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1.  Adult Height and Prevalence of Coronary Artery Calcium: The NHLBI Family Heart Study 
Background
Adult height has been hypothesized to be inversely associated with coronary heart disease but studies have produced conflicting results. We sought to examine the relationship between adult height and the prevalence of coronary artery calcium (CAC), a direct measure of subclinical atherosclerosis and surrogate marker of CHD.
Method and Results
We evaluated the relationship between adult height and CAC in 2,703 participants from the NHLBI Family Heart Study who underwent cardiac computed tomography. We used generalized estimating equations to calculate the prevalence odds ratios for the presence of CAC (CAC>0) across sex-specific quartiles of height. The mean age of the sample was 54.8 years and 60.2% were female. There was an inverse association between adult height and CAC. After adjusting for age, race, field center, waist circumference, smoking, alcohol, physical activity, systolic blood pressure, antihypertensive medications, diabetes, diabetic medications, LDL cholesterol, HDL cholesterol, lipid-lowering medications, and income, individuals in the tallest quartile had 30% lower odds of having prevalent CAC. The odds ratios (95% CI) for the presence of CAC across consecutive sex-specific quartiles of height were 1.0 (reference), 1.15 (0.86–1.53), 0.95(0.73–1.22), and 0.70 (0.53–0.93), p for trend <0.01. There was no evidence of effect modification for the relationship between adult height and CAC by age or socioeconomic status.
Conclusions
The results of our study suggest an inverse, independent association between adult height and CAC.
doi:10.1161/CIRCIMAGING.113.000681
PMCID: PMC3970195  PMID: 24336983
risk factor; imaging; epidemiology
2.  Three-Year Variability in Plasma Concentrations of the Soluble Receptor for Advanced Glycation End Products (sRAGE) 
Clinical biochemistry  2013;47(0):132-134.
Objectives
The soluble receptor for advanced glycation end products (sRAGE) has been implicated in the development of diabetes-related vascular complications, but the variability of concentrations of sRAGE in the blood is unknown. The objective of this study was to characterize within-person three-year variability of plasma levels of sRAGE.
Methods
We measured sRAGE in plasma samples from 179 men and women in the community-based Atherosclerosis Risk in Communities (ARIC) Study at two time points, three years apart. We calculated correlation coefficients and the within-person coefficient of variation (CVw) to characterize variability in sRAGE. We compared these estimates to total cholesterol and white blood cell count (WBC) in the same participants.
Results
Mean sRAGE concentrations at the two time points (mean time between measurements = 2.9 years) were 1096.2 pg/mL and 990.2 pg/mL, respectively (mean difference = −106.0 pg/mL, p-value < 0.001). The Pearson’s correlation was 0.78 (Spearman’s, 0.73). The intra-class correlation coefficient was 0.76 and the CVw was 26.6%. Compared to sRAGE, Pearson’s and Spearman’s correlations for total cholesterol (0.76 and 0.77) and white blood cell count (0.61 and 0.72) were similar, although CVw for both were lower (8.7% for cholesterol, 15.6% for WBC). Less than 4% of participants’ values changed substantially (50% or greater) over the three-year interval.
Conclusions
We observed that sRAGE concentrations remained relatively stable over three years. Our findings suggest that a single measure of circulating sRAGE tracks well in a community-based population and could be a useful measure in clinical and epidemiologic studies of long-term risk.
doi:10.1016/j.clinbiochem.2013.11.005
PMCID: PMC4263345  PMID: 24246851
sRAGE; Advanced glycation end products; reliability and validity; biological markers
3.  Genetic diversity is a predictor of mortality in humans 
BMC Genetics  2014;15(1):159.
Background
It has been well-established, both by population genetics theory and direct observation in many organisms, that increased genetic diversity provides a survival advantage. However, given the limitations of both sample size and genome-wide metrics, this hypothesis has not been comprehensively tested in human populations. Moreover, the presence of numerous segregating small effect alleles that influence traits that directly impact health directly raises the question as to whether global measures of genomic variation are themselves associated with human health and disease.
Results
We performed a meta-analysis of 17 cohorts followed prospectively, with a combined sample size of 46,716 individuals, including a total of 15,234 deaths. We find a significant association between increased heterozygosity and survival (P = 0.03). We estimate that within a single population, every standard deviation of heterozygosity an individual has over the mean decreases that person’s risk of death by 1.57%.
Conclusions
This effect was consistent between European and African ancestry cohorts, men and women, and major causes of death (cancer and cardiovascular disease), demonstrating the broad positive impact of genomic diversity on human survival.
Electronic supplementary material
The online version of this article (doi:10.1186/s12863-014-0159-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12863-014-0159-7
PMCID: PMC4301661  PMID: 25543667
Heterozygosity; Human; Survival; GWAS
4.  Association of dietary omega-3 fatty acids with prevalence of metabolic syndrome: The National Heart, Lung, and Blood Institute Family Heart Study 
Clinical nutrition (Edinburgh, Scotland)  2013;32(6):10.1016/j.clnu.2013.05.002.
Background & Aims
Metabolic syndrome (MetS), characterized by abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, and insulin resistance is a major public health concern in the United States. Omega-3 fatty acids have been relatively well studied in relation to many individual cardiovascular risk factors; however, their effects on MetS are not well established.
Methods
We conducted a cross-sectional study consisting of 4,941 participants from the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study to assess the relation of dietary omega-3 fatty acids with the prevalence of MetS. Omega-3 intake was assessed using a food frequency questionnaire and we used generalized estimating equations to estimate adjusted odds ratios for prevalent MetS.
