Georgetown and Howard Universities Center for Clinical and Translational Science

Washington, WA, United States

Georgetown and Howard Universities Center for Clinical and Translational Science

Washington, WA, United States
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Qi L.,University of California at Davis | Nassir R.,University of California at Davis | Kosoy R.,University of California at Davis | Garcia L.,University of California at Davis | And 6 more authors.
Diabetologia | Year: 2012

Aims/hypothesis Type 2 diabetes is more prevalent in African- Americans (AFAs) and Hispanic-Americans (HAs) than in European-Americans.We assessed whether continental admixture was correlated with diabetes risk in these high-risk roups. Methods We estimated the proportion of sub-Saharan African (AFR), Amerindian (AMI) and European admixture using 92 ancestry-informative marker genotypes in 16,476 AFA and HA women from the Women's Health Initiative. Cox regression models were used to examine the association between admixture and diabetes risk, with and without accounting for socioeconomic status (SES) and adiposity measurements. Results AFR admixture was significantly associated with diabetes risk in AFA women when adjusting for entry age, neighbourhood SES and BMI or waist/hip ratio (WHR) (all p<0.0001). In HA women, AMI admixture had significant associations with diabetes risk that remained significant after adjustment for SES and BMI (all p<0.0005). In both AFAs and HAs, SES showed significant negative associations while BMI or WHR had significant positive associations with diabetes risk, with and without adjustment for genetic admixture. Conclusions/interpretation In AFAs, admixture, SES and BMI/WHR each independently contribute to diabetes risk after accounting for each of the other factors; in HAs, admixture, SES and BMI each independently contribute to diabetes risk after accounting for each of the other factors, whereas admixture is not significantly associated with diabetes riskafter accounting for SES and WHR. The findings emphasise the importance of considering both genetic and environmental causes in the aetiology of type 2 diabetes. © 2012 Springer-Verlag.

Zhang Y.,The University of Oklahoma Health Sciences Center | Lee E.T.,The University of Oklahoma Health Sciences Center | Howard B.V.,MedStar Research Institute | Howard B.V.,Georgetown and Howard Universities Center for Clinical and Translational science | And 9 more authors.
Diabetes Care | Year: 2013

OBJECTIVE Prevalence of insulin resistance is high in the American Indian population, likely as a result of the high prevalence of obesity. This condition may be influential for clinical outcomes such as cardiovascular disease (CVD) and decreased kidney function. RESEARCH DESIGNANDMETHODSdNormal glucose tolerant (NGT) participants free of hypertension and CVD at the baseline examination (1989-1992) (N = 964) of the Strong Heart Study were selected to explore the cross-sectional association between insulin resistance quantified by homeostasis model assessment (HOMA-IR) and demographic, behavioral, and cardiometabolic variables. The longitudinal association between baseline HOMA-IR and the development of CVD was also explored. The longitudinal association between baselineHOMA-IR and the development of high urinary albumin-to-creatinine ratio was explored among nondiabetic participants (N = 1,401). RESULTSdCross- sectionally, HOMA-IR was associated with sex, residence location, smoking, and high-risk cardiometabolic profile. Prospectively, insulin resistance is associated with the development of CVD and decreased kidney function in this population. CONCLUSIONSdInsulin resistance may have an important role in the pathogenesis of CVD and chronic kidney disease. Since obesity contributes to the development of insulin resistance, intervention focusing on modifiable factors such as physical activity and weight control may reduce the development of these diseases. © 2013 by the American Diabetes Association.

Barac A.,Washington Hospital Center | Wang H.,MedStar Research Institute | Wang H.,Georgetown and Howard Universities Center for Clinical and Translational science | Shara N.M.,MedStar Research Institute | And 13 more authors.
Journal of Clinical Hypertension | Year: 2012

