Amanda J Cox

Wake Forest School of Medicine, Winston-Salem, North Carolina, United States

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Publications (22)102.15 Total impact

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    ABSTRACT: The use of calcium supplements to prevent declines in bone mineral density and fractures is widespread in the United States, and thus reports of elevated cardiovascular disease (CVD) risk in users of calcium supplements are a major public health concern. Any elevation in CVD risk with calcium supplement use would be of particular concern in individuals with type 2 diabetes (T2D) because of increased risks of CVD and fractures observed in this population.
    American Journal of Clinical Nutrition 08/2014; · 6.50 Impact Factor
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    ABSTRACT: Not all individuals with type 2 diabetes and high coronary artery calcified plaque (CAC) experience the same risk for adverse outcomes. This study examined a subset of high-risk individuals based on CAC >1,000 mg (using a total mass score) and evaluated whether differences in a range of modifiable cardiovascular disease (CVD) risk factors provided further insights into risk for mortality.RESEARCH DESIGN AND METHODS: We assessed contributors to all-cause mortality among 371 European American individuals with type 2 diabetes and CAC >1,000 from the Diabetes Heart Study (DHS) after 8.2 ± 3.0 years (mean ± SD) of follow-up. Differences in known CVD risk factors, including modifiable CVD risk factors, were compared between living (n = 218) and deceased (n = 153) participants. Cox proportional hazards regression models were used to quantify risk for all-cause mortality.RESULTS: Deceased participants had a longer duration of type 2 diabetes (P = 0.02) and reduced use of cholesterol-lowering medications (P = 0.004). Adjusted analyses revealed that vascular calcified plaque scores were associated with increased risk for mortality (hazard ratio 1.31-1.63; 3.89 × 10(-5) < P < 0.03). Higher HbA1c, lipids, and C-reactive protein and reduced kidney function also were associated with a 1.1- to 1.5-fold increased risk for mortality (3.45 × 10(-6) < P < 0.03) after adjusting for confounding factors.CONCLUSIONS: Even in this high-risk group, vascular calcification and known CVD risk factors provide useful information for ongoing assessment. The use of cholesterol-lowering medication seemed to be protective for mortality.
    Diabetes care. 07/2014;
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    ABSTRACT: Type 2 diabetes mellitus (T2DM) is a major cardiovascular disease (CVD) risk factor. Identification of genetic risk factors for CVD is important to understand disease risk. Two recent genome-wide association study (GWAS) meta-analyses in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium detected CVD-associated loci. Variants identified in CHARGE were tested for association with CVD phenotypes, including vascular calcification, and conventional CVD risk factors, in the Diabetes Heart Study (DHS) (n = 1208; >80% T2DM affected). This included 36 genotyped or imputed single nucleotide polymorphisms (SNPs) from DHS GWAS data. 28 coding SNPs from 14 top CHARGE genes were also identified from exome sequencing resources and genotyped, along with 209 coding variants from the Illumina HumanExome BeadChip genotype data in the DHS were also tested. Genetic risk scores (GRS) were calculated to evaluate the association of combinations of variants with CVD measures. After correction for multiple comparisons, none of the CHARGE SNPs were associated with vascular calcification (p < 0.0014). Multiple SNPs showed nominal significance with calcification, including rs599839 (PSRC1, p = 0.008), rs646776 (CELSR2, p = 0.01), and rs17398575 (PIK3CG, p = 0.009). Additional COL4A2 and CXCL12 SNPs were nominally associated with all-cause or CVD-cause mortality. Three SNPs were significantly or nominally associated with serum lipids: rs3135506 (Ser19Trp, APOA5) with triglycerides (TG) (p = 5x10-5), LDL (p = 0.00070), and nominally with high density lipoprotein (HDL) (p = 0.0054); rs651821 (5[prime]UTR, APOA5) with increased TGs (p = 0.0008); rs13832449 (splice donor, APOC3) associated with decreased TGs (p = 0.0015). Rs45456595 (CDKN2A, Gly63Arg), rs5128 (APOC3, 3[prime]UTR), and rs72650673 (SH2B3, Glu400Lys) were nominally associated with history of CVD, subclinical CVD, or CVD risk factors (p < 0.010). From the exome chip, rs3750103 (CHN2, His204Arg/His68Arg) with carotid intima-medial thickness (IMT) (p = 3.9X10-5), and rs61937878 (HAL, Val549Met) with infra-renal abdominal aorta CP (AACP) (p = 7.1X10-5). The unweighted GRS containing coronary artery calcified plaque (CAC) SNPs was nominally associated with history of prior CVD (p = 0.033; OR = 1.09). The weighted GRS containing SNPs was associated with CAC and myocardial infarction (MI) was associated with history of MI (p = 0.026; OR = 1.15). Genetic risk factors for subclinical CVD in the general population (CHARGE) were modestly associated with T2DM-related risk factors and CVD outcomes in the DHS.