Results
Our study population had a mean age (SD) of 52.1 (13.9) years and 45.9% were men. The mean (SD) of dietary omega-3 fatty acids was 0.25g/day (0.27). From the lowest to the highest quintile of dietary omega-3 fatty acids, multivariable adjusted ORs (95% CI) for MetS were 1.00 (ref), 0.90 (0.72–1.13), 1.03 (0.82–1.28), 0.94 (0.74–1.18), and 0.99 (0.77–1.25), respectively. In a secondary analysis, neither fish consumption nor dietary alpha-linolenic acid was associated with MetS.
Conclusions
Our findings do not support an association between dietary omega-3 fatty acids and MetS in a large US population.
doi:10.1016/j.clnu.2013.05.002
PMCID: PMC3791144  PMID: 23711994
Omega-3 fatty acids; fish; dietary alpha-linolenic acid (ALA); metabolic syndrome
5.  Plasma C-reactive protein, genetic risk score, and risk of common cancers in the Atherosclerosis Risk in Communities study 
Cancer causes & control : CCC  2013;24(12):10.1007/s10552-013-0285-y.
Purpose
Many studies, including the Atherosclerosis Risk in Communities (ARIC) cohort, reported a positive association between plasma C-reactive protein (CRP) – a biomarker of low-grade chronic inflammation – and colorectal cancer risk, although it is unclear if the association is causal. Our aims were to assess the associations of a CRP genetic risk score (CRP-GRS) created from single nucleotide polymorphisms (SNPs) with colorectal cancer risk, as well as examine plasma CRP and CRP-GRS in relation to common cancers in the ARIC cohort.
Methods
Cox proportional hazards models were used to prospectively estimate hazard ratios (HR) and (95% confidence interval, CI) of total, colorectal, lung, prostate, and breast cancers in relation to: 1) CRP-GRS among 8,657 Whites followed in 1987–2006 and 2) log-transformed plasma CRP among 7,603 Whites followed in 1996–2006. A weighted CRP-GRS was comprised of 20 CRP-related SNPs located in/near CRP, APOC1, HNF1A, LEPR and 16 other genes that were identified in genome-wide association studies.
Results
After multivariable adjustment, one standard deviation increment of the CRP-GRS was associated with colorectal cancer risk (HR=1.19; 95% CI, 1.03–1.37) but not with any other cancer. One unit of log-transformed plasma CRP was associated with the risk of total, colorectal, lung, and breast cancers: HRs (95% CIs) were 1.08 (1.01–1.15), 1.24 (1.01–1.51), 1.29 (1.08–1.54), and 1.27 (1.07–1.51), respectively. HRs remained elevated, although lost statistical significance for all but breast cancer, after excluding subjects with <2 years of follow-up.
Conclusions
The study corroborates a causative role of chronic low-grade inflammation in colorectal carcinogenesis.
doi:10.1007/s10552-013-0285-y
PMCID: PMC3836434  PMID: 24036889
inflammation; CRP; cancer risk; genetic risk score; genetic polymorphism; ARIC cohort
6.  Factors Related to Fungiform Papillae Density: The Beaver Dam Offspring Study 
Chemical Senses  2013;38(8):669-677.
The distribution of fungiform papillae density and associated factors were examined in the Beaver Dam Offspring Study. Data were from 2371 participants (mean age = 48.8 years, range = 21–84 years) with 1108 males and 1263 females. Fungiform papillae were highlighted with blue food coloring and the number of fungiform papillae within a standard 6-mm circle was counted. Whole mouth suprathreshold taste intensity was measured. The mean fungiform papillae density was 103.5 papillae/cm2 (range = 0–212.2 papillae/cm2). For each 5-year increase in age, the mean fungiform papillae density was 2.8 papillae/cm2 lower and the mean density for males was 10.2 papillae/cm2 lower than for females. Smokers had significantly lower mean densities (former smokers: −5.1 papillae/cm2; current smokers: −9.3 papillae/cm2) than nonsmokers, and heavy alcohol drinkers had a mean density that was 4.7 papillae/cm2 lower than nonheavy drinkers. Solvent exposure was related to a significantly higher density (+6.8 papillae/cm2). The heritability estimate for fungiform papillae density was 40.2%. Propylthiouracil taster status, TAS2R38 haplotype, and perceived taste intensity were not related to density. In summary, wide variability in fungiform papillae density was observed and a number of related factors were found including the modifiable factors of smoking and alcohol consumption.
