Amanda J Cox

Griffith University, Queensland, Australia

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Publications (59)230.53 Total impact

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    ABSTRACT: Genetic differences between ethnic populations affect susceptibility to disease and efficacy of drugs. We examined and compared the prevalence of single nucleotide polymorphisms (SNPs) in genes of the renin-angiotensin system (RAS) in a desert community of Indigenous Australians and in non-Indigenous Australians. The polymorphisms were angiotensinogen, AGT G-217A (rs5049); AGT G+174A (rs4762); Angiotensin II type 1 receptor, AGTR1 A+1166C (rs5186); angiotensin converting enzyme, ACE A-240T (rs4291), ACE T-93C (rs4292); renin, REN T+1142C (rs5706). They were measured using allelic discrimination assays. The prevalence of REN T+1142C SNP was similar in the two populations; 99% were homozygous for the T allele. All other SNPs were differently distributed between the two populations (P<0.0001). In non-Indigenous Australians, in ACE, rs4291, the A allele at position 204 was prevalent (61.8%) whereas in the Indigenous Australians the A allele was less prevalent (28%). For rs4292, the C allele had a prevalence of 37.9% in non-Indigenous Australians but in Indigenous Australians the prevalence was only 1%. No Indigenous individuals were homozygous for the C allele of AGTR1 (rs5186). Thus the prevalence of RAS SNPs in this Indigenous Australian desert community was different from non-Indigenous Australians as was the prevalence of cytokine SNPs (previous study). These differences may affect susceptibility to chronic renal and cardiovascular disease and may alter the efficacy of drugs used to inhibit the RAS. Our unique studies highlight the need to study the pharmacogenetics of drug absorption, distribution, metabolism and excretion in Indigenous Australians for safe prescribing guidelines. This article is protected by copyright. All rights reserved.
    No preview · Article · Dec 2015 · Clinical and Experimental Pharmacology and Physiology
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    ABSTRACT: Aims: 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. Methods: 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. Results: Adjusting for multiple comparisons, T2D status was associated with reduced white matter volume (p = 2.48 × 10(-6)) and reduced gray and white matter fractional anisotropy (p ≤ 0.001) in fully adjusted models, with a trend toward increased white matter lesion volume (p = 0.008) and increased gray and white matter mean diffusivity (p ≤ 0.031). Among T2D-affected participants, neither fasting glucose, glycated hemoglobin, nor diabetes duration were associated with the neuroimaging measures assessed (p > 0.05). Conclusions: 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.
    No preview · Article · Nov 2015 · Acta Diabetologica
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    ABSTRACT: Aims: Human studies of links between advanced glycation end-products (AGEs) and disease phenotypes are less common than studies of animal and cell models. Here, we examined the association of total AGEs with diabetes risk factors in a predominately type 2 diabetes (T2D) affected cohort. Methods: AGEs were measured using an enzyme linked immunosorbant assay in 816 individuals from the DHS Mind Study (n=709 T2D affected), and association analyses were completed. Results: Total AGEs were associated with estimated glomerular filtration rate (p=0.0054; β=-0.1291) and coronary artery calcification (p=0.0352; β=1.1489) in the entire cohort. No significant associations were observed when individuals with T2D were analyzed separately. In individuals without T2D, increased circulating AGEs were associated with increased BMI (p=0.02, β=0.138), low density lipoproteins (p=0.046, β=17.07) and triglycerides (p=0.0004, β=0.125), and decreased carotid artery calcification (p=0.0004, β=-1.2632) and estimated glomerular filtration rate (p=0.0018, β=-0.1405). Strong trends were also observed for an association between AGEs and poorer cognitive performance on the digit symbol substitution test (p=0.046, β=-6.64) and decreased grey matter volume (p=0.037, β=-14.87). Conclusions: AGEs may play an important role in a number of phenotypes and diseases, although not necessarily in interindividual variation in people with T2D. Further evaluation of specific AGE molecules may shed more light on these relationships.
