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1.  Three Approaches to Modeling Gene-Environment Interactions in Longitudinal Family Data: Gene-Smoking Interactions in Blood Pressure 
Genetic epidemiology  2015;40(1):73-80.
Blood pressure (BP) has been shown to be substantially heritable, yet identified genetic variants explain only a small fraction of the heritability. Gene-smoking interactions have detected novel BP loci in cross-sectional family data. Longitudinal family data are available and have additional promise to identify BP loci. However, this type of data presents unique analysis challenges. Although several methods for analyzing longitudinal family data are available, which method is the most appropriate and under what conditions has not been fully studied.
Using data from three clinic visits from the Framingham Heart Study, we performed association analysis accounting for gene-smoking interactions in BP at 31,203 markers on chromosome 22. We evaluated three different modeling frameworks: generalized estimating equations, hierarchical linear modeling, and pedigree-based mixed modeling.
The three models performed somewhat comparably, with multiple overlaps in the most strongly associated loci from each model. Loci with the greatest significance were more strongly supported in the longitudinal analyses than in any of the component single-visit analyses. The pedigree-based mixed model was more conservative, with less inflation in the variant main effect and greater deflation in the gene-smoking interactions. The generalized estimating equations, but not the other two models, resulted in substantial inflation in the tail of the distribution when variants with minor allele frequency < 1% were included in the analysis.
The choice of analysis method should depend on the model and the structure and complexity of the familial and longitudinal data.
PMCID: PMC4867544  PMID: 26625943
2.  Gene–Smoking Interactions Identify Several Novel Blood Pressure Loci in the Framingham Heart Study 
American Journal of Hypertension  2014;28(3):343-354.
Cardiovascular diseases are among the most significant health problems in the United States. Blood pressure (BP) variability has a genetic component, and most of the genetic variance remains to be identified. One promising strategy for gene discovery is genome-wide analysis of interactions between single nucleotide polymorphisms (SNPs) and environmental factors related to cardiovascular diseases.
We investigated SNP–smoking interaction effects on BP in genome-wide data in 6,889 participants from the Framingham Heart Study. We performed the standard 1 degree of freedom (df) test of the interaction effect and the joint 2 df test of main and interaction effects. Three smoking measures were used: cigarettes per day (CPD), pack years of smoking, and smoking status.
We identified 7 significant and 21 suggestive BP loci. Identified through the joint 2 df test, significant SBP loci include: rs12149862 (P = 3.65×10–9) in CYB5B, rs2268365 (P = 4.85×10–8) in LRP2, rs133980 (P = 1.71×10–8 with CPD and P = 1.07×10–8 with pack-years) near MN1, and rs12634933 (P = 4.05×10–8) in MECOM. Through 1 df interaction analysis, 1 suggestive SBP locus at SNP rs8010717 near NRXN3 was identified using all 3 smoking measures (P = 3.27×10–7 with CPD, P = 1.03×10–7 with pack-years, and P = 1.19×10–7 with smoking status).
Several of these BP loci are biologically plausible, providing physiological connection to BP regulation. Our study demonstrates that SNP–smoking interactions can enhance gene discovery and provide insight into novel pathways and mechanisms regulating BP.
PMCID: PMC4402348  PMID: 25189868
blood pressure; gene–environment interaction; genome-wide association study; hypertension; single nucleotide polymorphisms; smoking.
3.  Single Nucleotide Polymorphism–Single Nucleotide Polymorphism Interactions Among Inflammation Genes in the Genetic Architecture of Blood Pressure in the Framingham Heart Study 
American Journal of Hypertension  2014;28(2):248-255.
Hypertension is a major global health burden, but, although systolic and diastolic blood pressure (BP) each have estimated heritability of at least 30%, <3% of their variance has been attributed to particular genetic variants. Few studies have shown interactions between pairs of single nucleotide polymorphisms (SNPs) to be associated with BP. Although many studies use a Bonferroni correction for multiple testing to control type I error, thereby potentially reducing power, false discovery rate (FDR) approaches are also used in genome-wide studies. Renal ion balance genes have been associated with BP regulation, but, although inflammation has been studied in connection with BP, few studies have reported associations between inflammation genes and BP.
We analyzed SNP-SNP interactions among 31 SNPs from genes involved in renal ion balance and 30 SNPs from genes involved in inflammation using data from the Framingham Heart Study.
No evidence of association was found for interactions among renal ion balance SNPs for either systolic or diastolic BP. A group of 3 interactions involving 6 inflammation genes (IKBKB–NFKBIA, IKBKE–CHUK, and ADIPOR2–RETN) showed evidence of association with diastolic BP with an FDR of 4.2%; no single interaction reached experiment-wide significance.
This study identified promising and biologically plausible candidates for interactions between inflammation genes that may be associated with DBP. Analysis using the FDR may allow detection of signals in the presence of modest noise (false positives) that a stringent approach based on Bonferroni-corrected P value thresholds may miss.
PMCID: PMC4400411  PMID: 25063733
blood pressure; false discovery rate; hypertension; inflammation; interaction; NFκB; single nucleotide polymorphism.
