Faculty Bibliography
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242
Type 1 Diabetes Risk in African-Ancestry Participants and Utility of an Ancestry-Specific Genetic Risk Score
OBJECTIVE:Genetic risk scores (GRS) have been developed that differentiate individuals with type 1 diabetes from those with other forms of diabetes and are starting to be used for population screening; however, most studies were conducted in European-ancestry populations. This study identifies novel genetic variants associated with type 1 diabetes risk in African-ancestry participants and develops an African-specific GRS. RESEARCH DESIGN AND METHODS/METHODS:). RESULTS:*03:02) were significantly associated with type 1 diabetes risk. Among European-ancestry defined non-HLA risk loci, six risk loci were significantly associated with type 1 diabetes in subjects of African ancestry. An African-specific GRS provided strong prediction of type 1 diabetes risk (area under the curve 0.871), performing significantly better than a European-based GRS and two polygenic risk scores in independent discovery and validation cohorts. CONCLUSIONS:Genetic risk of type 1 diabetes includes ancestry-specific, disease-associated variants. The GRS developed here provides improved prediction of type 1 diabetes in African-ancestry subjects and a means to identify groups of individuals who would benefit from immune monitoring for early detection of islet autoimmunity.
PMID: 30659077
ISSN: 1935-5548
CID: 3682642
Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity
Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.
PMCID:6342931
PMID: 30670697
ISSN: 2041-1723
CID: 4318842
Protective association between JC polyoma viruria and kidney disease
PURPOSE OF REVIEW:The presence of viruses in urine (urine virome) typically reflects infection in the kidneys and urinary tract. The urinary virome is associated with HIV-associated nephropathy and chronic glomerulosclerosis. There are many associations of this microbiome with human diseases that remain to be described. This manuscript reviews emerging data on relationships between kidney disease and urinary tract infection/colonization with JC polyomavirus (JCPyV). RECENT FINDINGS:Approximately 30% of the adult population sheds JCPyV in the urine. Further, urinary tract infection with one polyomavirus strain appears to inhibit secondary infections. The presence of urinary JCPyV and BK polyomavirus (BKPyV) replication were measured with polymerase chain reaction in African Americans to assess relationships with apolipoprotein L1 gene (APOL1)-associated nephropathy. Urinary JCPyV was associated with paradoxically lower rates of nephropathy in those with APOL1 high-risk genotypes. Subsequent studies revealed African Americans with JCPyV viruria had lower rates of nondiabetic nephropathy independent from APOL1. SUMMARY:Urinary tract JCPyV replication is common and associates with lower rates of nephropathy. This relationship is observed in diverse settings. Results support a host immune system that fails to eradicate nonnephropathic viruses and is also less likely to manifest renal parenchymal inflammation resulting in glomerulosclerosis.
PMID: 30320619
ISSN: 1473-6543
CID: 4318822
The African Descent and Glaucoma Evaluation Study (ADAGES) III: Contribution of Genotype to Glaucoma Phenotype in African Americans: Study Design and Baseline Data
PURPOSE/OBJECTIVE:To describe the study protocol and baseline characteristics of the African Descent and Glaucoma Evaluation Study (ADAGES) III. DESIGN/METHODS:Cross-sectional, case-control study. PARTICIPANTS/METHODS:Three thousand two hundred sixty-six glaucoma patients and control participants without glaucoma of African or European descent were recruited from 5 study centers in different regions of the United States. METHODS:Individuals of African descent (AD) and European descent (ED) with primary open-angle glaucoma (POAG) and control participants completed a detailed demographic and medical history interview. Standardized height, weight, and blood pressure measurements were obtained. Saliva and blood samples to provide serum, plasma, DNA, and RNA were collected for standardized processing. Visual fields, stereoscopic disc photographs, and details of the ophthalmic examination were obtained and transferred to the University of California, San Diego, Data Coordinating Center for standardized processing and quality review. MAIN OUTCOME MEASURES/METHODS:Participant gender, age, race, body mass index, blood pressure, history of smoking and alcohol use in POAG patients and control participants were described. Ophthalmic measures included intraocular pressure, visual field mean deviation, central corneal thickness, glaucoma medication use, or past glaucoma surgery. Ocular conditions, including diabetic retinopathy, age-related macular degeneration, and past cataract surgery, were recorded. RESULTS:The 3266 ADAGES III study participants in this report include 2146 AD POAG patients, 695 ED POAG patients, 198 AD control participants, and 227 ED control participants. The AD POAG patients and control participants were significantly younger (both, 67.4 years) than ED POAG patients and control participants (73.4 and 70.2 years, respectively). After adjusting for age, AD POAG patients had different phenotypic characteristics compared with ED POAG patients, including higher intraocular pressure, worse visual acuity and visual field mean deviation, and thinner corneas (all P < 0.001). Family history of glaucoma did not differ between AD and ED POAG patients. CONCLUSIONS:With its large sample size, extensive specimen collection, and deep phenotyping of AD and ED glaucoma patients and control participants from different regions in the United States, the ADAGES IIIÂ genomics study will address gaps in our knowledge of the genetics of POAG in this high-risk population.
