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1.  Differential Associations of Oral Glucose Tolerance Test–Derived Measures of Insulin Sensitivity and Pancreatic β-Cell Function With Coronary Artery Calcification and Microalbuminuria in Type 2 Diabetes 
Diabetes Care  2013;37(1):124-133.
We evaluated relationships of oral glucose tolerance testing (OGTT)–derived measures of insulin sensitivity and pancreatic β-cell function with indices of diabetes complications in a cross-sectional study of patients with type 2 diabetes who are free of overt cardiovascular or renal disease.
A subset of participants from the Penn Diabetes Heart Study (n = 672; mean age 59 ± 8 years; 67% male; 60% Caucasian) underwent a standard 2-h, 75-g OGTT. Insulin sensitivity was estimated using the Matsuda Insulin Sensitivity Index (ISI), and β-cell function was estimated using the Insulinogenic Index. Multivariable modeling was used to analyze associations between quartiles of each index with coronary artery calcification (CAC) and microalbuminuria.
The Insulinogenic Index and Matsuda ISI had distinct associations with cardiometabolic risk factors. The top quartile of the Matsuda ISI had a negative association with CAC that remained significant after adjusting for traditional cardiovascular risk factors (Tobit ratio −0.78 [95% CI −1.51 to −0.05]; P = 0.035), but the Insulinogenic Index was not associated with CAC. Conversely, the highest quartile of the Insulinogenic Index, but not the Matsuda ISI, was associated with lower odds of microalbuminuria (OR 0.52 [95% CI 0.30–0.91]; P = 0.022); however, this association was attenuated in models that included duration of diabetes.
Lower β-cell function is associated with microalbuminuria, a microvascular complication, while impaired insulin sensitivity is associated with higher CAC, a predictor of macrovascular complications. Despite these pathophysiological insights, the Matsuda ISI and Insulinogenic Index are unlikely to be translated into clinical use in type 2 diabetes beyond established clinical variables, such as obesity or duration of diabetes.
PMCID: PMC3867998  PMID: 23949560
2.  Candidate Gene Association Study of Coronary Artery Calcification in Chronic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort Study 
To identify loci for coronary artery calcification (CAC) in patients with chronic kidney disease (CKD).
CKD is associated with increased CAC and subsequent coronary heart disease (CHD) but the mechanisms remain poorly defined. Genetic studies of CAC in CKD may provide a useful strategy for identifying novel pathways in CHD.
We performed a candidate gene study (~2,100 genes; ~50,000 SNPs) of CAC within the Chronic Renal Insufficiency Cohort (CRIC) Study (n=1,509; 57% European, 43% African ancestry). SNPs with preliminary evidence of association with CAC in CRIC were examined for association with CAC in PennCAC (n=2,560) and Amish Family Calcification Study (AFCS; n=784) samples. SNPs with suggestive replication were further analyzed for association with myocardial infarction (MI) in the Pakistan Risk of Myocardial Infarction study (PROMIS) (n=14,885).
Of 268 SNPs reaching P <5×10−4 for CAC in CRIC, 28 SNPs in 23 loci had nominal support (P <0.05 and in same direction) for CAC in PennCAC or AFCS. Besides chr9p21 and COL4A1, known loci for CHD, these included SNPs having reported GWAS association with hypertension (e.g., ATP2B1). In PROMIS, four of the 23 suggestive CAC loci (chr9p21, COL4A1, ATP2B1 and ABCA4) had significant associations with MI consistent with their direction of effect on CAC.
We identified several loci associated with CAC in CKD that also relate to MI in a general population sample. CKD imparts a high risk of CHD and may provide a useful setting for discovery of novel CHD genes and pathways.
PMCID: PMC3953823  PMID: 23727086
Coronary artery calcification (CAC); chronic kidney disease (CKD); Chronic Renal Insufficiency Cohort Study (CRIC); myocardial infarction (MI); risk factors; candidate genes; single nucleotide polymorphisms (SNPs)
3.  C-Reactive Protein Modifies the Association of Plasma Leptin With Coronary Calcium in Asymptomatic Overweight Individuals 
Obesity (Silver Spring, Md.)  2011;20(4):856-861.