    Cardiovascular Diabetology 04/2014; 13(1):77. · 4.21 Impact Factor
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    ABSTRACT: Cognitive performance is an important component of healthy aging. Type 2 diabetes (T2D) is associated with negative outcomes for the brain and cognition, although causal mechanisms have not been definitely determined. Genetic risk factors warrant further consideration in this context. This study examined the heritability of cognitive function as assessed by (1) the Digit Symbol Substitution Task; (2) the Modified Mini-Mental State Examination; (3) the Stroop Task; (4) the Rey Auditory-Verbal Learning Task; and (5) the Controlled Oral Word Association Task for Phonemic and Semantic Fluency, in the family-based, T2D-enriched, Diabetes Heart Study sample (n = 550 participants from 257 families). The genetic basis of these cognitive measures was further evaluated by association analysis with candidate single-nucleotide polymorphisms (SNPs) and genome-wide SNP data. Measures of cognitive function were significantly heritable (hˆ(2) = 0.28-0.62) following adjustment for age, gender, and education. A total of 31 SNPs (from 26 genes/regions) selected to form an a priori set of candidate SNPs showed limited evidence of association with cognitive function when applying conservative metrics of significance. Genome-wide assessment of both noncoding and coding variants revealed suggestive evidence of association for several coding variants including rs139509083 in CNST (p = 4.9 × 10(-9)), rs199968569 in PLAA (p = 4.9 × 10(-9)) and rs138487371 in PCDH8 (p = 3.7 × 10(-8)). The identification of a heritable component to cognitive performance in T2D suggests a role for genetic contributors to cognitive performance even in the presence of metabolic disease and other associated comorbidities and is supported by the identification of genetic association signals in functionally plausible candidates.
    Neurobiology of aging 03/2014; · 5.94 Impact Factor
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    ABSTRACT: OBJECTIVE Heart rate-corrected QT (QTc) interval is associated with mortality in the general population, but this association is less clear in individuals with type 2 diabetes. We assessed the association of QTc interval with all-cause and cardiovascular disease (CVD) mortality in the Diabetes Heart Study.RESEARCH DESIGN AND METHODS We studied 1,020 participants with type 2 diabetes (83% European Americans; 55% women; mean age 61.4 years) who were free of atrial fibrillation, major ventricular conduction defects, and antiarrhythmic therapy at baseline. QT duration was automatically calculated from a standard 12-lead electrocardiogram (ECG). Following American Heart Association/American College of Cardiology Foundation recommendations, a linear scale was used to correct the QT for heart rate. Using Cox regression, risk was estimated per 1-SD increase in QTc interval as well as prolonged QTc interval (>450 ms) vs. normal QTc interval for mortality.RESULTSAt baseline, the mean (SD) QTc duration was 414.9 ms (18.1 ms), and 3.0% of participants had prolonged QTc. After a median follow-up time of 8.5 years (maximum follow-up time 13.9 years), 204 participants were deceased. In adjusted multivariate models, a 1-SD increase in QTc interval was associated with an 18% higher risk for all-cause mortality (hazard ratio 1.18 [95% CI 1.03-1.36]) and 29% increased risk for CVD mortality (1.29 [1.05-1.59]). Similar results were obtained when QTc interval was used as a categorical variable (prolonged vs. normal) (all-cause mortality 1.73 [0.95-3.15]; CVD mortality 2.86 [1.35-6.08]).CONCLUSIONS Heart rate QTc interval is an independent predictor of all-cause and CVD mortality in this population with type 2 diabetes, suggesting that additional prognostic information may be available from this simple ECG measure.