doi:10.1093/chemse/bjt033
PMCID: PMC3777560  PMID: 23821729
fungiform papillae; heritability; taste
7.  Mendelian Randomization Studies Do Not Support a Causal Role for Reduced Circulating Adiponectin Levels in Insulin Resistance and Type 2 Diabetes 
Yaghootkar, Hanieh | Lamina, Claudia | Scott, Robert A. | Dastani, Zari | Hivert, Marie-France | Warren, Liling L. | Stancáková, Alena | Buxbaum, Sarah G. | Lyytikäinen, Leo-Pekka | Henneman, Peter | Wu, Ying | Cheung, Chloe Y.Y. | Pankow, James S. | Jackson, Anne U. | Gustafsson, Stefan | Zhao, Jing Hua | Ballantyne, Christie M. | Xie, Weijia | Bergman, Richard N. | Boehnke, Michael | el Bouazzaoui, Fatiha | Collins, Francis S. | Dunn, Sandra H. | Dupuis, Josee | Forouhi, Nita G. | Gillson, Christopher | Hattersley, Andrew T. | Hong, Jaeyoung | Kähönen, Mika | Kuusisto, Johanna | Kedenko, Lyudmyla | Kronenberg, Florian | Doria, Alessandro | Assimes, Themistocles L. | Ferrannini, Ele | Hansen, Torben | Hao, Ke | Häring, Hans | Knowles, Joshua W. | Lindgren, Cecilia M. | Nolan, John J. | Paananen, Jussi | Pedersen, Oluf | Quertermous, Thomas | Smith, Ulf | Lehtimäki, Terho | Liu, Ching-Ti | Loos, Ruth J.F. | McCarthy, Mark I. | Morris, Andrew D. | Vasan, Ramachandran S. | Spector, Tim D. | Teslovich, Tanya M. | Tuomilehto, Jaakko | van Dijk, Ko Willems | Viikari, Jorma S. | Zhu, Na | Langenberg, Claudia | Ingelsson, Erik | Semple, Robert K. | Sinaiko, Alan R. | Palmer, Colin N.A. | Walker, Mark | Lam, Karen S.L. | Paulweber, Bernhard | Mohlke, Karen L. | van Duijn, Cornelia | Raitakari, Olli T. | Bidulescu, Aurelian | Wareham, Nick J. | Laakso, Markku | Waterworth, Dawn M. | Lawlor, Debbie A. | Meigs, James B. | Richards, J. Brent | Frayling, Timothy M.
Diabetes  2013;62(10):3589-3598.
Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics–based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26–0.35) increase in fasting insulin, a 0.34-SD (0.30–0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47–2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI −0.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (−0.20 SD; 95% CI −0.38 to −0.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75–1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin-lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: −0.03 SD; 95% CI −0.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95–1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes.
doi:10.2337/db13-0128
PMCID: PMC3781444  PMID: 23835345
8.  No Association of 9p21 with Arterial Elasticity and Retinal Microvascular Findings 
Atherosclerosis  2013;230(2):301-303.
Objective
How 9p21 variation affects risk of cardiovascular disease is unclear, so we assessed whether 9p21 variants are associated with arterial elasticity or retinal microvascular findings.
Methods
In the prospective Multi-Ethnic Study of Atherosclerosis (MESA) we assessed 378 SNPs in the 9p21 locus. Within four ethnic groups, we used an additive genetic model to relate the 9p21 SNPs to five vascular phenotypes: small and large elasticity derived from radial diastolic pulse contour analysis; Young’s elastic modulus from carotid artery ultrasound measurements; and the diameter of the central retinal arteries and veins.
Results
In neither ethnic-specific nor pooled data was there any statistically significant association between any of the 9p21 SNPs and any of the five vascular phenotypes.
Conclusion
Our study does not support an association of 9p21 variation with arterial elasticity or retinal microvascular abnormalities.
doi:10.1016/j.atherosclerosis.2013.07.049
PMCID: PMC3787319  PMID: 24075760
Prospective study; 9p21 SNP; retinal microvascular abnormalities; arterial elasticity
9.  Evaluation of microarray-based DNA methylation measurement using technical replicates: the Atherosclerosis Risk In Communities (ARIC) Study 
BMC Bioinformatics  2014;15(1):312.
Background
DNA methylation is a widely studied epigenetic phenomenon; alterations in methylation patterns influence human phenotypes and risk of disease. As part of the Atherosclerosis Risk in Communities (ARIC) study, the Illumina Infinium HumanMethylation450 (HM450) BeadChip was used to measure DNA methylation in peripheral blood obtained from ~3000 African American study participants. Over 480,000 cytosine-guanine (CpG) dinucleotide sites were surveyed on the HM450 BeadChip. To evaluate the impact of technical variation, 265 technical replicates from 130 participants were included in the study.
Results
For each CpG site, we calculated the intraclass correlation coefficient (ICC) to compare variation of methylation levels within- and between-replicate pairs, ranging between 0 and 1. We modeled the distribution of ICC as a mixture of censored or truncated normal and normal distributions using an EM algorithm. The CpG sites were clustered into low- and high-reliability groups, according to the calculated posterior probabilities. We also demonstrated the performance of this clustering when applied to a study of association between methylation levels and smoking status of individuals. For the CpG sites showing genome-wide significant association with smoking status, most (~96%) were seen from sites in the high reliability cluster.
Conclusions
We suggest that CpG sites with low ICC may be excluded from subsequent association analyses, or extra caution needs to be taken for associations at such sites.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2105-15-312) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2105-15-312
PMCID: PMC4180315  PMID: 25239148
DNA methylation; Infinium 450 K chip; Technical error; Intraclass correlation; Normal mixture models
10.  Association of Levels of Fasting Glucose and Insulin with Rare Variants at the Chromosome 11p11.2-MADD Locus: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study 
Background
Common variation at the 11p11.2 locus, encompassing MADD, ACP2, NR1H3, MYBPC3 and SPI1, has been associated in genome-wide association studies with fasting glucose (FG) and insulin (FI). In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study, we sequenced five gene regions at 11p11.2 to identify rare, potentially functional variants influencing FG or FI levels.
