Wake Forest, NC, United States
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Sergeant S.,Center for Botanical Lipids and Inflammatory Disease Prevention | Hugenschmidt C.E.,Center for Diabetes Research | Rudock M.E.,Center for Human Genomics | Ivester P.,Center for Botanical Lipids and Inflammatory Disease Prevention | And 6 more authors.
British Journal of Nutrition | Year: 2012

Over the past 50 years, increases in dietary n-6 PUFA, such as linoleic acid, have been hypothesised to cause or exacerbate chronic inflammatory diseases. The present study examines an individual's innate capacity to synthesise n-6 long-chain PUFA (LC-PUFA) with respect to the fatty acid desaturase (FADS) locus in Americans of African and European descent with diabetes or the metabolic syndrome. Compared with European Americans (EAm), African Americans (AfAm) exhibited markedly higher serum levels of arachidonic acid (AA) (EAm 79 (sd 21), AfAm 98 (sd 19) % of total fatty acids; P < 229 × 10 - 9) and the AA:n-6-precursor fatty acid ratio, which estimates FADS1 activity (EAm 54 (sd 22), AfAm 69 (sd 22); P = 144 × 10 - 5). In all, seven SNP mapping to the FADS locus revealed strong association with AA, EPA and dihomo-γ-linolenic acid (DGLA) in the EAm. Importantly, EAm homozygous for the minor allele (T) had significantly lower AA levels (TT 63 (sd 10); GG 85 (sd 21); P = 30 × 10 - 5) and AA:DGLA ratios (TT 34 (sd 08), GG 65 (sd 23); P = 22 × 10 - 7) but higher DGLA levels (TT 19 (sd 04), GG 14 (sd 04); P = 33 × 10 - 7) compared with those homozygous for the major allele (GG). Allele frequency patterns suggest that the GG genotype at rs174537 (associated with higher circulating levels of AA) is much higher in AfAm (081) compared with EAm (046). Similarly, marked differences in rs174537 genotypic frequencies were observed in HapMap populations. These data suggest that there are probably important differences in the capacity of different populations to synthesise LC-PUFA. These differences may provide a genetic mechanism contributing to health disparities between populations of African and European descent. © The Authors 2011.

Cox A.J.,Center for Human Genomics | Cox A.J.,Center for Diabetes Research | Ng M.C.Y.,Center for Human Genomics | Ng M.C.Y.,Center for Diabetes Research | And 2 more authors.
Diabetes Care | Year: 2014

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. RESULTS: The 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, sex, 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. © 2014 by the American Diabetes Association.

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.

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.

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.

PubMed | Center for Human Genomics
Type: Journal Article | Journal: Journal of diabetes and its complications | Year: 2016

Anxiety, depression, accelerated cognitive decline, and increased risk of dementia are observed in individuals with type 2 diabetes. Anxiety and depression may contribute to lower performance on cognitive tests and differences in neuroimaging observed in individuals with type 2 diabetes.These relationships were assessed in 655 European Americans with type 2 diabetes from 504 Diabetes Heart Study families. Participants completed cognitive testing, brain magnetic resonance imaging, the Brief Symptom Inventory Anxiety subscale, and the Center for Epidemiologic Studies Depression-10.In analyses adjusted for age, sex, educational attainment, and use of psychotropic medications, individuals with comorbid anxiety and depression symptoms had lower performance on all cognitive testing measures assessed (p0.005). Those with both anxiety and depression also had increased white matter lesion volume (p=0.015), decreased gray matter cerebral blood flow (p=4.4310(-6)), decreased gray matter volume (p=0.002), increased white and gray matter mean diffusivity (p0.001), and decreased white matter fractional anisotropy (p=7.7910(-4)). These associations were somewhat attenuated upon further adjustment for health status related covariates.Comorbid anxiety and depression symptoms were associated with cognitive performance and brain structure in a European American cohort with type 2 diabetes.