Evidence suggests putative interactions of leptin and C-reactive protein (CRP) in the pathogenesis of adiposity-related atherosclerotic cardiovascular disease (CVD). Therefore, we investigated whether CRP levels modify the relationship of leptin levels with coronary artery calcium (CAC). We examined 1,460 asymptomatic individuals from two community-based cross-sectional studies coordinated at a single, university-based research center. We focused on subjects who were overweight or obese (BMI ≥25) given greater biologic plausibility in this setting. In multivariable CAC models, we analyzed the interaction of log-transformed plasma leptin levels with higher CRP levels as defined by three cut-points: two clinically based (2 mg/l, 3 mg/l) and one dataset specific (sex-specific upper quartile). The association of plasma leptin with CAC was modified by higher CRP regardless of cut-point (interaction term P values all <0.01 in fully adjusted models). Leptin levels were associated with CAC in those with high, but not low CRP levels (e.g., tobit ratio for a 1 unit increase in ln(leptin) (95% CI): 2.18 (1.29–3.66) if CRP level ≥3 mg/l; N = 461 vs. 0.94 (0.67–1.31) if CRP levels <3 mg/l; N = 999) in fully adjusted models. No interaction with CRP was present in control analyses with adiponectin, BMI and waist circumference. In conclusion, in asymptomatic overweight and obese adults, increased leptin levels were independently associated with increased CAC in the presence of high, but not low CRP levels, supporting a leptin-CRP interface in atherosclerosis risk.
PMCID: PMC4005808  PMID: 21738237
4.  Cardiovascular Risk Factors and Mitral Annular Calcification in Type 2 Diabetes 
Atherosclerosis  2012;226(2):419-424.
Mitral annular calcification (MAC) is a degenerative process of the mitral fibrous annulus associated with cardiac disease and stroke. Although thought to be more prevalent in type 2 diabetes (T2DM), MAC remains poorly characterized in this population, due to confounding by renal and cardiac disease. Our goal was to study the risk factors for MAC in asample of T2DM subjects without renal and cardiac disease.
The Penn Diabetes Heart Study (PDHS) is a cross-sectional study of diabetic individuals without clinical cardiovascular or renal disease. We quantified and analyzed MAC Agatston scores in baseline cardiac CTs from 1753 individuals. Logistic and tobit regression were used to assess MAC’s relationship with risk factors and coronary artery calcification (CAC).
MAC was present in 12.0% of -subjects, with a median Agatston score of 72.3 [Interquartile range (22.2 256.9)]. Older age, diabetes female gender, Caucasian race, and longer duration were independently associated with both the presence and extent MAC even after controlling for the CAC; hypertension, hyperlipidemia, comorbidities however, tobacco use, CRP levels, and other were not associated. CAC was strongly associated with MAC [OR of 4.0, (95% CI 2.4-6.6)] in multivariable models.
Age, AC female gender, Caucasian race, and diabetes duration were associated with the presence and extent of MAC in T2DM subjects, independent of CAC, which was also strongly associated with MAC. These data suggest that additional mechanisms for MAC formation in diabetics may exist which are distinct from those related to generalized atherosclerosis and deserve further investigation.
PMCID: PMC3568504  PMID: 23273961
Diabetes; Mitral Annular Calcification; Coronary Heart Disease; Risk Factors
5.  Periodontal Disease Is an Independent Predictor of Intracardiac Calcification 
BioMed Research International  2013;2013:854340.
Background. Periodontitis is the most common chronic inflammatory condition worldwide and is associated with incident coronary disease. Hypothesis. We hypothesized that periodontal disease would also be associated with cardiac calcification, a condition which shares many risk factors with atherosclerosis and is considered a marker of subclinical atherosclerosis. Methods. Cross-sectional study at two sites (USA and Japan) involving subjects with both clinical echocardiograms and detailed dental examinations. Semiquantitative scoring systems were used to assess severity of periodontal disease and echocardiographic calcification. Results. Fifty-six of 73 subjects (77%) had cardiac calcifications, and 51% had moderate to severe periodontal disease (score > 2). In unadjusted analysis, a significant relationship between periodontal score and cardiac calcification (Spearman rho = 0.4, P = 0.001) was noted, with increases in mean calcification score seen across increasing levels of periodontal disease. On multivariate logistic regression, adjusted for age, gender, race, glomerular filtration rate, and traditional risk factors, this association remained significant (P = 0.024). There was no significant interaction by study site, race, or gender. Conclusions. In a multiracial population, we found a significant association between the degree of periodontal disease, a chronic inflammatory condition, and cardiac calcification. Further, higher periodontal scores were associated with greater degrees of calcification.
PMCID: PMC3784081  PMID: 24106721
6.  Association Between the Chromosome 9p21 Locus and Angiographic Coronary Artery Disease Burden 
This study sought to ascertain the relationship of 9p21 locus with: 1) angiographic coronary artery disease (CAD) burden; and 2) myocardial infarction (MI) in individuals with underlying CAD.