Inflammation may play a role in increased risk of heart failure (HF) that is associated with obesity, metabolic syndrome (MS), and diabetes. This study investigated associations between inflammatory markers, MS, and incident HF in a population with a high prevalence of diabetes, obesity, and MS. The cohort consisted of 3098 American Indians without prevalent cardiovascular disease who had C-reactive protein (CRP) and fibrinogen measured at the Strong Heart Study phase II examination. Independent associations between inflammatory markers, MS, and HF were analyzed by Cox hazard models. During a mean follow-up of 11years, 218 participants developed HF. After the adjustment for cardiovascular risk factors, fibrinogen, (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.15-1.59) but not CRP (HR, 1.25; 95% CI, 0.97-1.32) remained a significant HF predictor. In individuals without diabetes, concomitant presence of MS and elevated CRP or fibrinogen increased HF risk (for MS and CRP: HR, 2.02; 95% CI, 0.95-4.31; for CRP and fibrinogen: HR, 1.75; 95% CI, 0.83-3.72). In a population with a high prevalence of obesity, MS, and diabetes, elevated CRP and fibrinogen increased HF risk. These associations are attenuated by the adjustments for conventional risk factors suggesting that inflammation acts in concert with metabolic and clinical risk factors in increasing HF risk. © 2011 Wiley Periodicals, Inc.

Konatalapalli R.M.,Washington Hospital Center | Lumezanu E.,Washington Hospital Center | Jelinek J.S.,Washington Hospital Center | Murphey M.D.,American Institute for Radiologic Pathology | And 5 more authors.
Journal of Rheumatology | Year: 2012

Objective. A cross-sectional study was undertaken to determine the prevalence of axial gout in patients with established gouty arthritis and to analyze clinical, laboratory, and radiological correlations. Methods. Forty-eight subjects with a history of gouty arthritis (American College of Rheumatology criteria) for ≥ 3 years under poor control were included. Subjects underwent history, physical examination, laboratory testing, and imaging studies, including radiographs of the hands and feet and computerized tomography (CT) of the cervical and lumbar spines and sacroiliac joints (SIJ). Patients with characteristic erosions and/or tophi in the spine or SIJ were considered to have axial or spinal gout. Results. Seventeen patients (35%) had CT evidence of spinal erosions and/or tophi, with tophi identified in 7 of the 48 subjects (15%). The spinal location of axial gout was cervical in 7 patients (15%), lumbar in 16 (94%), SIJ in 1 (6%), and more than 1 location in 14 (82%). Duration of gout, presence of back pain, and serum uric acid levels did not correlate with axial gout. Extremity radiographs characteristic of gouty arthropathy found in 21 patients (45%) were strongly correlated with CT evidence of axial gout (p < 0.001). All patients with tophi in the spine had abnormal hand or feet radiographs (p = 0.005). Conclusion. Axial gout may be a common feature of chronic gouty arthritis. The lack of correlation with back pain, the infrequent use of CT imaging in patients with back pain, and the lack of recognition of the problem of spinal involvement in gouty arthritis suggest that this diagnosis is often missed. The Journal of Rheumatology Copyright © 2012. All rights reserved.

Franceschini N.,University of North Carolina at Chapel Hill | Haack K.,The Texas Institute | Almasy L.,The Texas Institute | Laston S.,The Texas Institute | And 8 more authors.
Clinical Journal of the American Society of Nephrology | Year: 2014

Background and objectives CKD disproportionally affects American Indians, who similar to other populations, show genetic susceptibility to kidney outcomes. Recent studies have identified several loci associated with kidney traits, but their relevance in American Indians is unknown. Design, setting, participants, & measurements This study used data from a large, family-based genetic study of American Indians (the Strong Heart Family Study), which includes 94 multigenerational families enrolled from communities located in Oklahoma, the Dakotas, and Arizona. Individuals were recruited from the Strong Heart Study, a population-based study of cardiovascular disease in American Indians. This study selected 25 single nucleotide polymorphisms in 23 loci identified from recently published kidney-related genome-wide association studies in individuals of European ancestry to evaluate their associations with kidney function (estimated GFR; individuals 18 years or older, up to 3282 individuals) and albuminuria (urinary albumin to creatinine ratio; n=3552) in the Strong Heart Family Study. This study also examined the association of single nucleotide polymorphisms in the APOL1 region with estimated GFR in 1121 Strong Heart Family Study participants. GFR was estimated using the abbreviated Modification of Diet in Renal Disease Equation. Additive genetic models adjusted for age and sex were used. Results This study identified significant associations of single nucleotide polymorphisms with estimated GFR in or nearby PRKAG2, SLC6A13, UBE2Q2, PIP5K1B, and WDR72 (P<2.1 × 10-3 to account for multiple testing). Single nucleotide polymorphisms in these loci explained 2.2% of the estimated GFR total variance and 2.9% of its heritability. An intronic variant of BCAS3 was significantly associated with urinary albumin to creatinine ratio. APOL1 single nucleotide polymorphisms were not associated with estimated GFR in a single variant test or haplotype analyses, and the at-risk variants identified in individuals with African ancestry were not detected in DNA sequencing of American Indians. Conclusion This study extends the genetic associations of loci affecting kidney function to American Indians, a population at high risk of kidney disease, and provides additional support for a potential biologic relevance of these loci across ancestries. © 2014 by the American Society of Nephrology.