5.  A custom correlation coefficient (CCC) approach for fast identification of multi-SNP association patterns in genome-wide SNPs data 
Genetic epidemiology  2014;38(7):610-621.
Complex diseases are often associated with sets of multiple interacting genetic factors and possibly with unique sets of the genetic factors in different groups of individuals (genetic heterogeneity). We introduce a novel concept of Custom Correlation Coefficient (CCC) between single nucleotide polymorphisms (SNPs) that address genetic heterogeneity by measuring subset correlations autonomously. It is used to develop a 3-step process to identify candidate multi-SNP patterns: (1) pairwise (SNP-SNP) correlations are computed using CCC; (2) clusters of so-correlated SNPs identified; and (3) frequencies of these clusters in disease cases and controls compared to identify disease-associated multi-SNP patterns. This method identified 42 candidate multi-SNP associations with hypertensive heart disease (HHD), among which one cluster of 22 SNPs (6 genes) included 13 in SLC8A1 (aka NCX1, an essential component of cardiac excitation-contraction coupling) and another of 32 SNPs had 29 from a different segment of SLC8A1. While allele frequencies show little difference between cases and controls, the cluster of 22 associated alleles were found in 20% of controls but no cases and the other in 3% of controls but 20% of cases. These suggest that both protective and risk effects on HHD could be exerted by combinations of variants in different regions of SLC8A1, modified by variants from other genes. The results demonstrate that this new correlation metric identifies disease-associated multi-SNP patterns overlooked by commonly used correlation measures. Furthermore, computation time using CCC is a small fraction of that required by other methods, thereby enabling the analyses of large GWAS datasets.
PMCID: PMC4190009  PMID: 25168954
gene-gene interaction; multi-SNP association; custom correlation coefficient; genome-wide interactions study (GWIS); network analysis
6.  Cardiovascular Phenotype in Patients with Heart Failure and Preserved Ejection Fraction with or without Diabetes: A RELAX Trial Ancillary Study 
RELAX was a multicenter randomized trial of sildenafil versus placebo in heart failure and preserved ejection fraction (HFpEF) with rigorous entry criteria and extensive phenotypic characterization of participants.
To characterize clinical features, exercise capacity, and outcomes in patients with HFpEF with or without diabetes and gain insight into contributing pathophysiologic mechanisms.
RELAX enrolled 216 stable outpatients with heart failure, EF ≥50%, elevated natriuretic peptide or intracardiac pressures, and reduced exercise capacity. Prospectively collected data included echocardiography, cardiac magnetic resonance imaging, a comprehensive biomarker panel, exercise testing, and clinical events over 6 months.
Compared with non-diabetics (n=123), diabetic (n=93) HFpEF patients were younger, more obese, more often male, and had a higher prevalence of hypertension, renal dysfunction, pulmonary disease, and vascular disease (p<0.05 for all). Uric acid, C-reactive protein, galectin-3, carboxy-terminal telopeptide of collagen type I, and endothelin-1 levels were higher in diabetics (p<0.05 for all). Diabetic patients had more ventricular hypertrophy but systolic and diastolic ventricular function parameters were similar in diabetics and non-diabetics except for a trend toward higher filling pressures (E/e′) in diabetics. Diabetics had worse maximal (peak oxygen uptake) and submaximal (6-minute walk distance) exercise capacity (p<0.01 for both). Diabetic patients were more likely to have been hospitalized for HF in the year prior to study entry (47% vs 28%, p=0.004) and had a higher incidence of cardiac or renal hospitalization at 6 months after enrollment (23.7% vs 4.9%, p<0.001).
HFpEF patients with diabetes are at increased risk of hospitalization and have reduced exercise capacity. Multi-morbidity, impaired chronotropic reserve, left ventricular hypertrophy and activation of inflammatory, pro-oxidative, vasoconstrictor, and pro-fibrotic pathways may contribute to adverse outcomes in HFpEF patients with diabetes. (NCT00763867)
PMCID: PMC4133145  PMID: 25104521
heart failure with preserved ejection fraction; diabetes mellitus; biomarkers; exercise capacity; left ventricular structure
7.  Aggregate blood pressure responses to serial dietary sodium and potassium intervention: defining responses using independent component analysis 
BMC Genetics  2015;16:64.
Hypertension is a complex trait that often co-occurs with other conditions such as obesity and is affected by genetic and environmental factors. Aggregate indices such as principal components among these variables and their responses to environmental interventions may represent novel information that is potentially useful for genetic studies.
In this study of families participating in the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) Study, blood pressure (BP) responses to dietary sodium interventions are explored. Independent component analysis (ICA) was applied to 20 variables indexing obesity and BP measured at baseline and during low sodium, high sodium and high sodium plus potassium dietary intervention periods. A “heat map” protocol that classifies subjects based on risk for hypertension is used to interpret the extracted components. ICA and heat map suggest four components best describe the data: (1) systolic hypertension, (2) general hypertension, (3) response to sodium intervention and (4) obesity. The largest heritabilities are for the systolic (64 %) and general hypertension (56 %) components. There is a pattern of higher heritability for the component response to intervention (40–42 %) as compared to those for the traditional intervention responses computed as delta scores (24 %–40 %).