Chromosome 9p21 variants have been robustly associated with coronary heart disease, but questions remain on the mechanism of risk, specifically whether the locus contributes to coronary atheroma burden or plaque instability.
We established a collaboration of 21 studies consisting of 33,673 subjects with information on both CAD (clinical or angiographic) and MI status along with 9p21 genotype. Tabular data are provided for each cohort on the presence and burden of angiographic CAD, MI cases with underlying CAD, and the diabetic status of all subjects.
We first confirmed an association between 9p21 and CAD with angiographically defined cases and control subjects (pooled odds ratio [OR]: 1.31, 95% confidence interval [CI]: 1.20 to 1.43). Among subjects with angiographic CAD (n = 20,987), random-effects model identified an association with multivessel CAD, compared with those with single-vessel disease (OR: 1.10, 95% CI: 1.04 to 1.17)/copy of risk allele). Genotypic models showed an OR of 1.15, 95% CI: 1.04 to 1.26 for heterozygous carrier and OR: 1.23, 95% CI: 1.08 to 1.39 for homozygous carrier. Finally, there was no significant association between 9p21 and prevalent MI when both cases (n = 17,791) and control subjects (n = 15,882) had underlying CAD (OR: 0.99, 95% CI: 0.95 to 1.03)/risk allele.
The 9p21 locus shows convincing association with greater burden of CAD but not with MI in the presence of underlying CAD. This adds further weight to the hypothesis that 9p21 locus primarily mediates an atherosclerotic phenotype.
PMCID: PMC3653306  PMID: 23352782
9p21; angiography; coronary artery disease; meta-analysis; myocardial infarction; single nucleotide polymorphism
7.  Gender Differences in the Association of C-Reactive Protein with Coronary Artery Calcium in Type-2 Diabetes 
Clinical endocrinology  2011;74(1):44-50.
Plasma C-reactive protein (CRP) is associated with cardiovascular disease (CVD) but effects may vary by gender and degree of CVD risk. Whether CRP has value as a CVD risk marker in type-2 diabetes (T2DM) is unclear. We examined whether CRP has gender differences in the association of coronary artery calcium (CAC) in diabetic and non diabetic samples without clinical CVD.
We performed cross-sectional analyses of gender influence on CRP association with CAC in the Penn Diabetes Heart Study (N = 1299 with T2DM), the Study of Inherited Risk of Coronary Atherosclerosis (N = 860 non diabetic subjects), and a combined sample.
Female gender was associated with higher plasma CRP in diabetic and non-diabetic samples after adjustment for covariates. There was a strong interaction by gender in the association of CRP with CAC (interaction p < 0.001). In diabetic women, CRP was associated with higher CAC even after further adjustment for age, race, medications, metabolic syndrome, Framingham risk score, and body mass index [Tobit ratio 1.60, 95% CI (1.03-2.47)]. Although this relationship was attenuated in non diabetic women, the combined sample maintained this association in fully adjusted models [1.44, 95% CI (1.13-1.83)]. There was no association of CRP with CAC in either diabetic or non diabetic men.
CRP may be a useful marker of cardiovascular risk in women, particularly in diabetic women who otherwise have no known CVD. Prospective studies are needed to better assess gender differences in CRP utility and the use of CRP in T2DM.
PMCID: PMC3005137  PMID: 20874770
Coronary artery calcium; C-reactive protein; Diabetes; Gender
8.  Lack of association between the Trp719Arg polymorphism in kinesin-like protein 6 and coronary artery disease in 19 case-control studies 
Assimes, Themistocles L | Hólm, Hilma | Kathiresan, Sekar | Reilly, Muredach P | Thorleifsson, Gudmar | Voight, Benjamin F | Erdmann, Jeanette | Willenborg, Christina | Vaidya, Dhananjay | Xie, Changchun | Patterson, Chris C | Morgan, Thomas M | Burnett, Mary Susan | Li, Mingyao | Hlatky, Mark A | Knowles, Joshua W | Thompson, John R | Absher, Devin | Iribarren, Carlos | Go, Alan | Fortmann, Stephen P | Sidney, Stephen | Risch, Neil | Tang, Hua | Myers, Richard M | Berger, Klaus | Stoll, Monika | Shah, Svati H. | Thorgeirsson, Gudmundur | Andersen, Karl | Havulinna, Aki S | Herrera, J. Enrique | Faraday, Nauder | Kim, Yoonhee | Kral, Brian G. | Mathias, Rasika | Ruczinski, Ingo | Suktitipat, Bhoom | Wilson, Alexander F | Yanek, Lisa R. | Becker, Lewis C | Linsel-Nitschke, Patrick | Lieb, Wolfgang | König, Inke R | Hengstenberg, Christian | Fischer, Marcus | Stark, Klaus | Reinhard, Wibke | Winogradow, Janina | Grassl, Martina | Grosshennig, Anika | Preuss, Michael | Eifert, Sandra | Schreiber, Stefan | Wichmann, H-Erich | Meisinger, Christa | Yee, Jean | Friedlander, Yechiel | Do, Ron | Meigs, James B | Williams, Gordon | Nathan, David M | MacRae, Calum A | Qu, Liming | Wilensky, Robert L | Matthai, William H. | Qasim, Atif N | Hakonarson, Hakon | Pichard, Augusto D | Kent, Kenneth M | Satler, Lowell | Lindsay, Joseph M | Waksman, Ron | Knouff, Christopher W | Waterworth, Dawn M | Walker, Max C | Mooser, Vincent | Marrugat, Jaume | Lucas, Gavin | Subirana, Isaac | Sala, Joan | Ramos, Rafael | Martinelli, Nicola | Olivieri, Oliviero | Trabetti, Elisabetta | Malerba, Giovanni | Pignatti, Pier Franco | Guiducci, Candace | Mirel, Daniel | Parkin, Melissa | Hirschhorn, Joel N | Asselta, Rosanna | Duga, Stefano | Musunuru, Kiran | Daly, Mark J | Purcell, Shaun | Braund, Peter S | Wright, Benjamin J | Balmforth, Anthony J | Ball, Stephen G | Ouwehand, Willem H | Deloukas, Panos | Scholz, Michael | Cambien, Francois | Huge, Andreas | Scheffold, Thomas | Salomaa, Veikko | Girelli, Domenico | Granger, Christopher B. | Peltonen, Leena | McKeown, Pascal P | Altshuler, David | Melander, Olle | Devaney, Joseph M | Epstein, Stephen E | Rader, Daniel J | Elosua, Roberto | Engert, James C | Anand, Sonia S | Hall, Alistair S | Ziegler, Andreas | O’Donnell, Christopher J | Spertus, John A | Siscovick, David | Schwartz, Stephen M | Becker, Diane | Thorsteinsdottir, Unnur | Stefansson, Kari | Schunkert, Heribert | Samani, Nilesh J | Quertermous, Thomas
We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455) and clinical coronary artery disease (CAD).
Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with non-carriers.
The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in nineteen case-control studies of non-fatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports.
Over 17 000 cases and 39 000 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls were successfully genotyped. None of the nineteen studies demonstrated an increased risk of CAD in carriers of the 719Arg allele compared with non-carriers. Regression analyses and fixed effect meta-analyses ruled out with high degree of confidence an increase of ≥2% in the risk of CAD among European 719Arg carriers. We also observed no increase in the risk of CAD among 719Arg carriers in the subset of Europeans with early onset disease (<50 years of age for males and <60 years for females) compared with similarly aged controls as well as all non-European subgroups.
The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study.
PMCID: PMC3084526  PMID: 20933357
kinesin-like protein 6; KIF6; coronary artery disease; myocardial infarction; polymorphism
9.  Lipoprotein(a) is strongly associated with coronary artery calcification in type-2 diabetic women 
Lp(a), implicated in both atherogenesis and thrombosis pathways, varies significantly by demographic and metabolic factors, providing challenges for its use in Coronary Heart Disease (CHD) risk. The purpose of this study was to investigate whether type-2 diabetic subjects, relative to non-diabetics, might benefit more from Lp(a) measurement in the prediction of CHD risk, as measured by coronary artery calcium (CAC).
We performed cross sectional analyses in two community-based studies: the Penn Diabetes Heart Study [N=1299 with type-2 diabetes] and the Study of Inherited Risk of Coronary Atherosclerosis [N=860 without diabetes].
Blacks had 2–3 fold higher Lp(a) levels than whites in diabetic and non-diabetic samples. There was significant difference by gender (interaction p<0.001), but not race, in the association of Lp(a) with CAC in type-2 diabetic subjects. In age and race adjusted analysis of diabetic women, Lp(a) was associated with CAC [Tobit regression ratio 2.76 (95% CI 1.73–4.40), p<0.001]. Adjustment for exercise, medications, Framingham risk score, metabolic syndrome, BMI, CRP and hemoglobin A1c attenuated this effect, but the association of Lp(a) with CAC remained significant [2.25, (1.34–3.79), p=0.002]. This relationship was further maintained in women stratified by race, or by the use of HRT or lipid lowering drugs. In contrast, Lp(a) was not associated with CAC in diabetic men, nor in non-diabetic men and women.