    No preview · Article · Nov 2015 · Journal of diabetes and its complications
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    ABSTRACT: Aims: 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. Methods: 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. Results: 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 (p≤0.005). Those with both anxiety and depression also had increased white matter lesion volume (p=0.015), decreased gray matter cerebral blood flow (p=4.43×10(-6)), decreased gray matter volume (p=0.002), increased white and gray matter mean diffusivity (p≤0.001), and decreased white matter fractional anisotropy (p=7.79×10(-4)). These associations were somewhat attenuated upon further adjustment for health status related covariates. Conclusions: Comorbid anxiety and depression symptoms were associated with cognitive performance and brain structure in a European American cohort with type 2 diabetes.
    No preview · Article · Sep 2015 · Journal of diabetes and its complications
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    ABSTRACT: Type 2 diabetes mellitus increases the risk of cognitive decline and dementia, and elevated burdens of vascular disease are hypothesized to contribute to this risk. These relationships were examined in the Diabetes Heart Study-MIND using a battery of cognitive tests, neuroimaging measures and subclinical cardiovascular disease (CVD) burden assessed by coronary artery calcified (CAC) plaque. We hypothesized that CAC would attenuate the association between neuroimaging measures and cognition performance. Associations were examined using marginal models in this family-based cohort of 572 European Americans from 263 families. All models were adjusted for age, gender, education, type 2 diabetes and hypertension, with some neuroimaging measures additionally adjusted for intracranial volume. Higher total brain volume was associated with better performance on the Digit Symbol Substitution Task and Semantic Fluency (both p ≤ 7.0 × 10(-4)). Higher gray matter volume was associated with better performance on the Modified Mini-Mental State Examination and Semantic Fluency (both p ≤ 9.0 × 10(-4)). Adjusting for CAC caused minimal changes to the results. Relationships exist between neuroimaging measures and cognitive performance in a type 2 diabetes-enriched European American cohort. Associations were minimally attenuated after adjusting for subclinical CVD. Additional work is needed to understand how subclinical CVD burden interacts with other factors and impacts relationships between neuroimaging and cognitive testing measures. © 2015 S. Karger AG, Basel.
    No preview · Article · Jul 2015 · Neuroepidemiology
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    ABSTRACT: Obesity is a strong predictive factor in the development of chronic disease and has now superseded under-nutrition as a major public health issue. Chronic inflammation is one mechanism thought to link excess body weight with disease. Increasingly, the gut and its extensive population of commensal microflora are recognized as playing an important role in the development of obesity-related chronic inflammation. Obesity and a high fat diet are associated with altered commensal microbial communities and increased intestinal permeability which contributes to systemic inflammation as a result of the translocation of lipopolysaccharide into the circulation and metabolic endotoxemia. Various milk proteins are showing promise in the prevention and treatment of obesity and chronic low grade inflammation via reductions in visceral fat, neutralization of bacteria at the mucosa and reduced intestinal permeability. In this review, we focus on evidence supporting the potential anti-obesogenic and anti-inflammatory effects of bovine whey-derived lactoferrin and immunoglobulins.
    No preview · Article · Jun 2015 · Critical reviews in food science and nutrition
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    ABSTRACT: 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. 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. 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. This analysis highlights important demographic and clinical factors, notably CAC and albuminuria, which predict mortality in the general population of patients with T2D.