In summary, the present study provides intermediate phenotypes that are heritable. Using these derived components may prove useful in gene discovery applications.
Electronic supplementary material
The online version of this article (doi:10.1186/s12863-015-0226-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4474450  PMID: 26088064
Blood pressure; Cardiovascular diseases; Hypertension; Independent component analysis
8.  Gene–Education Interactions Identify Novel Blood Pressure Loci in the Framingham Heart Study 
American Journal of Hypertension  2014;27(3):431-444.
Blood pressure (BP) variability has a genetic component, most of which has yet to be attributed to specific variants. One promising strategy for gene discovery is analysis of interactions between single-nucleotide polymorphisms (SNPs) and BP-related factors, including age, sex, and body mass index (BMI). Educational attainment, a marker for socioeconomic status, has effects on both BP and BMI.
We investigated SNP–education interaction effects on BP in genome-wide data on 3,836 subjects in families from the Framingham Heart Study. The ABEL suite was used to adjust for age, sex, BMI, medication use, and kinship and to perform 1 degree-of-freedrom (df) and 2 df SNP–education interaction tests.
An SNP in PTN was associated with increased systolic BP (5.4mm Hg per minor allele) in those without a bachelor’s degree but decreased systolic BP (1.6mm Hg per allele) in those with a bachelor’s degree (2 df; P = 2.08×10–8). An SNP in TOX2 was associated with increased diastolic BP (DBP; 4.1mm Hg per minor allele) in those with no more educational attainment than high school but decreased DBP in those with education past high school (−0.7; 1 df; P = 3.74×10–8). Three suggestive associations were also found: in MYO16 (pulse pressure: 2 df; P = 2.89×10–7), in HAS2 (DBP: 1 df; P = 1.41×10–7), and in DLEU2 (DBP: 2 df; P = 1.93×10–7). All 5 genes are related to BP, including roles in vasodilation and angiogenesis for PTN and TOX2.
PTN and TOX2 are associated with BP. Analyzing SNP–education interactions may detect novel associations. Education may be a surrogate for unmeasured exposures and behaviors modifying SNP effects on BP.
PMCID: PMC3915746  PMID: 24473254
blood pressure; educational attainment; gene–education interaction; GWAS; hypertension; interaction.
9.  Effects of Phosphate Binder Therapy on Vascular Stiffness in Early Stage Chronic Kidney Disease 
American journal of nephrology  2013;38(2):10.1159/000353569.
Cardiovascular disease (CVD) is increased in chronic kidney disease (CKD), and contributed to by the CKD-mineral bone disorder (CKD-MBD). The CKD-MBD begins in early CKD and its vascular manifestations begin with vascular stiffness proceeding to increased carotid artery intima-media thickness (cIMT) and vascular calcification (VC). Phosphorus is associated with this progression and is considered a CVD risk factor in CKD. We hypothesized that modifying phosphorus balance with lanthanum carbonate (LaCO3) in early CKD would not produce hypophosphatemia and may affect vascular manifestations of the CKD-MBD.
We randomized 38 subjects with normophosphatemic stage 3 CKD to a fixed dose of LaCO3 or matching placebo without adjusting dietary phosphorus in a 12-month randomized, double-blind, pilot and feasibility study. The primary outcome was the change in serum phosphorus. Secondary outcomes were changes in measures of phosphate homeostasis and vascular stiffness assessed by carotid-femoral pulse wave velocity (PWV), cIMT and VC over 12 months.
There were no statistically significant differences between LaCO3 and placebo with respect to the change in serum phosphorus, urinary phosphorus, tubular reabsorption of phosphorus, PWV, cIMT, or VC. Biomarkers of the early CKD-MBD such as plasma fibroblast growth factor-23 (FGF23), Dickkopf-related protein 1 (DKK1), and sclerostin were increased 2–3-fold at baseline but were not affected by LaCO3.
12 months of LaCO3 had no effect on serum phosphorus and did not alter phosphate homeostasis, PWV, cIMT, VC, or biomarkers of the CKD-MBD.
PMCID: PMC3874122  PMID: 23941761
Cardiovascular disease; chronic kidney disease; phosphate binders; vascular calcification; randomized controlled trials
10.  Relationships Among HIV Infection, Metabolic Risk Factors, and Left Ventricular Structure and Function 
AIDS Research and Human Retroviruses  2013;29(8):1151-1160.