Lp(a) is a strong independent predictor of CAC in type-2 diabetic women, regardless of race, but not in men. Lp(a) does not relate to CAC in men or women without type-2 diabetes.
PMCID: PMC3132301  PMID: 20303190
Coronary artery calcium; Lipoprotein(a); Gender; Subclinical atherosclerosis
10.  Pathway-Wide Association Study Implicates Multiple Sterol Transport and Metabolism Genes in HDL Cholesterol Regulation 
Pathway-based association methods have been proposed to be an effective approach in identifying disease genes, when single-marker association tests do not have sufficient power. The analysis of quantitative traits may be benefited from these approaches, by sampling from two extreme tails of the distribution. Here we tested a pathway association approach on a small genome-wide association study (GWAS) on 653 subjects with extremely high high-density lipoprotein cholesterol (HDL-C) levels and 784 subjects with low HDL-C levels. We identified 102 genes in the sterol transport and metabolism pathways that collectively associate with HDL-C levels, and replicated these association signals in an independent GWAS. Interestingly, the pathways include 18 genes implicated in previous GWAS on lipid traits, suggesting that genuine HDL-C genes are highly enriched in these pathways. Additionally, multiple biologically relevant loci in the pathways were not detected by previous GWAS, including genes implicated in previous candidate gene association studies (such as LEPR, APOA2, HDLBP, SOAT2), genes that cause Mendelian forms of lipid disorders (such as DHCR24), and genes expressing dyslipidemia phenotypes in knockout mice (such as SOAT1, PON1). Our study suggests that sampling from two extreme tails of a quantitative trait and examining genetic pathways may yield biological insights from smaller samples than are generally required using single-marker analysis in large-scale GWAS. Our results also implicate that functionally related genes work together to regulate complex quantitative traits, and that future large-scale studies may benefit from pathway-association approaches to identify novel pathways regulating HDL-C levels.
PMCID: PMC3268595  PMID: 22303337
GWAS; lipid; HDL-C; pathway analysis; cholesterol; sterol transport; sterol metabolism; genetic association
11.  Resistin gene variation is associated with systemic inflammation but not plasma adipokine levels, metabolic syndrome or coronary atherosclerosis in nondiabetic Caucasians 
Clinical endocrinology  2008;70(5):698-705.
Resistin causes insulin resistance and diabetes in mice whereas in humans it is linked to inflammation and atherosclerosis. Few human genetic studies of resistin in inflammation and atherosclerosis have been performed. We hypothesized that the −420C>G putative gain-of-function resistin variant would be associated with inflammatory markers and atherosclerosis but not with metabolic syndrome or adipokines in humans.
Design and methods
We examined the association of three resistin polymorphisms, −852A>G, −420C>G and +157C>T, and related haplotypes with plasma resistin, cytokines, C-reactive protein (CRP), adipokines, plasma lipoproteins, metabolic syndrome and coronary artery calcification (CAC) in nondiabetic Caucasians (n = 851).
Resistin levels were higher, dose-dependently, with the −420G allele (CC 5·9 ± 2·7 ng/ml, GC 6·5 ± 4·0 ng/ml and GG 7·2 ± 4·8 ng/ml, trend P = 0·04) after age and gender adjustment [fold higher for GC + GG vs. CC; 1·07 (1·00–1·15), P < 0·05)]. The −852A>G single nucleotide polymorphism (SNP) was associated with higher soluble tumour necrosis factor-receptor 2 (sol-TNFR2) levels in fully adjusted models [1·06 (95% CI 1·01–1·11), P = 0·01)]. The estimated resistin haplotype (GGT) was associated with sol-TNFR2 (P = 0·04) and the AGT haplotype was related to CRP (P = 0·04) in the fully adjusted models. Resistin SNPs and haplotypes were not associated with body mass index (BMI), fasting glucose, insulin resistance, metabolic syndrome, adipokines or CAC scores.
Despite modest associations with plasma resistin and inflammatory biomarkers, resistin 5′ variants were not associated with metabolic parameters or coronary calcification. This suggests that resistin is an inflammatory cytokine in humans but has little influence on adiposity, metabolic syndrome or atherosclerosis.
PMCID: PMC3108432  PMID: 18710472
12.  Relation of Plasma Fatty Acid Binding Proteins 4 and 5 With the Metabolic Syndrome, Inflammation and Coronary Calcium in Patients With Type-2 Diabetes Mellitus 
The American journal of cardiology  2010;106(8):1118-1123.