    Preview · Article · Jun 2015 · Diabetology and Metabolic Syndrome
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    ABSTRACT: Advanced chronic kidney disease (CKD) is associated with altered cerebral structure and function. Relationships between mild-to-moderate CKD and brain morphology and cognitive performance were evaluated in European Americans (EAs). A total of 478 EAs with estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m(2) and urine albumin:creatinine ratio (UACR) < 300 mg/g, most with type 2 diabetes (T2D), were included. Measures of total intracranial volume (TICV), cerebrospinal fluid volume, total white matter volume (TWMV), total gray matter volume (TGMV), total white matter lesion volume (TWMLV), hippocampal white matter volume (HWMV) and hippocampal gray matter volume (HGMV) were obtained with magnetic resonance imaging. Cognitive testing included memory (Rey Auditory Visual Learning Test), global cognition (Modified Mini-Mental State Examination) and executive function (Stroop Task, Semantic Fluency, Digit Symbol Substitution Test). Associations with CKD were assessed using log-transformed eGFR and UACR, adjusted for age, sex, body mass index, smoking, hemoglobin A1c, blood pressure, diabetes duration, cardiovascular disease and education. Participants were 55.2% female, 78.2% had T2D; mean ± SD age 67.6 ± 9.0 years, T2D duration 16.4 ± 6.5 years, eGFR 92.0 ± 22.3 mL/min/1.73 m(2) and UACR 23.8 ± 39.6 mg/g. In adjusted models, eGFR was negatively associated with TICV only in participants with T2D [parameter estimate (β): -72.2, P = 0.002]. In non-diabetic participants, inverse relationships were observed between eGFR and HGMV (β: -1.0, P = 0.03) and UACR and normalized TWMLV (β: -0.2, P = 0.03). Kidney function and albuminuria did not correlate with cognitive testing. In EAs with mild CKD enriched for T2D, brain structure and cognitive performance were generally not impacted. Longitudinal studies are necessary to determine when cerebral structural changes and cognitive dysfunction develop with progressive CKD in EAs. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
    No preview · Article · Feb 2015 · Nephrology Dialysis Transplantation
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    ABSTRACT: It remains unclear whether the high cardiovascular disease (CVD) burden in people with type 2 diabetes (T2D) is associated with genetic variants that contribute to CVD in general populations. Recent studies have examined genetic risk scores of single-nucleotide polymorphisms (SNPs) identified by genome-wide association studies for their cumulative contribution to CVD-related traits. Most analyses combined SNPs associated with a single phenotypic class, e.g., lipids. In the present analysis, we examined a more comprehensive risk score comprised of SNPs associated with a broad range of CVD risk phenotypes. The composite risk score was analyzed for potential associations with subclinical CVD, self-reported CVD events, and mortality in 983 T2D-affected individuals of European descent from 466 Diabetes Heart Study (DHS) families. Genetic association was examined using marginal models with generalized estimating equations for subclinical CVD and prior CVD events and Cox proportional hazards models with sandwich-based variance estimation for mortality; analyses were adjusted for age and sex. An increase in genetic risk score was significantly associated with higher levels of coronary artery calcified plaque (p = 1.23 × 10(-4)); however, no significant associations with self-reported myocardial infarction and CVD events and all-cause and CVD mortality were observed. These results suggest that a genetic risk score of SNPs associated with CVD events and risk factors does not significantly account for CVD risk in the DHS, highlighting the limitations of applying current genetic markers for CVD in individuals with diabetes.
    Preview · Article · Feb 2015 · Acta Diabetologica
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    ABSTRACT: Background Vascular calcified plaque, a measure of subclinical cardiovascular disease (CVD), is unlikely to be limited to a single vascular bed in patients with multiple risk factors. Consideration of vascular calcified plaque as a global phenomenon may allow for a more accurate assessment of the CVD burden. The aim of this study was to examine the utility of a combined vascular calcified plaque score in the prediction of mortality.Methods Vascular calcified plaque scores from the coronary, carotid, and abdominal aortic vascular beds and a derived multi-bed score were examined for associations with all-cause and CVD-mortality in 699 European-American type 2 diabetes (T2D) affected individuals from the Diabetes Heart Study. The ability of calcified plaque to improve prediction beyond Framingham risk factors was assessed.ResultsOver 8.4¿±¿2.3 years (mean¿±¿standard deviation) of follow-up, 156 (22.3%) participants were deceased, 74 (10.6%) from CVD causes. All calcified plaque scores were significantly associated with all-cause (HR: 1.4-1.8; p¿<¿1x10¿5) and CVD-mortality (HR: 1.5-1.9; p¿<¿1×10¿4) following adjustment for Framingham risk factors. Associations were strongest for coronary calcified plaque. Improvement in prediction of outcome beyond Framingham risk factors was greatest using coronary calcified plaque for all-cause mortality (AUC: 0.720 to 0.757, p¿=¿0.004) and the multi-bed score for CVD mortality (AUC: 0.731 to 0.767, p¿=¿0.008).Conclusions Although coronary calcified plaque and the multi-bed score were the strongest predictors of all-cause mortality and CVD-mortality respectively in this T2D-affected sample, carotid and abdominal aortic calcified plaque scores also significantly improved prediction of outcome beyond traditional risk factors and should not be discounted as risk stratification tools.