Our objective was to determine if the presence of metabolic complications (MC) conveyed an additional risk for left ventricular (LV) dysfunction in people with HIV. HIV+ and HIV− men and women were categorized into four groups: (1) HIV+ with MC (43±7 years, n=64), (2) HIV+ without MC (42±7 years, n=59), (3) HIV− with MC (44±8 years, n=37), or (4) HIV− controls without MC (42±8 years, n=41). All participants underwent two-dimensional (2-D), Doppler, and tissue Doppler echocardiography. Overall, the prevalence of systolic dysfunction (15 vs. 4%, p=0.02) and LV hypertrophy (9 vs. 1%, p=0.03) was greater in HIV+ than in HIV− participants. Participants with MC had a greater prevalence of LV hypertrophy (10% vs. 1%). Early mitral annular velocity during diastole was significantly (p<0.005) lower in groups with MC (HIV+/MC+: 11.6±2.3, HIV−/MC+: 12.0±2.3 vs. HIV+/MC−: 12.4±2.3, HIV−/MC−: 13.1±2.4 cm/s) and tended to be lower in groups with HIV (p=0.10). However, there was no interaction effect of HIV and MC for any systolic or diastolic variable. Regardless of HIV status, participants with MC had reduced LV diastolic function. Although both the presence of MC and HIV infection were associated with lower diastolic function, there was no additive negative effect of HIV on diastolic function beyond the effect of MC. Also, HIV was independently associated with lower systolic function. Clinical monitoring of LV function in individuals with metabolic risk factors, regardless of HIV status, is warranted.
PMCID: PMC3715767  PMID: 23574474
11.  An Overview of the Genomics of Metabolic Syndrome 
This article provides a brief overview of the diagnostic criteria and genomic risk factors for the components of metabolic syndrome (MetS).
Organizing Constructs
Contributions of cardiovascular, obesity, and diabetes genomic risk factors to the development of MetS as reported in the literature have been reviewed.
The genomic risk factors for the development of MetS are strongly linked to the genomic risk factors that make up the components of the disease. Many of the cardiovascular and renal genomic risk factors for MetS development are similar to those found in the development of hypertension and dyslipidemia. Obesity may act as a master trigger to turn on the gene expression changes necessary for the other components of the disease. Studies in the genomics of type 2 diabetes show a number of overlapping genes and polymorphisms that influence both the development of diabetes and MetS.
Although health practitioners now have some insights into the genomics of risk factors associated with MetS, the overall understanding of MetS remains inadequate. Clinical applications based on some of the discussed genomic risk factors are being developed but are not yet available for the diagnosis and treatment of MetS.
Clinical Relevance
A broad knowledge of the genomic contributions to disease processes will enable the clinician to better utilize genomics to assess and tailor management of patients.
PMCID: PMC3594572  PMID: 23368731
Genomics; metabolic syndrome; cardiovascular; diabetes; obesity
12.  The role of SNP-loop diuretic interactions in hypertension across ethnic groups in HyperGEN 
Frontiers in Genetics  2013;4:304.
Blood pressure (BP) is significantly influenced by genetic factors; however, less than 3% of the BP variance has been accounted for by variants identified from genome-wide association studies (GWAS) of primarily European-descent cohorts. Other genetic influences, including gene-environment (GxE) interactions, may explain more of the unexplained variance in BP. African Americans (AA) have a higher prevalence and earlier age of onset of hypertension (HTN) as compared with European Americans (EA); responses to anti-hypertensive drugs vary across race groups. To examine potential interactions between the use of loop diuretics and HTN traits, we analyzed systolic (SBP) and diastolic (DBP) blood BP from 1222 AA and 1231 EA participants in the Hypertension Genetic Epidemiology Network (HyperGEN). Population-specific score tests were used to test associations of SBP and DBP, using a panel of genotyped and imputed single nucleotide polymorphisms (SNPs) for AA (2.9 million SNPs) and EA (2.3 million SNPs). Several promising loci were identified through gene-loop diuretic interactions, although no SNP reached genome-wide significance after adjustment for genomic inflation. In AA, SNPs in or near the genes NUDT12, CHL1, GRIA1, CACNB2, and PYHIN1 were identified for SBP, and SNPs near ID3 were identified for DBP. For EA, promising SNPs for SBP were identified in ESR1 and for DBP in SPATS2L and EYA2. Among these SNPs, none were common across phenotypes or population groups. Biologic plausibility exists for many of the identified genes, suggesting that these are candidate genes for regulation of BP and/or anti-hypertensive drug response. The lack of genome-wide significance is understandable in this small study employing gene-drug interactions. These findings provide a set of prioritized SNPs/candidate genes for future studies in HTN. Studies in more diversified population samples may help identify previously missed variants.
PMCID: PMC3872290  PMID: 24400021
blood pressure; hypertension; loop diuretic; gene-drug interaction; genome-wide association; african americans; european americans
13.  Pathway-based genome-wide association analysis of coronary heart disease identifies biologically important gene sets 
European Journal of Human Genetics  2012;20(11):1168-1173.
Genome-wide association (GWA) studies of complex diseases including coronary heart disease (CHD) challenge investigators attempting to identify relevant genetic variants among hundreds of thousands of markers being tested. A selection strategy based purely on statistical significance will result in many false negative findings after adjustment for multiple testing. Thus, an integrated analysis using information from the learned genetic pathways, molecular functions, and biological processes is desirable. In this study, we applied a customized method, variable set enrichment analysis (VSEA), to the Framingham Heart Study data (404 467 variants, n=6421) to evaluate enrichment of genetic association in 1395 gene sets for their contribution to CHD. We identified 25 gene sets with nominal P<0.01; at least four sets are previously known for their roles in CHD: vascular genesis (GO:0001570), fatty-acid biosynthetic process (GO:0006633), fatty-acid metabolic process (GO:0006631), and glycerolipid metabolic process (GO:0046486). Although the four gene sets include 170 genes, only three of the genes contain a variant ranked among the top 100 in single-variant association tests of the 404 467 variants tested. Significant enrichment for novel gene sets less known for their importance to CHD were also identified: Rac 1 cell-motility signaling pathway (h_rac1 Pathway, P<0.001) and sulfur amino-acid metabolic process (GO:0000096, P<0.001). In summary, we showed that the pathway-based VSEA can help prioritize association signals in GWA studies by identifying biologically plausible targets for downstream searches of genetic variants associated with CHD.
