albuminuria can be modified. Control of blood pressure and glucose level, smoking cessation, and use of angiotensin-converting enzyme inhibitors may reduce the incidence of albuminuria.

Background: Pulse pressure, a measure of central arterial stiffness and a predictor of cardiovascular mortality, has known genetic components., Methods: To localize the genetic effects of pulse pressure, we conducted a genome-wide linkage analysis of 1,892 American-Indian participants of the Strong Heart Family Study (SHFS). Blood pressure was measured three times and the average of the last two measures was used for analyses. Pulse pressure, the difference between systolic blood pressure (SBP) and diastolic blood pressure (DBP), was log-transformed and adjusted for the effects of age and sex within each study center. Variance component linkage analyses were performed using marker allele frequencies derived from all individuals and multipoint identity-by-descent matrices calculated in Loki., Results: We identified a quantitative-trait locus influencing pulse pressure on chromosome 7 at 37 cM (marker D7S493, LOD = 3.3) and suggestive evidence of linkage on chromosome 19 at 92 cM (marker D19S888, LOD = 1.8)., Conclusions: The signal on 7p15.3 overlaps positive findings for pulse pressure among Utah population samples, suggesting that this region may harbor gene variants for blood pressure related traits.

A wealth of genetic associations for cardiovascular and metabolic phenotypes in humans has been accumulating over the last decade, in particular a large number of loci derived from recent genome wide association studies (GWAS). True complex disease-associated loci often exert modest effects, so their delineation currently requires integration of diverse phenotypic data from large studies to ensure robust meta-analyses. We have designed a gene-centric 50 K single nucleotide polymorphism (SNP) array to assess potentially relevant loci across a range of cardiovascular, metabolic and inflammatory syndromes. The array utilizes a "cosmopolitan" tagging approach to capture the genetic diversity across approximately 2,000 loci in populations represented in the HapMap and SeattleSNPs projects. The array content is informed by GWAS of vascular and inflammatory disease, expression quantitative trait loci implicated in atherosclerosis, pathway based approaches and comprehensive literature searching. The custom flexibility of the array platform facilitated interrogation of loci at differing stringencies, according to a gene prioritization strategy that allows saturation of high priority loci with a greater density of markers than the existing GWAS tools, particularly in African HapMap samples. We also demonstrate that the IBC array can be used to complement GWAS, increasing coverage in high priority CVD-related loci across all major HapMap populations. DNA from over 200,000 extensively phenotyped individuals will be genotyped with this array with a significant portion of the generated data being released into the academic domain facilitating in silico replication attempts, analyses of rare variants and cross-cohort meta-analyses in diverse populations. These datasets will also facilitate more robust secondary analyses, such as explorations with alternative genetic models, epistasis and gene-environment interactions.

Fatty acids (FAs) have been related to changes in glucose and lipid metabolism. In this article, the authors assess the association between intake of specific FAs and components of the metabolic syndrome (MS) in adult Eskimos. A total of 691 Inupiat Eskimos (325 men and 366 women), aged 34 to 75 years, were examined as part of the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study. The investigation included a physical examination, blood pressure measurements, blood sampling under fasting conditions, 2-hour oral glucose tolerance test, and a personal interview including a validated food frequency questionnaire. Components of MS were defined according to the Third Report of the National Cholesterol Education Program Adult Treatment Panel criteria. Consumption of individual FAs showed associations with MS components. Long-chain omega-3 FAs, from fish and sea mammals, were associated with lower blood pressure, serum triglycerides, and 2-hour glucose and higher high-density lipoprotein cholesterol, fasting insulin, and homeostasis model assessment. Saturated fat consumption was associated with higher triglyceride levels and blood pressure. Trans-FA consumption was associated with higher blood pressure. Consumption of long-chain omega-3 FAs from marine sources may improve certain MS components, and thus may reduce risk for cardiovascular disease. High consumption of saturated FAs and trans-FAs may have an adverse effect on MS.

Background: Little research has explored the association of macronutrient intake and glycated hemoglobin (HbA(1c)) in adults with diabetes., Objective: The objective of the study was to examine the cross-sectional association between macronutrient intake and HbA(1c) in diabetic American Indians., Design: A total of 1284 participants aged 47-80 y who had diabetes for >or=1 y at the second examination (1993-1995) of the Strong Heart Study were included in this study. Dietary intake was assessed by using a 24-h recall. Logistic regression models were used to evaluate the odds of poor glycemic control (HbA(1c) >or= 7%) among sex-specific quintiles of macronutrient intake, after adjustment for the possible confounders age, sex, study center, body mass index, duration of diabetes, diabetes treatment, smoking, alcohol drinking, total energy intake, and physical activity., Results: Higher total fat (>25-30% of energy), saturated fatty acids (>13% of energy), and monounsaturated fatty acids (>10% of energy) and lower carbohydrate intake (<35-40% of energy) were associated with poor glycemic control. Lower fiber intake and higher protein intake were marginally associated with poor glycemic control (P for trend = 0.06 and 0.09, respectively). No significant association was found between polyunsaturated fatty acids or trans fatty acids and glycemic control in this population., Conclusions: These data suggest that a higher consumption of total fat and saturated and monounsaturated fatty acids and a lower intake of carbohydrates are associated with poor glycemic control in diabetic American Indians. Clinical trials focusing on whether modifications of macronutrient composition improve glycemic control in persons with diabetes are needed.