Method & Results
Sequencing (mean depth 38×) across 16.1kb in 3,566 non-diabetic individuals identified 653 variants, 79.9% of which were rare (MAF <1%) and novel. We analyzed rare variants in five gene regions with FI or FG using the Sequence Kernel Association Test (SKAT). At NR1H3, 53 rare variants were jointly associated with FI (p=2.73 × 10−3); of these, seven were predicted to have regulatory function and showed association with FI (p=1.28 × 10−3). Conditioning on two previously associated variants at MADD (rs7944584, rs10838687) did not attenuate this association, suggesting that there are more than two independent signals at 11p11.2. One predicted regulatory variant, chr11:47227430 (hg18; MAF 0.00068), contributed 20.6% to the overall SKAT score at NR1H3, lies in intron 2 of NR1H3 and is a predicted binding site for FOXA1, a transcription factor associated with insulin regulation. In human HepG2 hepatoma cells, the rare chr11:47227430 A allele disrupted FOXA1 binding and reduced FOXA1-dependent transcriptional activity.
Conclusion
Sequencing at 11p11.2- NR1H3 identified rare variation associated with FI. One variant, chr11:47227430, appears to be functional, with the rare A allele reducing transcription factor FOXA1 binding and FOXA1-dependent transcriptional activity.
doi:10.1161/CIRCGENETICS.113.000169
PMCID: PMC4066205  PMID: 24951664
fasting glucose; fasting insulin; chr11p11.2; target sequencing; next-generation sequencing
11.  Ceruloplasmin and Heart Failure in the Atherosclerosis Risk in Communities (ARIC) Study 
Circulation. Heart failure  2013;6(5):936-943.
Background
Ceruloplasmin (Cp) decreases nitric oxide bioavailability in blood and has been associated with cardiovascular disease (CVD) in clinical studies. We assessed the association between Cp and incident heart failure (HF), death and CVD in the Atherosclerosis Risk in Communities (ARIC) Study.
Methods and Results
Cp was measured at ARIC visit 4 (1996–1998). We studied 9,240 individuals without HF or CVD at ARIC visit 4, and followed them for a mean of 10.5 years. Genome-wide association study was performed to identify genetic determinants of Cp levels and evaluate their association with incident HF. Cp levels (mean±standard deviation) were higher in women vs men (335±79 vs 258±44 mg/L, p<0.0001), women on vs not on hormone-replacement therapy (398±89 vs 291±60 mg/L, p<0.0001) and African Americans vs Caucasians (299±63 vs 293±74 mg/L, p=0.0005). After adjusting for traditional risk factors, high-sensitivity C-reactive protein, N-terminal pro–B-type natriuretic peptide, and high-sensitivity cardiac troponin T, higher levels of Cp were associated with HF (hazard ratio [HR] 1.44, 95% confidence interval [CI] 1.13–1.83) and mortality (HR 1.38, 95% CI 1.11–1.63). A locus on the ceruloplasmin gene on chromosome 3 was significantly associated with Cp levels (normal 295.56±77.60mg/L, heterozygote 316.72±88.02mg/L; homozygote 331.04±85.40mg/L, p=8.3×10−) but not with incident HF. After adjustment for traditional risk factors Cp levels were also weekly associated with CVD.
Conclusions
Cp was associated with incident, HF mortality and CVD in the ARIC population. A single locus on chromosome 3 was associated with Cp levels but not with HF.
doi:10.1161/CIRCHEARTFAILURE.113.000270
PMCID: PMC3908901  PMID: 23861484
ceruloplasmin; heart failure; cardiovascular disease; single nucleotide polymorphism
12.  Estimation of Geographic Variation in Human Papillomavirus Vaccine Uptake in Men and Women: An Online Survey Using Facebook Recruitment 
Background
Federally funded surveys of human papillomavirus (HPV) vaccine uptake are important for pinpointing geographically based health disparities. Although national and state level data are available, local (ie, county and postal code level) data are not due to small sample sizes, confidentiality concerns, and cost. Local level HPV vaccine uptake data may be feasible to obtain by targeting specific geographic areas through social media advertising and recruitment strategies, in combination with online surveys.
Objective
Our goal was to use Facebook-based recruitment and online surveys to estimate local variation in HPV vaccine uptake among young men and women in Minnesota.
Methods
From November 2012 to January 2013, men and women were recruited via a targeted Facebook advertisement campaign to complete an online survey about HPV vaccination practices. The Facebook advertisements were targeted to recruit men and women by location (25 mile radius of Minneapolis, Minnesota, United States), age (18-30 years), and language (English).
Results
Of the 2079 men and women who responded to the Facebook advertisements and visited the study website, 1003 (48.2%) enrolled in the study and completed the survey. The average advertising cost per completed survey was US $1.36. Among those who reported their postal code, 90.6% (881/972) of the participants lived within the previously defined geographic study area. Receipt of 1 dose or more of HPV vaccine was reported by 65.6% women (351/535), and 13.0% (45/347) of men. These results differ from previously reported Minnesota state level estimates (53.8% for young women and 20.8% for young men) and from national estimates (34.5% for women and 2.3% for men).
Conclusions
This study shows that recruiting a representative sample of young men and women based on county and postal code location to complete a survey on HPV vaccination uptake via the Internet is a cost-effective and feasible strategy. This study also highlights the need for local estimates to assess the variation in HPV vaccine uptake, as these estimates differ considerably from those obtained using survey data that are aggregated to the state or federal level.
doi:10.2196/jmir.3506
PMCID: PMC4180348  PMID: 25231937
online recruitment; social media; Facebook; local estimation; geographic variability; human papillomavirus; HPV
13.  Chocolate consumption and prevalence of metabolic syndrome in the NHLBI Family Heart Study 
e-SPEN journal  2012;7(4):e139-e143.
SUMMARY
Background & aims
Previous studies have suggested that cocoa products, which are rich sources of flavonoids, may lower blood pressure, serum cholesterol, fasting blood glucose and improve endothelial function. However, it is unclear whether consumption of cocoa products including chocolate influences the risk of metabolic syndrome (MetS).
