Circulating cellular adhesion molecules and risk of diabetes: the Multi-Ethnic Study of Atherosclerosis (MESA).

Aims: To test the hypothesis that soluble cellular adhesion molecules would be positively and independently associated with risk of diabetes.

Methods: Soluble levels of six cellular adhesion molecules (ICAM-1, E-selectin, VCAM-1, E-cadherin, L-selectin and P-selectin) were measured in participants in the Multi-Ethnic Study of Atherosclerosis, a prospective cohort study. Participants were then followed for up to 10 years to ascertain incident diabetes.

Prospective study of γ' fibrinogen and incident venous thromboembolism: The Longitudinal Investigation of Thromboembolism Etiology (LITE).

Introduction: Epidemiological studies generally have not found plasma total fibrinogen to be a risk factor for venous thromboembolism (VTE), but several have reported associations between variants in the fibrinogen gamma gene (FGG) and VTE. A case-control study in whites suggested plasma γ' fibrinogen concentration may be associated inversely with VTE, but this was not replicated in African Americans.

Objective: To examine the prospective association between γ' fibrinogen concentrations and occurrence of VTE.

Circulating level of hepatocyte growth factor predicts incidence of type 2 diabetes mellitus: The Multi-Ethnic Study of Atherosclerosis (MESA).

Background: Hepatocyte growth factor (HGF) is a pleotropic factor posited to have metabolic homeostatic properties. The purpose of this study is to examine whether level of HGF is associated with the development of type 2 diabetes.

Methods: Data from the Multi-Ethnic Study of Atherosclerosis (MESA) were used to examine the prospective association between serum level of HGF and incident diabetes.

Imputation of missing covariate values in epigenome-wide analysis of DNA methylation data.

DNA methylation is a widely studied epigenetic mechanism and alterations in methylation patterns may be involved in the development of common diseases. Unlike inherited changes in genetic sequence, variation in site-specific methylation varies by tissue, developmental stage, and disease status, and may be impacted by aging and exposure to environmental factors, such as diet or smoking. These non-genetic factors are typically included in epigenome-wide association studies (EWAS) because they may be confounding factors to the association between methylation and disease.

Blood group antigen loci demonstrate multivariate genetic associations with circulating cellular adhesion protein levels in the Multi-Ethnic Study of Atherosclerosis.

The cellular adhesion pathway is critical in the pathophysiology of atherosclerosis, and genetic factors contributing to regulation of circulating levels of related proteins may be relevant to risk prediction of cardiovascular disease. In contrast to conducting separate genome-wide protein quantitative trait loci (pQTL) mapping analyses of each individual protein, joint genetic association analyses of multiple quantitative traits can leverage cross-trait co-variation and identify simultaneous regulatory effects on protein levels across the pathway. We conducted a multi-pQTL (mpQTL) analysis of 15 proteins related to cellular adhesion assayed on 2313 participants from the Multi-Ethnic Study of Atherosclerosis (MESA).

Parathyroid hormone and the risk of incident hypertension: the Atherosclerosis Risk in Communities study.

Background: Recent evidence suggests that parathyroid hormone (PTH) has effects on vascular smooth muscle cells, the rennin-angiotensin system and kidney function, but less is known about its role in the development of hypertension. The distribution of serum PTH also varies by race.

Methods And Results: Therefore, we examined the relation between PTH and incident hypertension and tested for interaction by race among 7504 Atherosclerosis Risk in Communities participants (1264 black, 6240 white, median age 56 years) without initial hypertension in 1990-1992.

Association of the IGF1 gene with fasting insulin levels.

Insulin-like growth factor 1 (IGF-I) has been associated with insulin resistance. Genome-wide association studies (GWASs) of fasting insulin (FI) identified single-nucleotide variants (SNVs) near the IGF1 gene, raising two hypotheses: (1) these associations are mediated by IGF-I levels and (2) these noncoding variants either tag other functional variants in the region or are directly functional. In our study, analyses including 5141 individuals from population-based cohorts suggest that FI associations near IGF1 are not mediated by IGF-I.

Diabetes, hyperglycemia, and the burden of functional disability among older adults in a community-based study.

Background: There is a need for continued surveillance of diabetes-related functional disability. In the present study, we examined associations between diabetes, hyperglycemia, and the burden of functional disability in a community-based population.

Methods: A cross-sectional analysis was conducted of 5035 participants who attended Visit 5 (2011-13) of the Atherosclerosis Risk in Communities study.

On Sample Size and Power Calculation for Variant Set-Based Association Tests.

Sample size and power calculations are an important part of designing new sequence-based association studies. The recently developed SEQPower and SPS programs adopted computationally intensive Monte Carlo simulations to empirically estimate power for a series of variant set association (VSA) test methods including the sequence kernel association test (SKAT). It is desirable to develop methods that can quickly and accurately compute power without intensive Monte Carlo simulations.

Sequence Kernel Association Test of Multiple Continuous Phenotypes.

Genetic studies often collect multiple correlated traits, which could be analyzed jointly to increase power by aggregating multiple weak effects and provide additional insights into the etiology of complex human diseases. Existing methods for multiple trait association tests have primarily focused on common variants. There is a surprising dearth of published methods for testing the association of rare variants with multiple correlated traits.