PMCID:6050158
PMID: 29361356
ISSN: 1549-4713
CID: 2988612
Co-occurrence of early diabetes-related complications in adolescents and young adults with type 1 diabetes: an observational cohort study
BACKGROUND:One in three adolescents and young adults with type 1 diabetes have at least one early diabetes-related complication or comorbidity. We aimed to examine the prevalence and pattern of co-occurring complications in this population, as well as the related risk factors. METHODS:This observational cohort study includes data from individuals diagnosed with type 1 diabetes before age 20 years who participated in the SEARCH for Diabetes in Youth Study across five sites in the USA. We assessed sociodemographic and metabolic risk factors at baseline and at follow-up, and diabetes complications at follow-up. A frequency analysis was done to examine the difference in observed versus expected prevalence (calculated using a contingency table assuming independence across cells) of co-occurring complications or comorbidities. A cluster analysis was done to identify unique clusters of participants based on demographic characteristics and metabolic risk factors. FINDINGS/RESULTS:1327 participants who completed the follow-up visit were included in the frequency analysis. The mean age was 10·1 (SD 3·9) years at the time of type 1 diabetes diagnosis and 18·0 (4·1) years at follow-up. At a mean diabetes duration of 7·8 [SD 1·9] years, co-occurrence of any two or more complications was observed in 78 (5·9%) participants, more frequently than expected by chance alone (58 [4·4%], p=0·015). Specifically, the complications that co-occurred more frequently than expected were retinopathy and diabetic kidney disease (11 [0·8%] vs three [0·2%]; p=0·0007), retinopathy and arterial stiffness (13 [1·0%] vs four [0·3%]; p=0·0016), and arterial stiffness and cardiovascular autonomic neuropathy (24 [1·8%] vs 13 [1·0%]; p=0·015). We identified four unique clusters characterised by progressively worsening metabolic risk factor profiles (longer duration of diabetes and higher glycated haemoglobin, non-HDL cholesterol, and waist-to-height ratio). The prevalence of at least two complications increased across the clusters (six [2·3%] of 261 in the low-risk cluster, 32 [6·3%] of 509 in the moderate-risk cluster, 28 [8%] of 348 in the high-risk cluster, and five [20·8%] of 24 in the highest-risk cluster). Compared with the low-risk and moderate-risk clusters, the high-risk and highest-risk clusters were characterised by a lower proportion of participants who were non-Hispanic white, and a higher proportion of participants who had a household income below US$50 000 and did not have private health insurance. INTERPRETATION/CONCLUSIONS:Early complications co-occur in adolescents and young adults with type 1 diabetes more frequently than expected. Identification of individuals with adverse risk factors could enable targeted behavioural or medical interventions that reduce the likelihood of early development of lifelong diabetes-related morbidity. FUNDING/BACKGROUND:US Centers for Disease Control and Prevention, US National Institutes of Health.
PMCID:6295346
PMID: 30409691
ISSN: 2352-4650
CID: 4325142
Genetic Architecture of Primary Open Angle Glaucoma in Individuals of African Descent: The African Descent & Glaucoma Evaluation Study (ADAGES) III
OBJECTIVE:Find genetic contributions to glaucoma in African Americans. DESIGN/METHODS:Cross-sectional, case-control study. PARTICIPANTS/METHODS:1875 POAG cases and 1709 controls, self-identified as African Descent (AD), from the African Descent and Glaucoma Evaluation Study (ADAGESIII) and Wake Forest School of Medicine. METHODS:MegaChip genotypes were imputed to Thousand Genomes data. Association of SNPs with POAG and advanced POAG was tested by linear mixed model correcting for relatedness and population stratification. Genetic risk scores were tested by Receiver Operator Characteristics (ROC-AUC). MAIN OUTCOME/RESULTS:POAG defined by visual field loss without other non-ocular conditions (N=1875). Advanced POAG was defined by age-based mean deviation of visual field (N=946). RESULTS:) was observed, not in LD with the previously reported ED SNP. Additional previously identified loci associated with POAG in AD were: 8q22, AFAP1, TMCO1. An AUC of 0.62 was observed with an unweighted genetic risk score composed of 11 SNPs in candidate genes. Two additional risk scores were studied by using a penalized matrix decomposition with cross-validation; risk scores of 50 and 400 SNPs were identified with ROC of AUC=0.74 and AUC=0.94, respectively. CONCLUSIONS:A novel association with advanced POAG in the ENO4 locus was putatively identified in subjects of African descent. In addition to this finding, this GWAS in AD POAG subjects contributes to POAG genetics by identification of novel signals in prior loci (9p21), as well as advancing the fine-mapping of regions due to shorter average linkage disequilibrium (FNDC3B). While not useful without confirmation and clinical trials, the use of genetic risk scores demonstrated that considerable AD-specific genetic information remains in these data.