Fatty acid–binding proteins (FABPs) 4 and 5 play coordinated roles in rodent models of inflammation, insulin resistance, and atherosclerosis, but little is known of their role in human disease. The aim of this study was to examine the hypothesis that plasma adipocyte and macrophage FABP4 and FABP5 levels would provide additive value in the association with metabolic and inflammatory risk factors for cardiovascular disease as well as subclinical atherosclerosis. Using the Penn Diabetes Heart Study (PDHS; n = 806), cross-sectional analysis of FABP4 and FABP5 levels with metabolic and inflammatory parameters and with coronary artery calcium, a measure of subclinical coronary atherosclerosis, was performed. FABP4 and FABP5 levels had strong independent associations with the metabolic syndrome (for a 1-SD change in FABP levels, odds ratio [OR] 1.85, 95% confidence interval [CI] 1.43 to 2.23, and OR 1.66, 95% CI 1.41 to 1.95, respectively) but had differential associations with metabolic syndrome components. FABP4 and FABP5 were also independently associated with C-reactive protein and interleukin-6 levels. FABP4 (OR 1.26, 95% CI 1.05 to 1.52) but not FABP5 (OR 1.13, 95% CI 0.97 to 1.32) was associated with the presence of coronary artery calcium. An integrated score combining FABP4 and FABP5 quartile data had even stronger associations with the metabolic syndrome, C-reactive protein, interleukin-6, and coronary artery calcium compared to either FABP alone. In conclusion, this study provides evidence for an additive relation of FABP4 and FABP5 with the metabolic syndrome, inflammatory cardiovascular disease risk factors, and coronary atherosclerosis in type 2 diabetes mellitus. These findings suggest that FABP4 and FABP5 may represent mediators of and biomarkers for metabolic and cardiovascular disease in type 2 diabetes mellitus.
PMCID: PMC3108486  PMID: 20920650
13.  Type 2 diabetes does not attenuate racial differences in coronary calcification 
Coronary artery calcification (CAC) is a strong predictor of atherosclerotic cardiovascular disease (CVD). Whites appear to have a higher prevalence of CAC than African-Americans (AAs), but it is unknown if type 2 diabetes, a major cardiovascular risk factor, attenuates this difference. We investigated the relationship of race and CAC in a sample of patients with type 2 diabetes without clinical CVD.
Multivariable analyses of self-reported ethnicity and CAC scores, stratified by gender, in 861 subjects [32% AA, 66.9% male] with type 2 diabetes.
AA race was associated with lower CAC scores in age-adjusted models in males [Tobit ratio for AAs vs. Whites 0.14 (95% CI 0.08–0.24, p < 0.001)] and females [Tobit ratio 0.26 (95% CI 0.09–0.77, p = 0.015)]. This persisted in men after adjustment for traditional, metabolic and inflammatory risk factors, but adjustment for plasma triglycerides [0.48 (95% CI 0.15–1.49, p = 0.201)] and HOMA-IR [0.28 (95% CI 0.08–1.03, p = 0.055)] partially attenuated the association in women.
Relative to African-Americans, White race is a strong predictor of CAC, even in the presence of type 2 diabetes. The relationship in women appears less robust possibly due to gender differences in metabolic risk factors.
PMCID: PMC3092471  PMID: 21067835
Race; Coronary artery calcification; Atherosclerosis; Type 2 diabetes
14.  Comparison of High-Density Lipoprotein Cholesterol to Apolipoprotein A-I and A-II to Predict Coronary Calcium and the Effect of Insulin Resistance 
The American journal of cardiology  2011;107(3):393-398.
High-density lipoprotein (HDL) cholesterol and its apolipoproteins each capture unique lipid and cardiometabolic information important to risk quantification. It was hypothesized that metabolic factors, including insulin resistance and type 2 diabetes, would confound the association of HDL cholesterol with coronary artery calcification (CAC) and that apolipoprotein A-I (apoA-I) and/or apolipoprotein A-II (apoA-II) would add to HDL cholesterol in predicting CAC. Two community-based cross-sectional studies of white subjects were analyzed: the Penn Diabetes Heart Study (PDHS; n = 611 subjects with type 2 diabetes, 71.4% men) and the Study of Inherited Risk of Coronary Atherosclerosis (SIRCA; n = 803 subjects without diabetes, 52.8% men) using multivariable analysis of apoA-I, apoA-II, and HDL cholesterol stratified by diabetes status. HDL cholesterol was inversely associated with CAC after adjusting for age and gender in whites with type 2 diabetes (tobit ratio for a 1-SD increase in HDL cholesterol 0.58, 95% confidence interval [CI] 0.44 to 0.77, p <0.001) as well as those without diabetes (tobit ratio 0.72, 95% CI 0.59 to 0.88, p = 0.001). In contrast, apoA-I was a weaker predictor in subjects with (tobit ratio 0.64, 95% CI 0.45 to 0.90, p = 0.010) and without (tobit ratio 0.79, 95% CI 0.66 to 0.94, p = 0.010) diabetes, while apoA-II had no association with CAC. Control for metabolic variables, including triglycerides, waist circumference, and homeostasis model assessment of insulin resistance, attenuated these relations, particularly in subjects without diabetes. In likelihood ratio test analyses, HDL cholesterol added to apoA-I, apoA-II, and atherogenic apolipoprotein B lipoproteins but improved CAC prediction over metabolic factors only in subjects with diabetes. In conclusion, HDL cholesterol outperformed apoA-I and apoA-II in CAC prediction, but its association with CAC was attenuated by measures of insulin resistance.