Parathyroid hormone is associated with incident diabetes in white, but not black adults: The Atherosclerosis Risk in Communities (ARIC) Study.

Objective: Accumulating evidence has linked elevated parathyroid hormone (PTH) with insulin resistance, beta cell dysfunction and dysglycaemia, however, its role in the development of diabetes is largely unclear, particularly among non-whites. We sought to examine the association of PTH with the incidence of diabetes.

Methods: We studied 8066 white and 2034 black adults aged 46-70 years at baseline (1990-92) from the ARIC Study with follow-up for incident diabetes ascertained during study visits conducted in 1993-95 and 1996-98.

Rare variant associations with waist-to-hip ratio in European-American and African-American women from the NHLBI-Exome Sequencing Project.

Waist-to-hip ratio (WHR), a relative comparison of waist and hip circumferences, is an easily accessible measurement of body fat distribution, in particular central abdominal fat. A high WHR indicates more intra-abdominal fat deposition and is an established risk factor for cardiovascular disease and type 2 diabetes. Recent genome-wide association studies have identified numerous common genetic loci influencing WHR, but the contributions of rare variants have not been previously reported.

On Efficient and Accurate Calculation of Significance P-Values for Sequence Kernel Association Testing of Variant Set.

The objective of this paper is to discuss and develop alternative computational methods to accurately and efficiently calculate significance P-values for the commonly used sequence kernel association test (SKAT) and adaptive sum of SKAT and burden test (SKAT-O) for variant set association. We show that the existing software can lead to either conservative or inflated type I errors. We develop alternative and efficient computational algorithms that quickly compute the SKAT P-value and have well-controlled type I errors.

USAT: A Unified Score-Based Association Test for Multiple Phenotype-Genotype Analysis.

Genome-wide association studies (GWASs) for complex diseases often collect data on multiple correlated endo-phenotypes. Multivariate analysis of these correlated phenotypes can improve the power to detect genetic variants. Multivariate analysis of variance (MANOVA) can perform such association analysis at a GWAS level, but the behavior of MANOVA under different trait models has not been carefully investigated.

Impact of adiposity on cellular adhesion: The Multi-Ethnic Study of atherosclerosis (MESA).

Objective: At the cellular level, how excess adiposity promotes atherogenesis is not fully understood. One pathway involves secretion of adipokines that stimulate endothelial dysfunction through increased expression of adhesion molecules. However, the relationship of adiposity to adhesion molecules that promote atherosclerosis is largely unknown.

Replication of a genetic risk score for venous thromboembolism in whites but not in African Americans.

Unlabelled: ESSENTIALS: There is little prospective information on genetic risk scores to predict venous thromboembolism (VT). Community based cohort followed a median of 22.6 years for VT occurrence.

Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation.

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium.

Association of 1,5-Anhydroglucitol With Cardiovascular Disease and Mortality.

In diabetes, low concentrations of the biomarker 1,5-anhydroglucitol (1,5-AG) reflect hyperglycemic excursions over the prior 1-2 weeks. To the extent that hyperglycemic excursions are important in atherogenesis, 1,5-AG may provide independent information regarding cardiovascular risk. Nonetheless, few studies have evaluated associations of 1,5-AG with long-term cardiovascular outcomes in a population-based setting.

Carboxymethyl lysine, an advanced glycation end product, and incident diabetes: a case-cohort analysis of the ARIC Study.

Aims: To verify whether elevated fasting levels of circulating carboxymethyl lysine (CML), an advanced glycation end product, predict the development of diabetes in middle-age adults.

Methods: Using a stratified case-cohort design, we followed 543 middle-aged individuals who developed diabetes and 514 who did not over a median 9 years in the Atherosclerosis Risk in Communities Study. Weighted Cox proportional hazards analyses were used to account for the design.

Consumption of meat is associated with higher fasting glucose and insulin concentrations regardless of glucose and insulin genetic risk scores: a meta-analysis of 50,345 Caucasians.

Background: Recent studies suggest that meat intake is associated with diabetes-related phenotypes. However, whether the associations of meat intake and glucose and insulin homeostasis are modified by genes related to glucose and insulin is unknown.

Objective: We investigated the associations of meat intake and the interaction of meat with genotype on fasting glucose and insulin concentrations in Caucasians free of diabetes mellitus.

Geospatial patterns of human papillomavirus vaccine uptake in Minnesota.

Objectives: To identify factors associated with human papillomavirus (HPV) vaccination and to determine the geographic distribution of vaccine uptake while accounting for spatial autocorrelation.

Design: This study is cross-sectional in design using data collected via the Internet from the Survey of Minnesotans About Screening and HPV study.

Setting And Participants: The sample consists of 760 individuals aged 18-30 years nested within 99 ZIP codes surrounding the downtown area of Minneapolis, Minnesota.

Six-year change in high-sensitivity C-reactive protein and risk of diabetes, cardiovascular disease, and mortality.

Background: Single measurements of elevated high-sensitivity C-reactive protein (hs-CRP) are associated with increased risk of diabetes, cardiovascular disease, and mortality. Large increases or sustained elevations in hs-CRP may be associated with even greater risk of these outcomes. The objective of this study was to characterize the association of 6-year change in hs-CRP with incident diabetes, incident cardiovascular events (heart disease, stroke, and heart failure), and mortality.