PMCID: PMC3477866  PMID: 22510845
gene set enrichment; pathway-based analysis; SNP; genome-wide association
14.  Role of Serotoninergic Pathways in Drug-induced Valvular Heart Disease and Diagnostic Features by Echocardiography 
Serotonin plays a significant role in the development of carcinoid heart disease, which primarily leads to fibrosis and contraction of right-sided heart valves. Recently, strong evidence has emerged that the use of specific drug classes such as ergot alkaloids (for migraine headaches), 5-hydroxytryptamine (5-HT or serotonin) uptake regulators/inhibitors (for weight reduction), and ergot-derived dopamine agonists (for Parkinson’s disease) can result in left-sided heart valve damage that resembles carcinoid heart disease. Recent studies suggest that both right- and left-sided drug-induced heart valve disease involves increased serotoninergic activity and in particular activation of the 5-HT receptors, including the 5-HT2B receptor subtype, which mediate many of the central and peripheral functions of serotonin. G-proteins that inhibit adenylate cyclase activity mediate the activity of the 5-HT2B receptor subunit which is widely expressed in a variety of tissues including liver, lung, heart, and coronary and pulmonary arteries; and it has also been reported in embryonic mouse heart, particularly on mouse heart valve leaflets. In this review we discuss the salient features of serotoninergic manifestations of both carcinoid heart disease and drug-induced cardiac valvulopathy with an emphasis on echocardiographic diagnosis.
PMCID: PMC3808845  PMID: 19553085
Carcinoid heart disease; Serotonin; Echocardiography
15.  The St. Louis African American health-heart study: methodology for the study of cardiovascular disease and depression in young-old African Americans 
Coronary artery disease (CAD) is a major cause of death and disability worldwide. Depression has complex bidirectional adverse associations with CAD, although the mechanisms mediating these relationships remain unclear. Compared to European Americans, African Americans (AAs) have higher rates of morbidity and mortality from CAD. Although depression is common in AAs, its role in the development and features of CAD in this group has not been well examined. This project hypothesizes that the relationships between depression and CAD can be explained by common physiological pathways and gene-environment interactions. Thus, the primary aims of this ongoing project are to: a) determine the prevalence of CAD and depression phenotypes in a population-based sample of community-dwelling older AAs; b) examine the relationships between CAD and depression phenotypes in this population; and c) evaluate genetic variants from serotoninP and inflammatory pathways to discover potential gene-depression interactions that contribute significantly to the presence of CAD in AAs.
The St. Louis African American Health (AAH) cohort is a population-based panel study of community-dwelling AAs born in 1936–1950 (inclusive) who have been followed from 2000/2001 through 2010. The AAH-Heart study group is a subset of AAH participants recruited in 2009–11 to examine the inter-relationships between depression and CAD in this population. State-of-the-art CAD phenotyping is based on cardiovascular characterizations (coronary artery calcium, carotid intima-media thickness, cardiac structure and function, and autonomic function). Depression phenotyping is based on standardized questionnaires and detailed interviews. Single nucleotide polymorphisms of selected genes in inflammatory and serotonin-signaling pathways are being examined to provide information for investigating potential gene-depression interactions as modifiers of CAD traits. Information from the parent AAH study is being used to provide population-based prevalence estimates. Inflammatory and other biomarkers provide information about potential pathways.
This population-based investigation will provide valuable information on the prevalence of both depression and CAD phenotypes in this population. The study will examine interactions between depression and genetic variants as modulators of CAD, with the intent of detecting mechanistic pathways linking these diseases to identify potential therapeutic targets. Analytic results will be reported as they become available.