In a cross-sectional design, we sought to examine the association between chocolate consumption and the prevalence of MetS.
Methods
We studied 4098 participants from the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study aged 25–93 years. Chocolate consumption was assessed using a semi-quantitative food-frequency questionnaire. MetS was defined using the NCEP III criteria. Generalized estimating equations were used to estimate prevalence odds ratios of MetS according to frequency of chocolate intake.
Results
Of the 4098 participants (mean age 51.7 y) included in the analyses, 2206 (53.8%) were female. The prevalence of metabolic syndrome in our population was 30.2%. Compared with those who did not consume any chocolate, multivariate adjusted odds ratios (95% CI) for MetS were 1.26 (0.94, 1.69), 1.15 (0.85, 1.55), and 0.99 (0.66, 1.51) among women who reported chocolate consumption of 1–3 times/ month, 1–4 times/week, and 5+ times/week, respectively. Corresponding values for men were: 1.13 (0.82, 1.57), 1.02 (0.74, 1.39), and 1.21 (0.79, 1.85).
Conclusion
These data do not support an association between chocolate intake and the prevalence of MetS in US adult men and women.
doi:10.1016/j.clnme.2012.04.002
PMCID: PMC4130386  PMID: 25126517
Chocolate; Metabolic syndrome; Cardiovascular disease risk
14.  Meta-Analysis of Genome-Wide Association Studies in African Americans Provides Insights into the Genetic Architecture of Type 2 Diabetes 
Ng, Maggie C. Y. | Shriner, Daniel | Chen, Brian H. | Li, Jiang | Chen, Wei-Min | Guo, Xiuqing | Liu, Jiankang | Bielinski, Suzette J. | Yanek, Lisa R. | Nalls, Michael A. | Comeau, Mary E. | Rasmussen-Torvik, Laura J. | Jensen, Richard A. | Evans, Daniel S. | Sun, Yan V. | An, Ping | Patel, Sanjay R. | Lu, Yingchang | Long, Jirong | Armstrong, Loren L. | Wagenknecht, Lynne | Yang, Lingyao | Snively, Beverly M. | Palmer, Nicholette D. | Mudgal, Poorva | Langefeld, Carl D. | Keene, Keith L. | Freedman, Barry I. | Mychaleckyj, Josyf C. | Nayak, Uma | Raffel, Leslie J. | Goodarzi, Mark O. | Chen, Y-D Ida | Taylor, Herman A. | Correa, Adolfo | Sims, Mario | Couper, David | Pankow, James S. | Boerwinkle, Eric | Adeyemo, Adebowale | Doumatey, Ayo | Chen, Guanjie | Mathias, Rasika A. | Vaidya, Dhananjay | Singleton, Andrew B. | Zonderman, Alan B. | Igo, Robert P. | Sedor, John R. | Kabagambe, Edmond K. | Siscovick, David S. | McKnight, Barbara | Rice, Kenneth | Liu, Yongmei | Hsueh, Wen-Chi | Zhao, Wei | Bielak, Lawrence F. | Kraja, Aldi | Province, Michael A. | Bottinger, Erwin P. | Gottesman, Omri | Cai, Qiuyin | Zheng, Wei | Blot, William J. | Lowe, William L. | Pacheco, Jennifer A. | Crawford, Dana C. | Grundberg, Elin | Rich, Stephen S. | Hayes, M. Geoffrey | Shu, Xiao-Ou | Loos, Ruth J. F. | Borecki, Ingrid B. | Peyser, Patricia A. | Cummings, Steven R. | Psaty, Bruce M. | Fornage, Myriam | Iyengar, Sudha K. | Evans, Michele K. | Becker, Diane M. | Kao, W. H. Linda | Wilson, James G. | Rotter, Jerome I. | Sale, Michèle M. | Liu, Simin | Rotimi, Charles N. | Bowden, Donald W.
PLoS Genetics  2014;10(8):e1004517.
Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15×10−94
Author Summary
Despite the higher prevalence of type 2 diabetes (T2D) in African Americans than in Europeans, recent genome-wide association studies (GWAS) were examined primarily in individuals of European ancestry. In this study, we performed meta-analysis of 17 GWAS in 8,284 cases and 15,543 controls to explore the genetic architecture of T2D in African Americans. Following replication in additional 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry, we identified two novel and three previous reported T2D loci reaching genome-wide significance. We also examined 158 loci previously reported to be associated with T2D or regulating glucose homeostasis. While 56% of these loci were shared between African Americans and the other populations, the strongest associations in African Americans are often found in nearby single nucleotide polymorphisms (SNPs) instead of the original SNPs reported in other populations due to differential genetic architecture across populations. Our results highlight the importance of performing genetic studies in non-European populations to fine map the causal genetic variants.
doi:10.1371/journal.pgen.1004517
PMCID: PMC4125087  PMID: 25102180
Genetic epidemiology  2013;37(5):512-521.
Venous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a 2-stage genome-wide association study (GWAS) among individuals of European ancestry in the extended CHARGE VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to ~2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (p≤0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case-control studies. In the combined data from these two stages, additional genome-wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG) (p<5.0×10−13 for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (p<5.0×10-6) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.
doi:10.1002/gepi.21731
PMCID: PMC3990406  PMID: 23650146
venous thrombosis; genetics; genome-wide association; genetic epidemiology
The Laryngoscope  2013;123(6):1399-1404.