    Diabetes care 02/2014; · 7.74 Impact Factor
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    ABSTRACT: OBJECTIVE Given the high rates of cardiovascular disease (CVD) and associated mortality in individuals with type 2 diabetes, identifying and understanding predictors of CVD events and mortality could help inform clinical management in this high-risk group. Recent large-scale genetic studies may provide additional tools in this regard.RESEARCH DESIGN AND METHODS Genetic risk scores (GRSs) were constructed in 1,175 self-identified European American (EA) individuals comprising the family-based Diabetes Heart Study based on 1) 13 single nucleotide polymorphisms (SNPs) and 2) 30 SNPs with previously documented associations with CVD in genome-wide association studies. Associations between each GRS and a self-reported history of CVD, coronary artery calcified plaque (CAC) determined by noncontrast computed tomography scan, all-cause mortality, and CVD mortality were examined using marginal models with generalized estimating equations and Cox proportional hazards models.RESULTSThe weighted 13-SNP GRS was associated with prior CVD (odds ratio [OR] 1.51 [95% CI 1.22-1.86]; P = 0.0002), CAC (β-coefficient [β] 0.22 [0.02-0.43]; P = 0.04) and CVD mortality (hazard ratio [HR] 1.35 [1.10-1.81]; P = 0.04) when adjusting for the other known CVD risk factors: age, gender, type 2 diabetes affection status, BMI, current smoking status, hypertension, and dyslipidemia. The weighted 30-SNP GRS was also associated with prior CVD (OR 1.33 [1.08-1.65]; P = 0.008), CAC (β 0.29 [0.08-0.50]; P = 0.006), all-cause mortality (HR 1.28 [1.05-1.56]; P = 0.01), and CVD mortality (HR 1.46 [1.08-1.96]; P = 0.01).CONCLUSIONS These findings support the utility of two simple GRSs in examining genetic associations for adverse outcomes in EAs with type 2 diabetes.
    Diabetes care 02/2014; · 7.74 Impact Factor
  • Donald W Bowden, Amanda J Cox
    Nature Reviews Endocrinology 10/2013; · 11.03 Impact Factor
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    ABSTRACT: Patients with type 2 diabetes (T2D) are at elevated risk for cardiovascular disease (CVD) events and mortality. Recent studies have assessed the impact of genetic variants affecting high-density lipoprotein cholesterol (HDL) concentrations on CVD risk in the general population. This study examined the utility of HDL-associated single nucleotide polymorphisms (SNPs) for CVD risk prediction in European Americans with T2D enrolled in the Diabetes Heart Study (DHS). Genetic risk scores (GRS) of HDL-associated SNPs were constructed and evaluated for potential associations with mortality and with coronary artery calcified atherosclerotic plaque (CAC), a measure of subclinical CVD strongly associated with CVD events and mortality. Two sets of SNPs were used to construct GRS; while all SNPs were selected primarily for their impacts on HDL, one set of SNPs had pleiotropic effects on other lipid parameters, while the other set lacked effects on low-density lipoprotein cholesterol (LDL) or triglyceride concentrations. The GRS were specifically associated with HDL concentrations (4.90 x 10-7 < p < 0.02) in models adjusted for age, sex, and body mass index (BMI), but were not associated with LDL or triglycerides. Cox proportional hazards regression analysis suggested the HDL-associated GRS had no impact on risk of CVD-mortality (0.48 < p <0.99) in models adjusted for other known CVD risk factors. However, associations between several of the GRS and CAC were observed (3.85 x 10-4 < p < 0.03) in models adjusted for other known CVD risk factors. The GRS analyzed in this study provide a tool for assessment of HDL-associated SNPs and their impact on CVD risk in T2D. The observed associations between several of the GRS and CAC suggest a potential role for HDL-associated SNPs on subclinical CVD risk in patients with T2D.