PubMed | Griffith University, Molecular Genetics and Genomics Program and Center for Human Genomics
Type: Journal Article | Journal: Acta diabetologica | Year: 2016

To examine the relationships between type 2 diabetes (T2D) status, glycemic control, and T2D duration with magnetic resonance imaging (MRI)-derived neuroimaging measures in European Americans from the Diabetes Heart Study (DHS) Mind cohort.Relationships were examined using marginal models with generalized estimating equations in 784 participants from 514 DHS Mind families. Fasting plasma glucose, glycated hemoglobin, and diabetes duration were analyzed in 682 participants with T2D. Models were adjusted for potential confounders, including age, sex, history of cardiovascular disease, smoking, educational attainment, and use of statins or blood pressure medications. Association was tested with gray and white matter volume, white matter lesion volume, gray matter cerebral blood flow, and white and gray matter fractional anisotropy and mean diffusivity.Adjusting for multiple comparisons, T2D status was associated with reduced white matter volume (p=2.4810(-6)) and reduced gray and white matter fractional anisotropy (p0.001) in fully adjusted models, with a trend toward increased white matter lesion volume (p=0.008) and increased gray and white matter mean diffusivity (p0.031). Among T2D-affected participants, neither fasting glucose, glycated hemoglobin, nor diabetes duration were associated with the neuroimaging measures assessed (p>0.05).While T2D was significantly associated with MRI-derived neuroimaging measures, differences in glycemic control in T2D-affected individuals in the DHS Mind study do not appear to significantly contribute to variation in these measures. This supports the idea that the presence or absence of T2D, not fine gradations of glycemic control, may be more significantly associated with age-related changes in the brain.

PubMed | Public Health science, The Broad Institute of MIT and Harvard, Harvard University, University of Oregon and 21 more.
Type: Journal Article | Journal: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research | Year: 2016

Genome-wide association studies (GWASs) have revealed numerous loci for areal bone mineral density (aBMD). We completed the first GWAS meta-analysis (n=15,275) of lumbar spine volumetric BMD (vBMD) measured by quantitative computed tomography (QCT), allowing for examination of the trabecular bone compartment. SNPs that were significantly associated with vBMD were also examined in two GWAS meta-analyses to determine associations with morphometric vertebral fracture (n=21,701) and clinical vertebral fracture (n=5893). Expression quantitative trait locus (eQTL) analyses of iliac crest biopsies were performed in 84 postmenopausal women, and murine osteoblast expression of genes implicated by eQTL or by proximity to vBMD-associated SNPs was examined. We identified significant vBMD associations with five loci, including: 1p36.12, containing WNT4 and ZBTB40; 8q24, containing TNFRSF11B; and 13q14, containing AKAP11 and TNFSF11. Two loci (5p13 and 1p36.12) also contained associations with radiographic and clinical vertebral fracture, respectively. In 5p13, rs2468531 (minor allele frequency [MAF]=3%) was associated with higher vBMD (=0.22, p=1.910

PubMed | U.S. National Institute on Aging, Karolinska Institutet, CNR Institute of Neuroscience, University of Houston and 17 more.
Type: Journal Article | Journal: Psychological medicine | Year: 2016

Major depressive disorder (MDD) is moderately heritable, however genome-wide association studies (GWAS) for MDD, as well as for related continuous outcomes, have not shown consistent results. Attempts to elucidate the genetic basis of MDD may be hindered by heterogeneity in diagnosis. The Center for Epidemiological Studies Depression (CES-D) scale provides a widely used tool for measuring depressive symptoms clustered in four different domains which can be combined together into a total score but also can be analysed as separate symptom domains.We performed a meta-analysis of GWAS of the CES-D symptom clusters. We recruited 12 cohorts with the 20- or 10-item CES-D scale (32 528 persons).One single nucleotide polymorphism (SNP), rs713224, located near the brain-expressed melatonin receptor (MTNR1A) gene, was associated with the somatic complaints domain of depression symptoms, with borderline genome-wide significance (p discovery = 3.82 10-8). The SNP was analysed in an additional five cohorts comprising the replication sample (6813 persons). However, the association was not consistent among the replication sample (p discovery+replication = 1.10 10-6) with evidence of heterogeneity.Despite the effort to harmonize the phenotypes across cohorts and participants, our study is still underpowered to detect consistent association for depression, even by means of symptom classification. On the contrary, the SNP-based heritability and co-heritability estimation results suggest that a very minor part of the variation could be captured by GWAS, explaining the reason of sparse findings.

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