PMCID: PMC3086062  PMID: 21257004
15.  Genome-Wide Association Study of Coronary Heart Disease and Its Risk Factors in 8,090 African Americans: The NHLBI CARe Project 
PLoS Genetics  2011;7(2):e1001300.
Coronary heart disease (CHD) is the leading cause of mortality in African Americans. To identify common genetic polymorphisms associated with CHD and its risk factors (LDL- and HDL-cholesterol (LDL-C and HDL-C), hypertension, smoking, and type-2 diabetes) in individuals of African ancestry, we performed a genome-wide association study (GWAS) in 8,090 African Americans from five population-based cohorts. We replicated 17 loci previously associated with CHD or its risk factors in Caucasians. For five of these regions (CHD: CDKN2A/CDKN2B; HDL-C: FADS1-3, PLTP, LPL, and ABCA1), we could leverage the distinct linkage disequilibrium (LD) patterns in African Americans to identify DNA polymorphisms more strongly associated with the phenotypes than the previously reported index SNPs found in Caucasian populations. We also developed a new approach for association testing in admixed populations that uses allelic and local ancestry variation. Using this method, we discovered several loci that would have been missed using the basic allelic and global ancestry information only. Our conclusions suggest that no major loci uniquely explain the high prevalence of CHD in African Americans. Our project has developed resources and methods that address both admixture- and SNP-association to maximize power for genetic discovery in even larger African-American consortia.
Author Summary
To date, most large-scale genome-wide association studies (GWAS) carried out to identify risk factors for complex human diseases and traits have focused on population of European ancestry. It is currently unknown whether the same loci associated with complex diseases and traits in Caucasians will replicate in population of African ancestry. Here, we conducted a large GWAS to identify common DNA polymorphisms associated with coronary heart disease (CHD) and its risk factors (type-2 diabetes, hypertension, smoking status, and LDL- and HDL-cholesterol) in 8,090 African Americans as part of the NHLBI Candidate gene Association Resource (CARe) Project. We replicated 17 associations previously reported in Caucasians, suggesting that the same loci carry common DNA sequence variants associated with CHD and its risk factors in Caucasians and African Americans. At five of these 17 loci, we used the different patterns of linkage disequilibrium between populations of European and African ancestry to identify DNA sequence variants more strongly associated with phenotypes than the index SNPs found in Caucasians, suggesting smaller genomic intervals to search for causal alleles. We also used the CARe data to develop new statistical methods to perform association studies in admixed populations. The CARe Project data represent an extraordinary resource to expand our understanding of the genetics of complex diseases and traits in non-European-derived populations.
PMCID: PMC3037413  PMID: 21347282
16.  Association of Lower Plasma Fetuin-A Levels With Peripheral Arterial Disease in Type 2 Diabetes 
Diabetes Care  2009;33(2):408-410.
Fetuin-A is an inhibitor of vascular calcification and a mediator of insulin resistance. This study evaluated the association of plasma fetuin-A and peripheral arterial disease (PAD).
A total of 738 individuals with type 2 diabetes (mean age 58.7 years, 37.1% female) without known cardiovascular or kidney disease were included in this cross-sectional analysis.
Subjects with PAD had a significantly lower fetuin-A (264.3 vs. 293.4 ng/dl, P < 0.001). In multivariable analysis, a 1-SD decrease in fetuin-A increased the odds of PAD (odds ratio 1.6, P = 0.02). Subgroup analysis revealed an increased odds even in subjects with glomerular filtration rate >80 (odds ratio 1.9, P = 0.05) or high-sensitivity C-reactive protein <3 mg/dl (odds ratio 2.7, P = 0.002).
Lower circulating fetuin-A is associated with PAD in type 2 diabetes beyond traditional and novel cardiovascular risk factors. Our findings suggest a potentially unique role for fetuin-A deficiency as a biomarker of PAD in patients with type 2 diabetes.