PMCID: PMC3847628  PMID: 24011389
Coronary artery disease; Depression; Genetic analyses; African Americans; Inflammatory biomarkers; Inflammatory pathway; Serotonin-signaling pathway; Heart rate variability; Built environment; Bayesian analysis
16.  Obesity–insulin targeted genes in the 3p26-25 region in human studies and LG/J and SM/J mice 
Identifying metabolic syndrome (MetS) genes is important for novel drug development and health care. This study extends the findings on human chromosome 3p26-25 for an identified obesity–insulin factor QTL, with an LOD score above 3. A focused association analysis comprising up to 9578 African American and Caucasian subjects from the HyperGEN Network (908 African Americans and 1025 whites), the Family Heart Study (3035 whites in time 1 and 1943 in time 2), and the Framingham Heart Study (1317 in Offspring and 1320 in Generation 3) was performed. The homologous mouse region was explored in an F16 generation of an advanced intercross between the LG/J and SM/J inbred strains, in an experiment where 1002 animals were fed low-fat (247 males; 254 females) or high-fat (253 males; 248 females) diets. Association results in humans indicate pleiotropic effects for SNPs within or surrounding CNTN4 on obesity, lipids and blood pressure traits and for SNPs near IL5RA, TRNT1, CRBN, and LRRN1 on central obesity and blood pressure. Linkage analyses of this region in LG/J × SM/J mice identify a highly significant pleiotropic QTL peak for insulin and glucose levels, as well as response to glucose challenge. The mouse results show that insulin and glucose levels interact with high and low fat diets and differential gene expression was identified for Crbn and Arl8b. In humans, ARL8B resides ~137 kbps away from BHLHE40, expression of which shows up-regulation in response to insulin treatment. This focused human genetic analysis, incorporating mouse research evidenced that 3p26-25 has important genetic contributions to MetS components. Several of the candidate genes have functions in the brain. Their interaction with MetS and the brain warrants further investigation.
PMCID: PMC3586585  PMID: 22386932
17.  Abnormalities in Cardiac Structure and Function in Adults with Sickle Cell Disease are not Associated with Pulmonary Hypertension 
In sickle cell disease (SCD), pulmonary hypertension (assessed by tricuspid regurgitant jet [TRJ] velocity ≥ 2.5 m/s) is associated with increased mortality. The relationships between TRJ velocity, left ventricular (LV) and right ventricular (RV) systolic and diastolic function (i.e., relaxation and compliance) have not been well characterized in SCD.
Design and Methods
Prospective study of 53 ambulatory SCD adults (age, mean: 34 years; range 21-65 years) and 33 African American controls to define the relationship between LV and RV function and TRJ velocity by use of echocardiography.
SCD subjects had larger left and right atrial volumes and increased LV mass compared to controls. When SCD cases were compared to controls, LV and RV relaxation (i.e., E’) were similar. Among SCD subjects, pulmonary hypertension (TRJ ≥ 2.5 m/s) was present in 40% of cases. Higher TRJ velocity was correlated with larger LA volumes and areas in SCD cases. Additionally, some measures of LV (peak A, lateral and septal annulus E/E’) and RV compliance (TV E/E’) were correlated with TRJ velocity. No other measures of LV/RV systolic function or LV diastolic function (i.e., relaxation and compliance) were associated with TRJ velocity.
Ambulatory adults with SCD exhibited structural (i.e., LV and RV chamber enlargement) and functional (i.e., higher surrogate measures of LV and RV filling pressure) abnormalities compared to the control group. In SCD subjects, few abnormalities of LV and RV structure/function were associated with TRJ velocity.
PMCID: PMC3200507  PMID: 21873028
Pulmonary hypertension; diastolic dysfunction; sickle cell disease
18.  Variable set enrichment analysis in genome-wide association studies 
Complex diseases such as hypertension are inherently multifactorial and involve many factors of mild-to-minute effect sizes. A genome-wide association study (GWAS) typically tests hundreds of thousands of single-nucleotide polymorphisms (SNPs), and offers opportunity to evaluate aggregated effects of many genetic variants with effects that are too small to detect individually. The gene-set-enrichment analysis (GSEA) is a pathway-based approach that tests for such aggregated effects of genes that are linked by biological functions. A key step in GSEA is the summary statistic (gene score) used to measure the overall relevance of a gene based on all SNPs tested in the gene. Existing GSEA methods use maximum statistics sensitive to gene size and linkage equilibrium. We propose the approach of variable set enrichment analysis (VSEA) and study new gene score methods that are less dependent on gene size. The new method treats groups of variables (SNPs or other variants) as base units for summarizing gene scores and relies less on gene definition itself. The power of VSEA is analyzed by simulation studies modeling various scenarios of complex multiloci interactions. Results show that the new gene scores generally performed better, some substantially so, than existing GSEA extension to GWAS. The new methods are implemented in an R package and when applied to a real GWAS data set demonstrated its practical utility in a GWAS setting.
PMCID: PMC3172928  PMID: 21427759
gene set enrichment; pathway-based analysis; SNP; genome-wide association
19.  Effects of Sodium Thiosulfate on Vascular Calcification in End-Stage Renal Disease: A Pilot Study of Feasibility, Safety and Efficacy 
American Journal of Nephrology  2011;33(2):131-138.
Background and Objectives
Vascular calcification is a major contributor to morbidity and mortality in hemodialysis. The objective of this pilot study was to determine the feasibility, safety and efficacy of sodium thiosulfate (STS) in the progression of vascular calcification in hemodialysis patients.
Chronic hemodialysis patients underwent a battery of cardiovascular tests. Those with coronary artery calcium (Agatston scores >50) received intravenous STS after each dialysis for 5 months (n = 22) and the tests were repeated. Changes in MDCT-determined calcification were assessed as the mean annualized rate of change in 3 vascular beds (coronary, thoracic and carotid arteries) and in L1-L2 vertebral bone density.