    Full-text · Article · Dec 2014 · Cardiovascular Diabetology
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    ABSTRACT: Previous studies have indicated that cytokine gene polymorphisms of Indigenous Australians were predominantly associated with strong pro-inflammatory responses. We tested the hypothesis that cells of donors with genetic profiles of inflammatory cytokine single nucleotide polymorphisms (SNPs) similar to Indigenous Australians produce higher pro-inflammatory responses. PBMCs from 14 donors with genetic profiles for a high risk of strong pro-inflammatory responses and 14 with low-risk profiles were stimulated with endotoxin and effects of gender, IFN-γ, cigarette smoke extract (CSE) and testosterone on cytokine responses analysed. Cytokines were calculated from standard curves (Luminex 2.3 software). No significant differences were associated with SNP profile alone. Lower pro-inflammatory responses were observed for cells from males with low- or high-risk profiles. For cells from females with high-risk profiles, anti-inflammatory IL-10 responses were significantly reduced. There was no effect of testosterone levels on responses from males. For females, results from IFN-γ-treated cells showed positive correlations between testosterone levels and IL-1β responses to endotoxin for both risk groups and TNF-α for the high-risk group. If interactions observed among CSE, IFN-γ, genetic background and testosterone reflect those in vivo, these might contribute to increased incidences of hospitalisations for infectious diseases among Indigenous women. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
    No preview · Article · Nov 2014 · Innate Immunity
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    ABSTRACT: Patients with type 2 diabetes are at increased risk of age-related cognitive decline and dementia. Neuroimaging measures such as white matter lesion volume, brain volume, and fractional anisotropy may reflect the pathogenesis of these cognitive declines, and genetic factors may contribute to variability in these measures. This study examined multiple neuroimaging measures in 465 participants from 238 families with extensive genotype data in the type 2 diabetes enriched Diabetes Heart Study-Mind cohort. Heritability of these phenotypes and their association with candidate single nucleotide polymorphisms (SNPs) and SNP data from genome- and exome-wide arrays was explored. All neuroimaging measures analysed were significantly heritable (hˆ2=0.55-0.99 in unadjusted models). Seventeen candidate SNPs (from 16 genes/regions) associated with neuroimaging phenotypes in prior studies showed no significant evidence of association. A missense variant (rs150706952, A432V) in PLEKHG4B from the exome-wide array was significantly associated with white matter mean diffusivity (p=3.66x10-7) and gray matter mean diffusivity (p=2.14x10-7). This analysis suggests genetic factors contribute to variation in neuroimaging measures in a population enriched for metabolic disease and other associated comorbidities.
    No preview · Article · Nov 2014 · Neurobiology of Aging
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    ABSTRACT: Abstract Probiotic supplementation has traditionally focused on gut health. However, in recent years, the clinical applications of probiotics have broadened to allergic, metabolic, inflammatory, gastrointestinal and respiratory conditions. Gastrointestinal health is important for regulating adaptation to exercise and physical activity. Symptoms such as nausea, bloating, cramping, pain, diarrhoea and bleeding occur in some athletes, particularly during prolonged exhaustive events. Several studies conducted since 2006 examining probiotic supplementation in athletes or highly active individuals indicate modest clinical benefits in terms of reduced frequency, severity and/or duration of respiratory and gastrointestinal illness. The likely mechanisms of action for probiotics include direct interaction with the gut microbiota, interaction with the mucosal immune system and immune signalling to a variety of organs and systems. Practical issues to consider include medical and dietary screening of athletes, sourcing of recommended probiotics and formulations, dose-response requirements for different probiotic strains, storage, handling and transport of supplements and timing of supplementation in relation to travel and competition.