    Cardiovascular Diabetology 06/2013; 12(1):95. · 4.21 Impact Factor
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    ABSTRACT: OBJECTIVE: A negative relationship between total bilirubin concentration (TBili) and CVD risk has been documented in a series of epidemiological studies. In addition, TBili is thought to be under strong genetic regulation via the UGT1A gene family, suggesting it may be a heritable CVD risk factor. However, few studies directly relate TBili-associated UGT1A variants to CVD severity or outcome. This study replicated the genetic association for TBili in the Diabetes Heart Study (DHS), and examined the relationships of TBili-associated SNPs with measures of subclinical CVD and mortality. METHODS: This investigation included 1220 self-described European American (EA) individuals from the DHS, a family-based study examining risk for macrovascular complications in type 2 diabetes (T2D). Genetic associations with TBili were examined using the Affymetrix Genome-wide Human SNP Array 5.0 and the Illumina Infinium Human Exome beadchip v1.0. Subsequent analyses assessed the relationships of the top TBili-associated SNPs with measures of vascular calcified plaque and mortality. RESULTS: A genome-wide association study detected 18 SNPs within the UGT1A gene family associated with TBili at p < 5 × 10(-8). The top hit was rs887829 (p = 8.67 × 10(-20)). There was no compelling evidence of association between the top TBili-associated SNPs and vascular calcified plaque (p = 0.05-0.88). There was, however, evidence of association with all-cause mortality (p = 0.0004-0.06), the top hit being rs2741034. CONCLUSION: These findings support a potential role for UGT1A genetic variants in risk for mortality in T2D. Further quantification of the extent of CVD risk conferred by UGT1A gene family variants in a high risk cohort with T2D is still required.
    Atherosclerosis 04/2013; · 3.71 Impact Factor
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    ABSTRACT: BACKGROUND: Risk stratification in individuals with type 2 diabetes (T2D) remains an important priority in the management of associated morbidity and mortality, including from cardiovascular disease (CVD). The current investigation examined whether estimated glomerular filtration rate (eGFR) and urine albumin:creatinine ratio (UACR) were independent predictors of CVD-mortality in European Americans (EAs) with T2D after accounting for subclinical CVD. METHODS: The family-based Diabetes Heart Study (DHS) cohort (n=1,220) had baseline measures of serum creatinine, eGFR, UACR and coronary artery calcified plaque (CAC) assessed by non-contrast computed tomography scan. Cox proportional hazards regression was performed to determine risk for all-cause mortality and CVD-mortality associated with indices of kidney disease after accounting for traditional CVD risk factors and CAC as a measure of subclinical CVD. RESULTS: Participants were followed for 8.2+/-2.6 years (mean+/-SD) during which time 247 (20.9%) were deceased, 107 (9.1%) from CVD. Univariate analyses revealed positive associations between serum creatinine (HR:1.56; 95% CI:1.37--1.80; p<0.0001) and UACR (1.59; 1.43--1.77; p>0.0001) and negative associations between serum albumin (0.74; 0.65--0.84; p<0.0001) and eGFR (0.66; 0.58--0.76; p<0.0001) with all-cause mortality. Associations remained significant after adjustment for traditional CVD risk factors, as well as for CAC. Similar trends were noted when predicting risk for CVD-mortality. CONCLUSIONS: The DHS reveals that kidney function and albuminuria are independent risk factors for all-cause mortality and CVD-mortality in EAs with T2D, even after accounting for CAC.