Although individual analyses showed coronary artery calcification progression in 14/22 subjects, there was no progression in the mean annualized rate of change of vascular calcification in the entire group. The L1-L2 vertebral bone density showed no changes. There were no correlations between rates of progression of vascular calcification and phosphorus, fetuin or C-reactive protein levels. Changes in coronary artery calcification scores correlated with those of the thoracic aorta.
STS treatment is feasible, appears safe and may decrease the rate of progression of vascular calcification in hemodialysis patients. A large, randomized, controlled trial is warranted.
PMCID: PMC3064860  PMID: 21242673
Hemodialysis; Sodium thiosulfate; Vascular calcification
20.  Are Normative Values for LV Geometry and Mass Based on Fundamental Imaging Valid With Use of Harmonic Imaging? 
Multiple studies have reported echocardiographically determined normal reference values for left ventricular mass (LVM) derived using fundamental imaging (FI). Modern ultrasound systems now use harmonic imaging (HI) due to the improved LV endomyocardial definition. However, the 2005 American Society of Echocardiography (ASE) Recommendations noted that the applicability of the reference values to HI-derived measurements has not been established.
LV end-diastolic volume, diameter, wall thickness, and mass were determined using HI in healthy subjects (n=251) including a normal weight (NW, body mass index [BMI] < 25 kg/m2, n=149, 68% women) and an otherwise-healthy overweight (OW, BMI ≥25 and <30 kg/m2, n=102, 41% women) groups. Measurements were compared to ASE-endorsed reference values. The agreement between FI and HI was determined in a prospective cohort of 51 subjects.
2D-derived LV volumes were similar between NW and OW subjects; although M-mode (MM)-derived LV diameters were slightly greater in OW. 2D- and MM-derived LVM was greater in OW compared to NW subjects, including after adjustment by height or height2.7; however, indexing to body surface area eliminated these differences. The partition values for abnormal 2D- and MM-derived LVM were generally greater in NW and OW subjects of both sexes compared with the ASE endorsed values (except MM-derived in NW men). However, there were no significant differences in LVM determined by HI compared to FI in a prospectively studied cohort.
Reference values for LVM derived from NW and OW cohorts are generally higher than the ASE-endorsed referenced values. The difference between NW and ASE-endorsed values is unlikely to result from the use of HI rather than FI since there is excellent agreement between these two imaging modalities. This study emphasizes the need to update normal reference values to reflect modern imaging methods.
PMCID: PMC2993783  PMID: 20863657
echocardiography; fundamental imaging; harmonic imaging; left ventricular mass; body mass index
21.  Insulin resistance predicts endothelial dysfunction and cardiovascular risk in HIV-infected persons on long-term highly active antiretroviral therapy 
AIDS (London, England)  2008;22(7):849-856.
Cardiovascular disease risk among persons with HIV is likely multifactorial, thus testing a variety of available noninvasive vascular ultrasound and other surrogate tests may yield differing results. To address this issue, we assessed multiple metabolic and clinical predictors of endothelial function and carotid intima–media thickness in HIV-infected subjects and compared results with HIV-negative controls.
Prospective, cross-sectional study of 50 HIV-infected, healthy adults on stable highly active antiretroviral therapy matched to 50 HIV-negative controls by age, sex, race, and body mass index.
Flow-mediated vasodilation of the brachial artery, carotid intima–media thickness, dual energy X-ray absorptiometry (HIV-infected subjects), and fasting insulin, lipids, and oral glucose tolerance tests were performed. Results were compared between HIV-infected and control groups.
Fifty percent of subjects were African–American with 34% women. Among HIV-infected, mean CD4 cell count was 547 cells/ µl; 90% had HIV RNA less than 50 copies/ml. There were no significant differences between HIV-infected and control subjects with regard to brachial artery flow-mediated vasodilation or carotid intima–media thickness. In multivariate analyses of the HIV cohort, independent predictors of endothelial dysfunction (lower flow-mediated vasodilation) were increasing insulin resistance, greater alcohol consumption, and higher baseline brachial artery diameter (P < 0.05); predictors of increased carotid intima–media thickness were hypertension, higher trunk/limb fat ratio, and insulin resistance (P < 0.05).
In this HIV cohort on modern highly active antiretroviral therapy with well controlled HIV, there were no significant differences with regard to preclinical markers of cardiovascular disease. Insulin resistance was a strong predictor of impaired brachial artery flow-mediated vasodilation and increased carotid intima–media thickness, and may be an important cardiovascular disease risk factor in the HIV population.
PMCID: PMC3166228  PMID: 18427203
endothelial dysfunction; HIV; insulin resistance
22.  Molecular Determinants of the Cardiometabolic Phenotype 
The metabolic syndrome represents a clustering of risk factors that has been shown to predict adverse cardiovascular outcomes. Although the precise mechanisms contributing to the cardiometabolic syndrome (CMS) remain poorly defined, accumulating evidence identifies two intersecting candidate pathways responsible for inflammation and energy homeostasis in the pathophysiology that underlie cardiometabolic traits. Although currently no pharmacologic interventions specifically target CMS, future drug development efforts should attempt to capitalize on molecular nodes at the intersections of these pathways in the CMS.