    Full-text · Article · Oct 2014 · European Journal of Sport Science
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    ABSTRACT: Background: 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. Objective: In this study, we examined associations between calcium intake from diet and supplements and measures of subclinical CVD (calcified plaque in the coronary artery, carotid artery, and abdominal aorta) and mortality in individuals affected by T2D. Design: We performed a cross-sectional analysis in individuals affected by T2D from the family-based Diabetes Heart Study (n=720). Results: We observed no significant associations of calcium from diet or supplements with any of our measures of calcified plaque, and no greater mortality risk was observed with increased calcium intake. Instead, calcium supplement use was modestly associated with reduced all-cause mortality in women (HR: 0.62; 95% CI: 0.42, 0.92; P = 0.017). Conclusion: Our results do not support a substantial association between calcium intake from diet or supplements and CVD risk in individuals with T2D.
    Preview · Article · Aug 2014 · American Journal of Clinical Nutrition
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    ABSTRACT: Use of probiotic-containing foods and probiotic supplements is increasing; however, few studies document safety and tolerability in conjunction with defined clinical end points. This paper reports the effects of 150 days of supplementation with either a single- (Bifidobacterium animalis subsp. lactis Bl-04) or a double-strain (Lactobacillus acidophilus NCFM and Bifidobacterium animalis subsp. lactis Bi-07) probiotic on routine haematology and clinical chemistry measures in healthy active adults. Pre- to post-intervention changes in laboratory measures were determined and compared between supplement and placebo groups. Overall there were few differences in routine haematology and clinical chemistry measures between supplement and placebo groups post-intervention. Exceptions included plasma calcium (P=0.03) and urea (P=0.015); however, observed changes were small and within assay-specific laboratory reference ranges. These data provide evidence supporting the use of these probiotic supplements over a period of 5 months in healthy active adults without obvious safety or tolerability issues.European Journal of Clinical Nutrition advance online publication, 23 July 2014; doi:10.1038/ejcn.2014.137.
    Full-text · Article · Jul 2014 · European Journal of Clinical Nutrition
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    ABSTRACT: Objective: 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.
    Preview · Article · Jul 2014 · Diabetes Care
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    Amanda J Cox · Nicholas P West · Allan W Cripps
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    ABSTRACT: As the prevalence of obesity and associated disease continues to rise and concerns for the spiralling economic and social costs also escalate, innovative management strategies beyond primary prevention and traditional lifestyle interventions are urgently needed. The biological basis of disease is one avenue for further exploration in this context. Several key inflammatory markers have been consistently associated with both obesity and risk of adverse outcomes in obesity-associated diseases, which suggests that a persistent, low-grade, inflammatory response is a potentially modifiable risk factor. In this Review, we provide evidence supporting perturbation of the intestinal microbiota and changes in intestinal permeability as potential triggers of inflammation in obesity. Further characterisation of the mechanisms underpinning the triggers of such inflammatory responses in overweight and obese individuals could offer unique opportunities for intervention strategies to help ameliorate the risk of obesity-associated disease.
    Full-text · Article · Jul 2014 · The Lancet Diabetes & Endocrinology
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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.
    Full-text · Article · Apr 2014 · Cardiovascular Diabetology
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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.
    No preview · Article · Mar 2014 · Neurobiology of aging
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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.
    Preview · Article · Feb 2014 · Diabetes care

Publication Stats

677 Citations
230.53 Total Impact Points

Institutions

  • 2013-2015
    • Griffith University
      • • Program in Molecular Basis of Disease
      • • School of Medical Science
      Queensland, Australia
  • 2011-2015
    • Wake Forest School of Medicine
      • Department of Biochemistry
      Winston-Salem, North Carolina, United States
    • Wake Forest University
      • Department of Biochemistry
      Winston-Salem, North Carolina, United States
  • 2004-2013
    • University of Newcastle
      • Department of Biological Sciences
      Newcastle, New South Wales, Australia
  • 2005-2010
    • Australian Institute of Sport (AIS)
      • Division of Physiology
      Canberra, Australian Capital Territory, Australia