PMCID: PMC2809293  PMID: 19910501
17.  Apolipoprotein B but not LDL Cholesterol Is Associated With Coronary Artery Calcification in Type 2 Diabetic Whites 
Diabetes  2009;58(8):1887-1892.
Evidence favors apolipoprotein B (apoB) over LDL cholesterol as a predictor of cardiovascular events, but data are lacking on coronary artery calcification (CAC), especially in type 2 diabetes, where LDL cholesterol may underestimate atherosclerotic burden. We investigated the hypothesis that apoB is a superior marker of CAC relative to LDL cholesterol.
We performed cross-sectional analyses of white subjects in two community-based studies: the Penn Diabetes Heart Study (N = 611 type 2 diabetic subjects, 71.4% men) and the Study of Inherited Risk of Coronary Atherosclerosis (N = 803 nondiabetic subjects, 52.8% men) using multivariate analysis of apoB and LDL cholesterol stratified by diabetes status.
In type 2 diabetes, apoB was associated with CAC after adjusting for age, sex, and medications [Tobit regression ratio of increased CAC for 1-SD increase in apoB; 1.36 (95% CI 1.06–1.75), P = 0.016] whereas LDL cholesterol was not [1.09 (0.85–1.41)]. In nondiabetic subjects, both were associated with CAC [apoB 1.65 (1.38–1.96), P < 0.001; LDL cholesterol 1.56 (1.30–1.86), P < 0.001]. In combined analysis of diabetic and nondiabetic subjects, apoB provided value in predicting CAC scores beyond LDL cholesterol, total cholesterol, the total cholesterol/HDL cholesterol and triglyceride/HDL cholesterol ratios, and marginally beyond non-HDL cholesterol.
Plasma apoB, but not LDL cholesterol, levels were associated with CAC scores in type 2 diabetic whites. ApoB levels may be particularly useful in assessing atherosclerotic burden and cardiovascular risk in type 2 diabetes.
PMCID: PMC2712798  PMID: 19491209
18.  Adipokines, Insulin Resistance and Coronary Artery Calcification 
We evaluated the hypothesis that plasma levels of adiponectin and leptin are independently but oppositely associated with coronary calcification (CAC), a measure of subclinical atherosclerosis. In addition, we assessed which biomarkers of adiposity and insulin resistance are the strongest predictors of CAC beyond traditional risk factors, the metabolic syndrome and plasma C-reactive protein (CRP).
Adipokines are fat-secreted biomolecules with pleiotropic actions that converge in diabetes and cardiovascular disease.
We examined the association of plasma adipocytokines with CAC in 860 asymptomatic, non-diabetic participants in the Study of Inherited Risk of Coronary Atherosclerosis (SIRCA).
Plasma adiponectin and leptin levels had opposite and distinct associations with adiposity, insulin resistance and inflammation. Plasma leptin was positively (top vs. bottom quartile) associated with higher CAC after adjusting for age, gender, traditional risk factors and Framingham Risk Scores (FRS) [tobit regression ratio 2.42 (95% CI 1.48–3.95, p=0.002)] and further adjusting for metabolic syndrome and CRP [ratio 2.31 (95% CI 1.36–3.94, p=0.002)]. In contrast, adiponectin levels were not associated with CAC. Comparative analyses suggested that levels of leptin, IL-6 and sol-TNFR2 as well as HOMA-IR predicted CAC scores but only leptin and HOMA-IR provided value beyond risk factors, the metabolic syndrome and CRP.
In SIRCA, while both leptin and adiponectin levels were associated with metabolic and inflammatory markers, only leptin was a significant independent predictor of CAC. Of several metabolic markers, leptin and the HOMA-IR index had the most robust, independent associations with CAC.
Condensed Abstract
Adipokines are fat-secreted biomolecules with pleiotropic actions and represent novel markers for cardiovascular risk. We examined the association of plasma adipocytokines with CAC in 860 asymptomatic, non-diabetic Caucasians. Leptin was positively (top vs. bottom quartile) associated with higher CAC even after adjustment for age, gender, traditional risk factors, Framingham Risk Score, metabolic syndrome, and CRP [ratio 2.31 (95% CI 1.36–3.94, p=0.002)]. Adiponectin levels were not associated with CAC. Comparative analyses suggested that levels of leptin, IL-6 and sol-TNFR2 as well as HOMA-IR predicted CAC scores, but only leptin and HOMA-IR provided value beyond risk factors, the metabolic syndrome and CRP.
PMCID: PMC2853595  PMID: 18617073
Adiponectin; Leptin; Coronary Artery Calcification; Atherosclerosis; Inflammation

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