Xu J.,Methodist Hospital Research Institute | Lee E.T.,The University of Oklahoma Health Sciences Center | Peterson L.E.,Methodist Hospital Research Institute | Devereux R.B.,New York Medical College | And 8 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: Coronary heart disease (CHD) is the leading cause of death in the United States. Objective: This study compares differences in risk factors for CHD in diabetic vs. nondiabetic Strong Heart Study participants. Design: This was an observational study. Setting: The study was conducted at three centers in Arizona, Oklahoma, and North and South Dakota. Participants: Data were obtained from 3563 of 4549 American Indians free of cardiovascular disease at baseline. Intervention(s): CHD events were ascertained during follow-up. Main Outcome Measure: CHD events were classified using standardized criteria. Results: In diabetic and nondiabetic participants, 545 and 216 CHD events, respectively, were ascertained during follow-up (21,194 and 22,990 person-years); age- and sex-adjusted incidence rates of CHD were higher for the diabetic group (27.5 vs. 12.1 per 1,000 person-years). Risk factors for incident CHD common to both groups included older age, male sex, prehypertension or hypertension, and elevated low-density lipoprotein cholesterol. Risk factors specific to the diabetic group were lower high-density lipoprotein cholesterol, current smoking, macroalbuminuria, lower estimated glomerular filtration rate, use of diabetes medication, and longer duration of diabetes. Higher body mass index was a risk factor only for the nondiabetic group. The association of male sex and CHD was greater in those without diabetes than in those with diabetes. Conclusions: In addition to higher incidence rates of CHD events in persons with diabetes compared with those without, the two groups differed in CHD risk factors. These differences must be recognized in estimating CHD risk and managing risk factors. Copyright © 2012 by The Endocrine Society.

Tsai C.-W.,China Medical University at Taichung | North K.E.,University of North Carolina at Chapel Hill | Haack K.,The Texas Institute | Franceschini N.,University of North Carolina at Chapel Hill | And 9 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2015

Context: Elevated LDL cholesterol (LDL-C) is an important risk factor for atherosclerosis and cardiovascular disease. Variants in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene have been associated not only with plasma LDL-C concentration, but also with ischemic heart disease. Little is known about the genetic architecture of PCSK9 and its influence on LDL-C in American Indians. Objective: We aimed to investigate the genetic architecture in the 1p32 region encompassing PCSK9 and its influence on LDL-C in American Indians. Design: The Strong Heart Family Study (SHFS) is a family-based genetic study. Participants: Two thousand four hundred fifty eight American Indians from Arizona, Oklahoma, North Dakota, and South Dakota, who were genotyped by Illumina MetaboChip. Results: We genotyped 486 SNPs in a 3.9 Mb region at chromosome 1p32 encompassing PCSK9 in 2458 American Indians. We examined the association between these SNPs and LDL-C. For common variants (MAF ≥ 1%), meta-analysis across the three geographic regions showed common variants in PCSK9 were significantly associated with higher LDL-C. The most significant SNP rs12067569 (MAF = 1.7 %, β= 16.9 ± 3.7, P = 5.9 × 10-6) was in complete LD (r2 = 1) with a nearby missense SNP, rs505151 (E670G) (β= 15.0 ± 3.6, P = 3.6 × 10-5). For rare variants (MAF < 1%), rs11591147 (R46L, MAF = 0.9%) was associated with lower LDL-C (β= - 31.1 ± 7.1, P = 1.4 × 10-5). The mean (SD) of LDL-C was 76.9 (7.8) and 107.4(1.0) mg/dL for those with and without the R46L mutation, respectively. One person who was homozygous for R46L had LDL-C levels of 11 mg/dL. In one family, 6 out of 8 members carrying the R46L mutation had LDL-C levels below the lower 10% percentile of LDL-C among all study participants. Conclusions: Both rare and common variants in PCSK9 influence plasma LDL-C levels in American Indians. Follow-up studies may disclose the influence of these mutations on the risk of CVD and responses to cholesterol-lowering medications. Copyright © 2015 by the Endocrine Society.

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