Objective
To determine the distribution of the perceived intensity of salt, sweet, sour, and bitter in a large population and to investigate factors associated with perceived taste intensity.
Study Design
Cross-sectional population.
Methods
Subjects (n = 2374, mean age=48.8 years) were participants in the Beaver Dam Offspring Study examined during 2005-2008. Perceived taste intensity was measured using paper disks and a general labeled magnitude scale. Multiple linear regression was performed.
Results
Mean intensity ratings were: salt=27.2 (standard deviation [s.d.]=18.5), sweet=20.4 (s.d.=15.0), sour=35.7 (s.d.=21.4), and bitter=49.6 (s.d.=23.3). Females and those with less than a college degree education rated tastes stronger. With adjustment for age, sex, and education, stronger perceived sour and bitter intensities were related to current smoking (Sour:B=2.8, 95% Confidence Interval [CI]=0.4,5.2; Bitter:B=2.8, 95% CI=0.3,5.4) and lipid-lowering medications (Sour:B=5.1, 95% CI=2.5,7.6; Bitter:B=3.2, 95% CI=0.6,5.8). Alcohol consumption in the past year was related to weaker salt (B= −2.8, 95% CI= −5.3,−0.3) and sweet intensity ratings (B= −2.3, 95% CI= −4.3,−0.3) while olfactory impairment was associated with higher sweet ratings (B=4.7, 95% CI=1.4,7.9).
Conclusion
Perceived intensities were strongest for bitter and weakest for sweet. Sex and education were associated with each taste while age did not demonstrate a consistent relationship. Associations with other factors differed by tastant with current smoking and alcohol consumption being related to some tastes.
doi:10.1002/lary.23894
PMCID: PMC3664123  PMID: 23625687
salt taste; sweet taste; sour taste; bitter taste
Background
Fibroblast growth factor‐23 (FGF‐23) is a hormone involved in phosphorous regulation and vitamin D metabolism that may be associated with cardiovascular risk, and it is a potential target for intervention. We tested whether elevated FGF‐23 is associated with incident coronary heart disease, heart failure, and cardiovascular mortality, even at normal kidney function.
Methods and Results
A total of 11 638 Atherosclerosis Risk In Communities study participants, median age 57 at baseline (1990–1992), were followed through 2010. Cox regression was used to evaluate the independent association of baseline serum active FGF‐23 with incident outcomes. Models were adjusted for traditional cardiovascular risk factors and estimated glomerular filtration rate. During a median follow‐up of 18.6 years, 1125 participants developed coronary heart disease, 1515 developed heart failure, and 802 died of cardiovascular causes. For all 3 outcomes, there was a threshold, whereby FGF‐23 was not associated with risk at <40 pg/mL but was positively associated with risk at >40 pg/mL. Compared with those with FGF‐23 <40 pg/mL, those in the highest FGF‐23 category (≥58.8 pg/mL) had a higher risk of incident coronary heart disease (adjusted hazard ratio, 95% CIs: 1.65, 1.40 to 1.94), heart failure (1.75, 1.52 to 2.01), and cardiovascular mortality (1.65, 1.36 to 2.01). Associations were modestly attenuated but remained statistically significant after further adjustment for estimated glomerular filtration rate. In stratified analyses, similar results were observed in African Americans and among persons with normal kidney function.
Conclusions
High levels of serum FGF‐23 were associated with increased risk of coronary heart disease, heart failure, and cardiovascular mortality in this large, biracial, population‐based cohort. This association was independent of traditional cardiovascular risk factors and kidney function.
doi:10.1161/JAHA.114.000936
PMCID: PMC4309096  PMID: 24922628
Atherosclerosis Risk In Communities; cardiovascular mortality; coronary heart disease; epidemiology; fibroblast growth factor 23; heart failure
Diabetes  2013;62(3):965-976.
Type 2 diabetes (T2D) disproportionally affects African Americans (AfA) but, to date, genetic variants identified from genome-wide association studies (GWAS) are primarily from European and Asian populations. We examined the single nucleotide polymorphism (SNP) and locus transferability of 40 reported T2D loci in six AfA GWAS consisting of 2,806 T2D case subjects with or without end-stage renal disease and 4,265 control subjects from the Candidate Gene Association Resource Plus Study. Our results revealed that seven index SNPs at the TCF7L2, KLF14, KCNQ1, ADCY5, CDKAL1, JAZF1, and GCKR loci were significantly associated with T2D (P < 0.05). The strongest association was observed at TCF7L2 rs7903146 (odds ratio [OR] 1.30; P = 6.86 × 10−8). Locus-wide analysis demonstrated significant associations (Pemp < 0.05) at regional best SNPs in the TCF7L2, KLF14, and HMGA2 loci as well as suggestive signals in KCNQ1 after correction for the effective number of SNPs at each locus. Of these loci, the regional best SNPs were in differential linkage disequilibrium (LD) with the index and adjacent SNPs. Our findings suggest that some loci discovered in prior reports affect T2D susceptibility in AfA with similar effect sizes. The reduced and differential LD pattern in AfA compared with European and Asian populations may facilitate fine mapping of causal variants at loci shared across populations.
doi:10.2337/db12-0266
PMCID: PMC3581206  PMID: 23193183
American Journal of Epidemiology  2012;177(2):103-115.