PMCID: PMC2887744  PMID: 20384572
Metabolic syndrome; cardiometabolic syndrome; substrate metabolism; inflammation; obesity; insulin resistance; hypertension; dyslipidemia
23.  Central Aortic Pressure is Independently Associated With Diastolic Function 
American heart journal  2010;159(6):1081-1088.
Studies investigating the association between central aortic pressures and diastolic function have been limited.
Consecutive ambulatory patients (n=281, mean age 49±13 yrs, 49% male) with normal LV systolic function were included. LV filling pressure (E/Em) was estimated by Doppler-derived ratio of mitral inflow velocity [E] to septal [Em] by tissue Doppler, LV relaxation by Em, central aortic pressures by radial tonometry. Central aortic systolic (cSBP), diastolic (cDBP), mean (cMAP), and pulse pressure (cPP) were entered individually into stepwise linear regression models to determine their association with E/Em or Em.
In univariate analysis, cPP correlated most strongly with E/Em (Spearman’s rho=0.45, p<0.001), while cSBP correlated most strongly with Em (Spearman’s rho=−0.51, p<0.001). Multivariate analysis demonstrated that the pulsatile component of afterload, cPP, contributed most to E/Em (partial r2=23%); meanwhile the nonpulsatile components (cDBP and cMAP), were significant but small contributors (partial r2 of 6% and 5% respectively) of LV relaxation (Em).
The nonpulsatile components of aortic afterload (central mean aortic pressure (cMAP) and central aortic diastolic blood pressure cDBP), exhibited a weak but significant association with LV relaxation, while the pulsatile component of afterload, central aortic pulse pressure (cPP), exhibited strong association with LV filling pressure.
PMCID: PMC2913412  PMID: 20569723
diastolic function; pulse pressure; aortic blood pressures
24.  Effect of moderate diet-induced weight loss and weight regain on cardiovascular structure and function 
The objective of this prospective, single-site, two-year dietary intervention study was to evaluate the effects of moderate weight reduction and subsequent partial weight regain on cardiovascular structure and function.
Obesity is associated with adverse cardiac and vascular structural and functional alterations.
Sixty obese subjects (age: 46±10 years, body mass index: 37±3 kg/m2) were evaluated during their participation in a weight loss study. Cardiac and vascular ultrasound studies were performed at baseline and at 3, 6, 12, and 24 months after start of intervention.
Forty-seven subjects (78%) completed the entire two-year follow-up. Average weight loss was 7.3±4.0, 9.2±5.6, 7.8±6.6 and 3.8±7.9% at 3, 6, 12, and 24 months, respectively. Age- and sex- adjusted mixed linear models revealed that the follow-up time was significantly associated with decreases in weight (p<0.0001), left ventricular (LV) mass (p=0.001), and carotid intima-media thickness (p<0.0001); there was also significant improvement in LV diastolic (E’, p≤0.0001) and systolic (S’, p=.001) function. Partial weight regain diminished the maximal observed beneficial effects of weight loss, however cardiovascular parameters measured at two years still showed a net benefit compared with baseline.
Diet-induced moderate weight loss in obese subjects is associated with beneficial changes in cardiovascular structure and function. Subsequent weight regain is associated with partial loss of these beneficial effects.
PMCID: PMC2818984  PMID: 20082927
obesity; echocardiography; hypertrophy; carotid arteries; diastolic function
25.  Interatrial Conduction Time and Left Atrial Function in Patients with Left Ventricular Systolic Dysfunction: Effects of Cardiac Resynchronization Therapy 
Prolonged inter-atrial conduction time (IACT) can be associated with abnormal left atrial (LA) function but has not been characterized in patients with left ventricular systolic dysfunction (LVSD) and a QRS interval >130 ms.
2D-Doppler echocardiography and tissue Doppler imaging (TDI) was performed in 41 patients with LVSD (LV ejection fraction 26±5%) and 41 similarly-age normal controls (NC). 2D measurements included LV volumes, ejection fraction and LA volumes for determination of LA emptying fraction and LA ejection fraction. IACT was defined as onset of P-wave to onset of the TDI-derived late diastolic (A') velocity at the lateral mitral annulus. 2D-Doppler measurements were re-assessed in LVSD patients 4 ± 2 months after cardiac resynchronization therapy (CRT).
IACT was longer in LVSD patients compared to NC (105±25 vs. 74±12 ms, p <.001);none of the NC had IACT> 100ms.In LVSD patients, IACT correlated modestly with measurements of LA volumes (r =.41-.48, all p <.009) but not with measurements of LA function. LVSD patients with IACT > 100 ms (n=20) prior to CRT had larger LA volumes and lower indices of LA function after CRT compared to the ≤ 100ms group. Significant reductions in LV end-systolic volume and increases in LV ejection fraction occurred in both groups after CRT.
TDI-derived IACT can be prolonged in patients with severe LVSD and a wide QRS interval. An IACT > 100 ms. can affect LA remodeling and function at early follow-up after CRT but does not influence the response in LV end-systolic volume or ejection fraction.
PMCID: PMC2684572  PMID: 19345063
interatrial conduction time; left ventricular systolic dysfunction; left atrial function; cardiac resynchronization therapy

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