Mapping adipose and muscle tissue expression quantitative trait loci in African Americans to identify genes for type 2 diabetes and obesity.

Relative to European Americans, type 2 diabetes (T2D) is more prevalent in African Americans (AAs). Genetic variation may modulate transcript abundance in insulin-responsive tissues and contribute to risk; yet, published studies identifying expression quantitative trait loci (eQTLs) in African ancestry populations are restricted to blood cells. This study aims to develop a map of genetically regulated transcripts expressed in tissues important for glucose homeostasis in AAs, critical for identifying the genetic etiology of T2D and related traits. Quantitative measures of adipose and muscle gene expression, and genotypic data were integrated in 260 non-diabetic AAs to identify expression regulatory variants. Their roles in genetic susceptibility to T2D, and related metabolic phenotypes, were evaluated by mining GWAS datasets. eQTL analysis identified 1971 and 2078 cis-eGenes in adipose and muscle, respectively. Cis-eQTLs for 885 transcripts including top cis-eGenes CHURC1, USMG5, and ERAP2 were identified in both tissues. 62.1 % of top cis-eSNPs were within ±50 kb of transcription start sites and cis-eGenes were enriched for mitochondrial transcripts. Mining GWAS databases revealed association of cis-eSNPs for more than 50 genes with T2D (e.g. PIK3C2A, RBMS1, UFSP1), gluco-metabolic phenotypes (e.g. INPP5E, SNX17, ERAP2, FN3KRP), and obesity (e.g. POMC, CPEB4). Integration of GWAS meta-analysis data from AA cohorts revealed the most significant association for cis-eSNPs of ATP5SL and MCCC1 genes, with T2D and BMI, respectively. This study developed the first comprehensive map of adipose and muscle tissue eQTLs in AAs (publically accessible at https://mdsetaa.phs.wakehealth.edu ) and identified genetically regulated transcripts for delineating genetic causes of T2D, and related metabolic phenotypes.

The impact of polyunsaturated fatty acid-based dietary supplements on disease biomarkers in a metabolic syndrome/diabetes population.

BACKGROUND: Ingestion of polyunsaturated fatty acids (PUFAs) has been proposed to influence several chronic diseases including coronary heart disease (CHD) and type-2 diabetes (T2D).There is strong evidence that omega-3 (n-3) PUFAs provide protection against CHD and biomarkers of atherosclerosis. In contrast, there is more limited and inconsistent data for T2D. Few studies have examined the impact of n-3 PUFA-containing botanical oils on T2D. METHODS: Fifty-nine subjects with early-stageT2D or metabolic syndrome participated in an 8-week, randomized, single-blind, parallel intervention study and were provided PUFA-containing oils. Individuals received either corn oil (CO), a botanical oil (BO) combination (borage [Borago officinalis L.]/echium oil [Echium plantagineum L.]) or fish oil (FO). The BO combination was enriched in alpha-linolenic, gamma-linolenic, and stearidonic acids and the FO in eicosapentaenoic and docosahexaenoic acids. Serum fatty acids and other serum lipids(triglycerides and total, HDL and LDL cholesterol), as well as markers of inflammation (leptin, and C-reactive protein) and glucose regulation (glucose and hemoglobin A1c) were assessed from fasting participants at baseline and after the intervention. RESULTS: Compliance was verified by expected increases in specific PUFAs in each of the three oil arms. Participants in the CO group showed no differences in serum lipids, markers of inflammation or glucose regulation between pre- and post-treatment measures. Supplementation with BO significantly lowered total and LDL cholesterol levels and FO reduced serum triglycerides, hemoglobin A1c and increased HDL-cholesterol. CONCLUSION: Short-term dietary supplementation with BO and FO improved biomarkers associated with T2D/metabolic syndrome. TRIAL REGISTRATION: Clinicaltrial.gov NCT01145066.

Effect of simvastatin (80 mg) on coronary and abdominal aortic arterial calcium (from the coronary artery calcification treatment with zocor [CATZ] study).

We tested the hypothesis that, compared with placebo, simvastatin would reduce the progression of coronary artery calcium (CAC) and abdominal aortic calcium (AAC) levels in participants asymptomatic for vascular disease. Total CAC and AAC were measured with multidetector cardiac computed tomography. Inclusion criteria were a CAC score of >or=50 Agatston units, high-density lipoprotein (HDL) cholesterol levelor=2 other risk factors. Diabetes and history of vascular disease were exclusion criteria. Participants were randomized to receive 80 mg simvastatin (n=40) or matching placebo (n=40) for 12 months. Lipids were measured at 3-month intervals, and CAC and AAC measurements were repeated at 6 and 12 months. Total cholesterol, triglycerides, and LDL decreased significantly with simvastatin treatment (p<0.0001 for all comparisons, adjusted for baseline levels), whereas lipids remained unchanged for subjects randomized to receive placebo. Total CAC volume increased from baseline in both treatment groups. For subjects in the active treatment group, CAC volume increased by 9%, whereas in the placebo group, plaque volume increased by 5% (p=0.12 for treatment effect). AAC volume also increased in both treatment groups (p=0.15 for treatment effect). In conclusion, simvastatin treatment does not reduce progression of CAC or AAC compared with placebo.

Coronary artery calcium outperforms carotid artery intima-media thickness as a noninvasive index of prevalent coronary artery stenosis.

OBJECTIVE: Increased carotid artery intima-media thickness (IMT) and increased coronary artery calcium (CAC) are noninvasive surrogate indices of prevalent coronary artery disease (CAD). We compared CAC to IMT for noninvasive detection of prevalent CAD in participants whose coronary status was identified by coronary angiography. METHODS AND RESULTS: Male and female CAD patients (> or =50% stenosis in one or more coronary artery, n=79) and controls (no lumen irregularities, n=93) were identified using coronary angiography. Mean maximum carotid IMT was quantified using B-mode ultrasound and total CAC was measured using ECG-gated helical computed tomography (HCT). Carotid IMT was approximately 20% higher in CAD cases compared with controls (P<0.001), whereas mean CAC was 1000% higher in CAD cases than controls (P<0.0001). In multivariable models adjusted for age and sex, IMT greater than the median (1.13 mm) was associated with 2-fold increase in likelihood of prevalent CAD compared with scores below that cut point (P=0.015). CAC scores that exceeded the median score of 92 were associated with 28-fold increase in likelihood of prevalent CAD (P<0.0001). Although associations of increased IMT with prevalent CAD were similar in males and females, CAC scores above the median in females were associated with 39-fold increase in odds of prevalent CAD, whereas males with elevated CAC had 19-fold risk of CAD. CONCLUSIONS: HCT-measured CAC compares favorably with carotid IMT measured by B-mode ultrasound as a noninvasive index of prevalent CAD.

Tissue-Specific and Genetic Regulation of Insulin Sensitivity-Associated Transcripts in African Americans.

Integrative multiomics analyses of adipose and muscle tissue transcripts, S, and genotypes revealed novel genetic regulatory mechanisms of insulin resistance in African Americans.