    Cardiovascular Diabetology 04/2013; 12(1):68. · 4.21 Impact Factor
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    ABSTRACT: Patients with type 2 diabetes mellitus are at increased risk for cardiovascular disease (CVD) and mortality. Beyond traditional CVD risk factors, novel measures reflecting additional aspects of disease pathophysiology, such as biventricular volume (BiVV), may be useful for risk stratification. The aim of this study was to examine the relationship between BiVV and risk for mortality in European Americans with type 2 diabetes mellitus from the Diabetes Heart Study (DHS). BiVV was calculated from 771 noncontrast computed tomographic scans performed to image coronary artery calcified plaque. Relationships between BiVV and traditional CVD risk factors were examined. Cox proportional-hazards regression was performed to determine risk for mortality (all-cause and CVD mortality) associated with increasing BiVV. Area under the curve analysis was used to assess BiVV utility in risk prediction models. During 8.4 ± 2.4 years of follow-up, 23% of the patients died. In unadjusted analyses, BiVV was significantly associated with increasing body mass index, height, coronary artery calcified plaque, history of hypertension, and previous myocardial infarction (p <0.0001 to 0.012). BiVV was significantly associated with all-cause (hazard ratio 2.45, 95% confidence interval 1.06 to 5.67, p = 0.036) and CVD (hazard ratio 4.36, 95% confidence interval 1.36 to 14.03, p = 0.014) mortality in models adjusted for other known CVD risk factors. Area under the curve increased from 0.76 to 0.78 (p = 0.04) and from 0.74 to 0.77 (p = 0.02) for all-cause and CVD mortality with the inclusion of BiVV. In conclusion, in the absence of echocardiography or other noninvasive imaging modalities to assess ventricular volumes, or when such methods are contraindicated, BiVV from computed tomography may be considered a tool for the stratification of high-risk patients, such as those with type 2 diabetes mellitus.
    The American journal of cardiology 01/2013; · 3.58 Impact Factor
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    ABSTRACT: Haptoglobin (HP) is an acute phase protein that binds to freely circulating hemoglobin. HP exists as two distinct forms, HP1 and HP2. The longer HP2 form has been associated with cardiovascular (CVD) events and mortality in individuals with type 2 diabetes (T2DM). This study examined the association of HP genotypes with subclinical CVD, T2DM risk, and associated risk factors in a T2DM-enriched sample. Haptoglobin genotypes were determined in 1208 European Americans (EA) from 473 Diabetes Heart Study (DHS) families via PCR. Three promoter SNPs (rs5467, rs5470, and rs5471) were also genotyped. Analyses revealed association between HP2-2 duplication and increased carotid intima-media thickness (IMT; p = 0.001). No association between HP and measures of calcified arterial plaque were observed, but the HP polymorphism was associated with triglyceride concentrations (p = 0.005) and CVD mortality (p = 0.04). We found that the HP2-2 genotype was associated with increased T2DM risk with an odds ratio (OR) of 1.49 (95% CI 1.18-1.86, p = 6.59x10-4). Promoter SNPs were not associated with any traits. This study suggests association between the HP duplication and IMT, triglycerides, CVD mortality, and T2DM in an EA population enriched for T2DM. Lack of association with atherosclerotic calcified plaque likely reflect differences in the pathogenesis of these CVD phenotypes. HP variation may contribute to the heritable risk for CVD complications in T2DM.
    Cardiovascular Diabetology 01/2013; 12:31. · 4.21 Impact Factor
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    ABSTRACT: BACKGROUND: -The presence and severity of coronary artery calcified plaque (CAC) differs markedly between individuals of African and European descent, suggesting that admixture mapping (AM) may be informative for identifying genetic variants associated with subclinical cardiovascular disease (CVD). METHODS AND RESULTS: -AM of CAC was performed in 1,040 unrelated African Americans with type 2 diabetes mellitus from the African American-Diabetes Heart Study (AA-DHS), Multi-Ethnic Study of Atherosclerosis (MESA), and Family Heart Study (FamHS) using the Illumina custom ancestry informative marker (AIM) panel. All cohorts obtained computed tomography scanning of the coronary arteries using identical protocols. For each AIM, the probability of inheriting 0, 1, and 2 copies of a European-derived allele was determined. Linkage analysis was performed by testing for association between each AIM using these probabilities and CAC, accounting for global ancestry, age, gender and study. Markers on 1p32.3 in the GLIS1 gene (rs6663966, LOD=3.7), 1q32.1 near CHIT1 (rs7530895, LOD=3.1), 4q21.2 near PRKG2 (rs1212373, LOD=3.0) and 11q25 in the OPCML gene (rs6590705, LOD=3.4) had statistically significant LOD scores, while markers on 8q22.2 (rs6994682, LOD=2.7), 9p21.2 (rs439314, LOD=2.7), and 13p32.1 (rs7492028, LOD=2.8) manifested suggestive evidence of linkage. These regions were uniformly characterized by higher levels of European ancestry associating with higher levels or odds of CAC. Findings were replicated in 1,350 AAs without diabetes and 2,497 diabetic European Americans from MESA and the Diabetes Heart Study. CONCLUSIONS: -Fine mapping these regions will likely identify novel genetic variants that contribute to CAC and clarify racial differences in susceptibility to subclinical CVD.