Whether loci that influence fasting glucose (FG) and fasting insulin (FI) levels, as identified by genome-wide association studies, modify associations of diet with FG or FI is unknown. We utilized data from 15 US and European cohort studies comprising 51,289 persons without diabetes to test whether genotype and diet interact to influence FG or FI concentration. We constructed a diet score using study-specific quartile rankings for intakes of whole grains, fish, fruits, vegetables, and nuts/seeds (favorable) and red/processed meats, sweets, sugared beverages, and fried potatoes (unfavorable). We used linear regression within studies, followed by inverse-variance-weighted meta-analysis, to quantify 1) associations of diet score with FG and FI levels and 2) interactions of diet score with 16 FG-associated loci and 2 FI-associated loci. Diet score (per unit increase) was inversely associated with FG (β = −0.004 mmol/L, 95% confidence interval: −0.005, −0.003) and FI (β = −0.008 ln-pmol/L, 95% confidence interval: −0.009, −0.007) levels after adjustment for demographic factors, lifestyle, and body mass index. Genotype variation at the studied loci did not modify these associations. Healthier diets were associated with lower FG and FI concentrations regardless of genotype at previously replicated FG- and FI-associated loci. Studies focusing on genomic regions that do not yield highly statistically significant associations from main-effect genome-wide association studies may be more fruitful in identifying diet-gene interactions.
doi:10.1093/aje/kws297
PMCID: PMC3707424  PMID: 23255780
diabetes; dietary pattern; gene-environment interaction; glucose; insulin
Objective
Evidence from pre-clinical studies suggests inhibition of Stearoyl Co-A Desaturase-1 (SCD-1) activity improves insulin sensitivity. Translation of these findings to humans remains less defined. The purpose of this research was to evaluate the association between different measures of SCD-1 activity and incident diabetes in a large, prospective human study.
Methods
In 2738 white participants (aged 45-64 yrs, 47% men) who were free of diabetes at baseline, SCD-1 activity was estimated at baseline by plasma fatty acid ratios in cholesterol esters (SCD16c=16:1n-7/16:0, SCD18c =18:1n-9/18:0) and in phospholipids (SCD16p=16:1n-7/16:0, SCD18p=18:1n-9/18:0). Incident diabetes was ascertained during 3 follow-up visits. Cox proportional hazards regression was used to determine the association between estimated SCD-1 activity and incident diabetes.
Results
During follow-up (mean 8.0 ± SE 2.1 years), 207 (7.6%) participants developed diabetes. After adjusting for age and sex, higher SCD16c, higher SCD16p, and lower SCD18p were significantly associated with incident diabetes. After additional adjustment for education, parental history of diabetes, smoking, dietary intake (carbohydrate, fiber, saturated/monounsaturated/polyunsaturated fat), alcohol use, physical activity, body mass index (BMI), waist-hip ratio, blood pressure, and lipid composition – only SCD16c remained significantly associated with incident diabetes (Hazard Ratio=1.1 linearly across decreasing quintiles, 95% CI 1.01-1.30; p =0.03) which remained nominally associated after adjusting for insulin resistance (p=0.05).
Conclusions
In a large community-based prospective cohort study, the estimate of SCD-1 activity by SCD16c had the strongest association with incident diabetes. Refinement of SCD-1 measurement and replication of its association with incident diabetes in an independent cohort is recommended.
doi:10.1016/j.metabol.2012.06.004
PMCID: PMC3518662  PMID: 22819528
fatty acid ratio; Type 2 Diabetes; prospective study
Diabetes Care  2012;36(1):70-76.
OBJECTIVE
The objective of this study was to determine potential added value of novel risk factors in predicting the development of type 2 diabetes beyond that provided by standard clinical risk factors.
RESEARCH DESIGN AND METHODS
The Atherosclerosis Risk in Communities (ARIC) Study is a population-based prospective cohort study in four U.S. communities. Novel risk factors were either measured in the full cohort or in a case-control sample nested within the cohort. We started with a basic prediction model, previously validated in ARIC, and evaluated 35 novel risk factors by adding them independently to the basic model. The area under the curve (AUC), net reclassification index (NRI), and integrated discrimination index (IDI) were calculated to determine if each of the novel risk factors improved risk prediction.
RESULTS
There were 1,457 incident cases of diabetes with a mean of >7.6 years of follow-up among 12,277 participants at risk. None of the novel risk factors significantly improved the AUC. Forced expiratory volume in 1 s was the only novel risk factor that resulted in a significant NRI (0.54%; 95% CI: 0.33–0.86%). Adiponectin, leptin, γ-glutamyl transferase, ferritin, intercellular adhesion molecule 1, complement C3, white blood cell count, albumin, activated partial thromboplastin time, factor VIII, magnesium, hip circumference, heart rate, and a genetic risk score each significantly improved the IDI, but net changes were small.
CONCLUSIONS
Evaluation of a large panel of novel risk factors for type 2 diabetes indicated only small improvements in risk prediction, which are unlikely to meaningfully alter clinical risk reclassification or discrimination strategies.
doi:10.2337/dc12-0609
PMCID: PMC3526210  PMID: 22933437
PLoS ONE  2013;8(11):e79466.
