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Wake Forest, NC, United States

Hixson J.E.,University of Texas Health Science Center at Houston | Shimmin L.C.,University of Texas Health Science Center at Houston | Montasser M.E.,University of Texas Health Science Center at Houston | Kim D.-K.,University of Texas Health Science Center at Houston | And 10 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2011

Objective-: We investigated the influence of genetic variants (rare and common) in the gene encoding periostin (POSTN) on atherosclerosis as measured in arterial specimens from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study. Methods and Results-: A comprehensive survey of common POSTN variants (87 single-nucleotide polymorphisms [SNPs]) in PDAY subjects (n=2527) identified numerous SNPs associated with raised lesions in abdominal aorta and with fatty streaks in thoracic aorta. These SNPs belonged to a small number of correlation bins that spanned the entire locus. To examine effects of rare variants, we resequenced POSTN functional regions in PDAY cases with raised lesions (n=291) and controls with no raised lesions (n=294). However, we found no significant associations with case-control status for carriers of POSTN rare variants using the weighted-sum method for rare variant analysis. Conclusion-: We identified common variants in POSTN that are associated with arterial lesions in young persons from the PDAY study. This finding strongly supports a role for periostin in atherogenesis, as suggested by recent proteomics analysis that found abundant expression of periostin in atherosclerotic lesions. Genetic variation may influence atherosclerosis via periostin's known involvement in multiple relevant pathways, including angiogenesis, vascular remodeling, and stimulation of migration and differentiation of vascular smooth muscle cells. © 2011 American Heart Association, Inc. Source

Cox A.J.,Center for Human Genomics
Neurobiology of aging | Year: 2014

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. Copyright © 2014. Published by Elsevier Inc. Source

Cox A.J.,Center for Human Genomics | Cox A.J.,Center for Diabetes Research | Agarwal S.,Oakwood | Bowden D.W.,Center for Human Genomics | Bowden D.W.,Center for Diabetes Research
Diabetic Medicine | Year: 2012

Aims 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. Methods 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±2.1years (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. Results 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±7.91mg/l; P<0.0001). Participants with C-reactive protein concentrations of 3-10mg/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 >10mg/l were more than five times more likely to be deceased (OR 5.24; CI 2.80-9.38). Conclusions 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. © 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK. Source

Raffield L.M.,Center for Human Genomics | Cox A.J.,Center for Human Genomics | Carr J.J.,Vanderbilt University | Bowden D.W.,Center for Human Genomics
Diabetology and Metabolic Syndrome | Year: 2015

Background: Many studies evaluated the best predictors for cardiovascular disease (CVD) events in individuals with type 2 diabetes (T2D), but few studies examined the factors most strongly associated with mortality in T2D. The Diabetes Heart Study (DHS), an intensively phenotyped family-based cohort enriched for T2D, provided an opportunity to address this question. Methods: Associations with mortality were examined in 1022 European Americans affected by T2D from 476 DHS families. All-cause mortality was 31.2 % over an average 9.6 years of follow-up. Cox proportional hazards models with sandwich-based variance estimation were used to evaluate associations between all-cause and CVD mortality and 24 demographic and clinical factors, including coronary artery calcified plaque (CAC), carotid artery intima-media thickness, medications, body mass index, waist hip ratio, lipids, blood pressure, kidney function, QT interval, educational attainment, and glycemic control. Nominally significant factors (p < 0.25) from univariate analyses were included in model selection (backward elimination, forward selection, and stepwise selection). Age and sex were included in all models. Results: The all-cause mortality model selected from the full DHS sample included age, sex, CAC, urine albumin: creatinine ratio (UACR), insulin use, current smoking, and educational attainment. The CVD mortality model selected from the full sample included age, sex, CAC, UACR, triglycerides, and history of CVD events. Beyond age, the most significant associations for both mortality models were CAC (2.03 × 10-4 ≤ p ≤ 0.001) and UACR (1.99 × 10-8 ≤ p ≤ 2.23 × 10-8). To confirm the validity of the main predictors identified with model selection using the full sample, a two-fold cross-validation approach was used, and similar results were observed. Conclusions: This analysis highlights important demographic and clinical factors, notably CAC and albuminuria, which predict mortality in the general population of patients with T2D. © 2015 Raffield et al. Source

Cox A.J.,Center for Human Genomics | Cox A.J.,Center for Diabetes Research | Bowden D.W.,Center for Human Genomics | Bowden D.W.,Center for Diabetes Research
Cardiovascular Diabetology | Year: 2013

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. © 2013 Cox et al.; licensee BioMed Central Ltd. Source

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