    Circulation Cardiovascular Genetics 12/2012; · 6.73 Impact Factor
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    ABSTRACT: OBJECTIVE In type 2 diabetes mellitus (T2DM), it remains unclear whether coronary artery calcium (CAC) provides additional information about cardiovascular disease (CVD) mortality beyond the Framingham Risk Score (FRS) factors.RESEARCH DESIGN AND METHODSA total of 1,123 T2DM participants, ages 34-86 years, in the Diabetes Heart Study followed up for an average of 7.4 years were separated using baseline computed tomography scans of CAC (0-9, 10-99, 100-299, 300-999, and ≥1,000). Logistic regression was performed to examine the association between CAC and CVD mortality adjusting for FRS. Areas under the curve (AUC) with and without CAC were compared. Net reclassification improvement (NRI) compared FRS (model 1) versus FRS+CAC (model 2) using 7.4-year CVD mortality risk categories 0% to <7%, 7% to <20%, and ≥20%.RESULTSOverall, 8% of participants died of cardiovascular causes during follow-up. In multivariate analysis, the odds ratios (95% CI) for CVD mortality using CAC 0-9 as the reference group were, CAC 10-99: 2.93 (0.74-19.55); CAC 100-299: 3.17 (0.70-22.22); CAC 300-999: 4.41(1.15-29.00); and CAC ≥1,000: 11.23 (3.24-71.00). AUC (95% CI) without CAC was 0.70 (0.67-0.73), AUC with CAC was 0.75 (0.72-0.78), and NRI was 0.13 (0.07-0.19).CONCLUSIONS In T2DM, CAC predicts CVD mortality and meaningfully reclassifies participants, suggesting clinical utility as a risk stratification tool in a population already at increased CVD risk.
    Diabetes care 12/2012; · 7.74 Impact Factor
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    ABSTRACT: OBJECTIVE: Understanding the interplay between adiposity, inflammation, and cardiovascular complications in type 2 diabetes mellitus (T2DM) remains a challenge. Signaling from adipocytes is considered important in this context. Adiponectin is the most abundant adipocytokine and has been associated with various measures of cardiovascular disease (CVD). This study examines the relationships between genetic variants in the adiponectin (ADIPOQ) and adiponectin-related signaling pathway genes and measures of subclinical CVD (vascular calcified plaque and carotid intima-media thickness), plasma lipids, and inflammation in T2DM. DESIGN AND METHODS: Single-nucleotide polymorphisms (SNPs) in ADIPOQ (n = 45), SNPs tagging ADIPOR1 (n = 6), APIPOR2 (n = 8), APPL1 (n = 6) and known rare coding variants in KNG1 (n = 3) and LYZL1 (n = 3) were genotyped in 1220 European Americans from the family-based Diabetes Heart Study. Associations between SNPs and phenotypes of interest were assessed using a variance components analysis with adjustment for age, sex, T2DM-affected status, and body mass index. RESULTS AND CONCLUSION: There was minimal evidence of association between SNPs in the adiponectin signaling pathway genes and measures of calcified plaque; eight of the 71 SNPs showed evidence of association with subclinical CVD (P = 0.007-0.046) but not with other phenotypes examined. Nine additional SNPs were associated with at least one of the plasma lipid measures (P = 0.008-0.05). Findings from this study do not support a significant role for variants in the adiponectin signaling pathway genes in contributing to risk for vascular calcification in T2DM. However, further understanding the interplay between adiposity, plasma lipids, and inflammation may prove important in the prediction and management of cardiovascular complications in T2DM.