Endothelial nitric oxide synthase 3 (NOS3) catalyzes the production of nitric oxide from L-arginine in endothelial cells. Obesity is a modifiable risk factor for diabetes, and obese individuals have been reported to have reduced nitric oxide availability compared to controls whose weight is in the normal range. Since homozygous carriers of the NOS3 G894T variant are predicted to have decreased enzyme activity, the association between NOS3 genotype and type 2 diabetes, and possible effect modification by body mass index (BMI) were evaluated. The prevalence of diabetes and BMI was determined at baseline in 14,374 participants 45–66 years of age from the prospective biracial population-based Atherosclerosis Risk in Communities (ARIC) Study of the development of atherosclerosis in four communities in the United States. Individuals with a BMI ≥30 kg/m2 were considered obese. Those subjects not meeting the case definition were the comparison groups for the 728 African American and 980 white participants with diabetes. Multivariable logistic regression models adjusted for age, sex, and field center were used to test for main genetic effects and interaction with obesity. Although the NOS3 G894T variant was not independently associated with diabetes in either African Americans or whites, significant interaction between BMI and the NOS3 polymorphism indicated that obesity was an effect modifier of diabetes risk for white individuals with the TT genotype (odds ratio (OR) for interaction = 1.65, p = 0.04). In stratified analyses, homozygosity for the NOS3 T allele in obese white participants but not in those whose BMI <30 kg/m2 was associated with an elevated risk of diabetes (OR = 1.47, p = 0.02) when compared to the common GG genotype. These results suggest that interaction between obesity and NOS3 genotype may be a determinant of diabetes case status in whites in the ARIC cohort. Replication in other populations will be required to confirm these observations.
doi:10.1371/journal.pone.0079466
PMCID: PMC3835793  PMID: 24278136
American Journal of Epidemiology  2012;176(8):738-743.
The objective of this study was to assess the validity of prevalent and incident self-reported diabetes compared with multiple reference definitions and to assess the reliability (repeatability) of a self-reported diagnosis of diabetes. Data from 10,321 participants in the Atherosclerosis Risk in Communities (ARIC) Study who attended visit 4 (1996–1998) were analyzed. Prevalent self-reported diabetes was compared with reference definitions defined by fasting glucose and medication use obtained at visit 4. Incident self-reported diabetes was assessed during annual follow-up telephone calls and was compared with reference definitions defined by fasting glucose, hemoglobin A1c, and medication use obtained during an in-person visit attended by a subsample of participants (n = 1,738) in 2004–2005. The sensitivity of prevalent self-reported diabetes ranged from 58.5% to 70.8%, and specificity ranged from 95.6% to 96.8%, depending on the reference definition. Similarly, the sensitivity of incident self-reported diabetes ranged from 55.9% to 80.4%, and specificity ranged from 84.5% to 90.6%. Percent positive agreement of self-reported diabetes during 9 years of repeat assessments ranged from 92.7% to 95.4%. Both prevalent self-reported diabetes and incident self-reported diabetes were 84%–97% specific and 55%–80% sensitive as compared with reference definitions using glucose and medication criteria. Self-reported diabetes was >92% reliable over time.
doi:10.1093/aje/kws156
PMCID: PMC3571247  PMID: 23013620
diabetes; validation study
Atherosclerosis  2012;224(2):435-439.
Objective
To determine whether the 9p21 SNP association with coronary heart disease is modified by other classical or novel risk markers.
Methods
The 9p21 SNP (rs10757274) and multiple risk markers were measured in the Atherosclerosis Risk in Communities Study, and incident coronary disease events were ascertained. Effect modification (interaction) of the 9p21 SNP with risk markers was tested in Cox proportional hazard regression models.
Results
The incidence rates of coronary heart disease per 1000 person-years were 14.4, 17.0, and 18.7 for AA, AG, and GG genotypes, yielding hazard ratios of 1.0, 1.20 (95% CI = 1.07-1.36), and 1.34 (95% CI = 1.16-1.53). There was no meaningful evidence of an interaction (all p-interaction > 0.04) between 9p21 SNP and any of 14 other risk markers for coronary heart disease. These included novel markers not previously explored for 9p21 interaction (e.g., cardiac troponin T and N-terminal pro-brain natriuretic peptide).
Conclusion
Our study extends evidence that the 9p21 SNP association with coronary heart disease is not modified by classical or novel risk markers. Our findings therefore rule out additional plausible pathways by which 9p21 might have increased coronary heart disease risk.
doi:10.1016/j.atherosclerosis.2012.08.007
PMCID: PMC3459136  PMID: 22935634
coronary disease; prospective study; 9p21 SNP
BMC Medical Genetics  2013;14:98.
Background
Multiple genome-wide association studies (GWAS) within European populations have implicated common genetic variants associated with insulin and glucose concentrations. In contrast, few studies have been conducted within minority groups, which carry the highest burden of impaired glucose homeostasis and type 2 diabetes in the U.S.
Methods
As part of the 'Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we investigated the association of up to 10 GWAS-identified single nucleotide polymorphisms (SNPs) in 8 genetic regions with glucose or insulin concentrations in up to 36,579 non-diabetic subjects including 23,323 European Americans (EA) and 7,526 African Americans (AA), 3,140 Hispanics, 1,779 American Indians (AI), and 811 Asians. We estimated the association between each SNP and fasting glucose or log-transformed fasting insulin, followed by meta-analysis to combine results across PAGE sites.
Results
Overall, our results show that 9/9 GWAS SNPs are associated with glucose in EA (p = 0.04 to 9 × 10-15), versus 3/9 in AA (p= 0.03 to 6 × 10-5), 3/4 SNPs in Hispanics, 2/4 SNPs in AI, and 1/2 SNPs in Asians. For insulin we observed a significant association with rs780094/GCKR in EA, Hispanics and AI only.
Conclusions
Generalization of results across multiple racial/ethnic groups helps confirm the relevance of some of these loci for glucose and insulin metabolism. Lack of association in non-EA groups may be due to insufficient power, or to unique patterns of linkage disequilibrium.
doi:10.1186/1471-2350-14-98
PMCID: PMC3849560  PMID: 24063630

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