    Obesity 11/2012; · 3.92 Impact Factor
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    ABSTRACT: Selenoprotein S (SelS) has previously been associated with a range of inflammatory markers, particularly in the context of cardiovascular disease (CVD). The aim of this study was to examine the role of SELS genetic variants in risk for subclinical CVD and mortality in individuals with type 2 diabetes mellitus (T2DM). The association between 10 polymorphisms tagging SELS and coronary (CAC), carotid (CarCP) and abdominal aortic calcified plaque, carotid intima media thickness and other known CVD risk factors was examined in 1220 European Americans from the family-based Diabetes Heart Study. The strongest evidence of association for SELS SNPs was observed for CarCP; rs28665122 (5' region; β = 0.329, p = 0.044), rs4965814 (intron 5; β = 0.329, p = 0.036), rs28628459 (3' region; β = 0.331, p = 0.039) and rs7178239 (downstream; β = 0.375, p = 0.016) were all associated. In addition, rs12917258 (intron 5) was associated with CAC (β = -0.230, p = 0.032), and rs4965814, rs28628459 and rs9806366 were all associated with self-reported history of prior CVD (p = 0.020-0.043). These results suggest a potential role for the SELS region in the development subclinical CVD in this sample enriched for T2DM. Further understanding the mechanisms underpinning these relationships may prove important in predicting and managing CVD complications in T2DM.
    Acta Diabetologica 11/2012; · 4.63 Impact Factor
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    ABSTRACT: Although current American Heart Association guidelines address C-reactive protein concentration and cardiovascular disease risk, it remains unclear whether this paradigm is consistent across populations with differing disease burdens. Individuals with Type 2 diabetes mellitus represent one group at increased risk of cardiovascular disease and subsequent mortality. This study aimed to examine the relationship between C-reactive protein concentrations and risk for all-cause mortality in European Americans with Type 2 diabetes from the Diabetes Heart Study. A total of 846 European Americans with Type 2 diabetes and baseline measures of C-reactive protein were evaluated. Vital status was determined after a follow-up period of 7.3 ± 2.1 years (mean ± SD). C-reactive protein concentrations were compared between living and deceased subgroups along with other known risk factors for cardiovascular disease, including blood lipids. Logistic regression was performed to determine risk for mortality associated with increasing C-reactive protein concentrations. At follow-up 160 individuals (18.7%) were deceased. No significant differences in baseline serum glucose or lipid measures were observed between living and deceased subgroups. Baseline C-reactive protein concentrations were significantly higher in the deceased subgroup (9.37 ± 15.94) compared with the living subgroup (5.36 ± 7.91 mg/l; P < 0.0001). Participants with C-reactive protein concentrations of 3-10 mg/l were approximately two times more likely to be deceased at follow-up (OR 2.06; 95% CI 1.17-3.62); those with C-reactive protein >10 mg/l were more than five times more likely to be deceased (OR 5.24; CI 2.80-9.38). This study documents the utility of C-reactive protein in predicting risk for all-cause mortality in European Americans with Type 2 diabetes and supports its use as a screening tool in risk prediction models.
    Diabetic Medicine 12/2011; 29(6):767-70. · 3.24 Impact Factor
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    ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is commonly diagnosed in patients with obesity and type 2 diabetes mellitus (T2DM), and has been associated with the single nucleotide polymorphism (SNP) rs738409 in the PNPLA3 gene. This association remains to be investigated in African Americans with T2DM, a group at lower risk for hepatic steatosis relative to European Americans with T2DM. We examined 422 African Americans with T2DM (40.3% male; age: 56.4±9.6 years; Body Mass Index: 35.2±8.2 kg/m(2)), all with measures of liver density reflecting hepatic fat content on abdominal computed tomography, and blood glucose and lipid profiles. Associations between rs738409 and phenotypes of interest were determined using SOLAR, assuming an additive model of inheritance with covariates age, sex, BMI and use of lipid-lowering medications. Mean±SD liver density was 55.4±10.2 Hounsfield Units. SNP rs738409 in PNPLA3 was significantly associated with liver density (P=0.0075) and hepatic steatosis (P=0.0350), but not with blood glucose, HbA(1c), total cholesterol, triglycerides, high-density or low-density lipoprotein levels or liver function tests (P=0.15-0.96). These findings provide evidence that the PNPLA3 SNP rs738409 contributes to risk for increased liver fat content in African Americans with T2DM, an effect that appears to be independent from serum lipids. Although African Americans are less susceptible to fatty liver than European Americans, PNPLA3 appears to be a risk locus for hepatic steatosis in diabetic African Americans.
    Diabetes & Metabolism 06/2011; 37(5):452-5. · 2.39 Impact Factor
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    ABSTRACT: A linkage peak for carotid artery calcified plaque (CarCP) on chromosome 16p (LOD 4.39 at 8.4 cM) in families with type 2 diabetes mellitus (T2DM) from the Diabetes Heart Study (DHS) has been refined. Fine mapping encompassed 104 single-nucleotide polymorphisms (SNPs) in 937 subjects from 315 families; including 45 SNPs in six candidate genes (CACNA1H, SEPX1, ABCA3, IL32, SOCS1, CLEC16A). Linkage and association analyses using variance components analysis adjusting for age, gender, body mass index (BMI), and diabetes status refined the CarCP linkage into two distinct peaks (LODs: 3.89 at 6.9 cM and 4.86 at 16.0 cM). Evidence of linkage for coronary calcified plaque (LOD: 2.27 at 19 cM) and a vascular calcification principle component (LOD: 3.71 at 16.0 cM) was also observed. The strongest evidence for association with CarCP was observed with SNPs in the A2BP1 gene region (rs4337300 P= 0.005) with modest evidence of association with SNPs in CACNA1H (P= 0.010-0.033). Bayesian quantitative trait nucleotide (BQTN) analysis identified a SNP, rs1358489, with either a functional effect on CarCP or in linkage disequilibrium (LD) with a functional SNP. This study refined the 16p region contributing to vascular calcification. The causal variants remain to be identified, but results are consistent with a linkage peak that is due to multiple common variants, though rare variants cannot be excluded.
    Annals of Human Genetics 03/2011; 75(2):222-35. · 2.22 Impact Factor
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    ABSTRACT: In diabetes, it remains unclear whether the coronary artery calcium (CAC) score provides additional information about total mortality risk beyond traditional risk factors. A total of 1,051 participants, aged 34-86 years, in the Diabetes Heart Study (DHS) were followed for 7.4 years. Subjects were separated into five groups using baseline computed tomography scans and CAC scores (0-9, 10-99, 100-299, 300-999, and ≥1,000). Logistic regression was performed adjusting for age, sex, race, smoking, and LDL cholesterol to examine the association between CAC and all-cause mortality. Areas under the curve with and without CAC were compared. Natural splines using continuous measures of CAC were fitted to estimate the relationship between observed CAC and mortality risk. A total of 17% (178 of 1,051) of participants died during the follow-up. In multivariate analysis, the odds ratios (95% CIs) for all-cause mortality, using CAC 0-9 as the reference group, were CAC 10-99: 1.40 (0.57-3.74); CAC 100-299: 2.87 (1.17-7.77); CAC 300-999: 3.04 (1.32-7.90); and CAC ≥ 1,000: 6.71 (3.09-16.87). The area under the curve without CAC was 0.68 (95% CI 0.66-0.70), and the area under the curve with CAC was 0.72 (0.70-0.74) (P = 0.0001). Using splines, the estimated risk (95% CI) of mortality for a CAC of 0 was 6.7% (4.6-9.7), and the risk increased nearly linearly, plateauing at CAC ≥ 1,000 (20.0% [15.7-25.2]). In diabetes, CAC was shown to be an independent predictor of mortality. Participants with CAC (0-9) were at lower risk (0.9% annual mortality). The risk of mortality increased with increasing levels of CAC, plateauing at approximately CAC ≥ 1,000 (2.7% annual mortality). More research is warranted to determine the potential utility of CAC scans in diabetes.
    Diabetes care 03/2011; 34(5):1219-24. · 7.74 Impact Factor

Publication Stats

86 Citations
102.15 Total Impact Points

Institutions

  • 2011–2014
    • Wake Forest School of Medicine
      • Department of Biochemistry
      Winston-Salem, North Carolina, United States
    • Wake Forest University
      • Department of Cardiology
      Winston-Salem, North Carolina, United States
  • 2012
    • Oakwood Hospital & Medical Center
      Dearborn, Michigan, United States