PMID: 30352225
ISSN: 1549-4713
CID: 3384612
A framework for selection of blood-based biomarkers for geroscience-guided clinical trials: report from the TAME Biomarkers Workgroup
Recent advances indicate that biological aging is a potentially modifiable driver of late-life function and chronic disease and have led to the development of geroscience-guided therapeutic trials such as TAME (Targeting Aging with MEtformin). TAME is a proposed randomized clinical trial using metformin to affect molecular aging pathways to slow the incidence of age-related multi-morbidity and functional decline. In trials focusing on clinical end-points (e.g., disease diagnosis or death), biomarkers help show that the intervention is affecting the underlying aging biology before sufficient clinical events have accumulated to test the study hypothesis. Since there is no standard set of biomarkers of aging for clinical trials, an expert panel was convened and comprehensive literature reviews conducted to identify 258 initial candidate biomarkers of aging and age-related disease. Next selection criteria were derived and applied to refine this set emphasizing: (1) measurement reliability and feasibility; (2) relevance to aging; (3) robust and consistent ability to predict all-cause mortality, clinical and functional outcomes; and (4) responsiveness to intervention. Application of these selection criteria to the current literature resulted in a short list of blood-based biomarkers proposed for TAME: IL-6, TNFα-receptor I or II, CRP, GDF15, insulin, IGF1, cystatin C, NT-proBNP, and hemoglobin A1c. The present report provides a conceptual framework for the selection of blood-based biomarkers for use in geroscience-guided clinical trials. This work also revealed the scarcity of well-vetted biomarkers for human studies that reflect underlying biologic aging hallmarks, and the need to leverage proposed trials for future biomarker discovery and validation.
PMCID:6294728
PMID: 30151729
ISSN: 2509-2723
CID: 4318802
The early natural history of albuminuria in young adults with youth-onset type 1 and type 2 diabetes
AIMS:To determine among adolescents and young adults with youth-onset type 1 diabetes and type 2 diabetes the rates and risk factors for albuminuria regression and progression. METHODS:Data from SEARCH, a longitudinal observational study of youth-onset type 1 diabetes (N = 1316) and type 2 diabetes (N = 143) were analyzed. Urine albumin:creatinine ratio (UACR) was measured from random urine specimens at baseline and follow-up visits (mean 7 years later). Albuminuria regression was defined as halving of baseline UACR when baseline UACR was ≥30 μg/mg; progression was defined as doubling of baseline UACR when follow-up UACR was ≥30 μg/mg, respectively. Multivariable regression assessed risk factors associated with low-risk albuminuria category (combined persistently-low albuminuria and regression) versus moderate-risk albuminuria category (combined persistently-high albuminuria and progression). RESULTS:Albuminuria progression was more common in type 2 diabetes versus type 1 diabetes (15.4% versus 6.0%, p<0.001). Moderate-risk albuminuria was associated with increasing HbA1c (adjusted OR (aOR) = 1.3, 95% CI 1.1-1.6) and lack of private health insurance (aOR = 2.7, 95%CI 1.1-6.5) in type 1 diabetes; and African American race (OR = 4.6, 95% CI 1.2-14.2), lower estimated insulin sensitivity score (aOR = 2.1, 95% CI 1.4-3.3), baseline UACR (aOR = 3.2, 95% CI 1.7-5.8), and follow-up estimated glomerular filtration rate (eGFR) (10-unit increase aOR = 1.3, 95% CI 1.0, 1.5) in type 2 diabetes. CONCLUSIONS:In the first decade of diabetes duration, kidney complications in type 2 diabetes are significantly more aggressive than in type 1 diabetes and may be associated with less modifiable risk factors including race, insulin sensitivity, and eGFR. Early interventions may help reduce long-term kidney complications.
PMCID:6289668
PMID: 30316542
ISSN: 1873-460x
CID: 4318812
JC polyoma viruria associates with protection from chronic kidney disease independently from apolipoprotein L1 genotype in African Americans
Background:Viral infections can trigger chronic kidney disease (CKD) and the urine virome may inform risk. The Natural History of APOL1-Associated Nephropathy Study (NHAANS) reported that urine JC polyomavirus (JCPyV) associated with a lower risk of APOL1-associated nephropathy in African Americans. Herein, association was assessed between urine JCPyV with CKD in African Americans independent from the APOL1 genotype. Methods:Quantitative polymerase chain reaction was performed for urinary detection of JCPyV and BK polyoma virus (BKPyV) in 200 newly recruited nondiabetic African Americans. A combined analysis was performed in these individuals plus 300 NHAANS participants. Results:In the 200 new participants, urine JCPyV was present in 8.8% of CKD cases and 45.8% of nonnephropathy controls (P = 3.0 × 10-8). In those with APOL1 renal-risk genotypes, JCPyV was detected in 5.1% of cases and 40.0% of controls (P = 0.0002). In those lacking APOL1 renal-risk genotypes, JCPyV was detected in 12.2% of cases and 48.8% of controls (P = 8.5 × 10-5). BKPyV was detected in 1.3% of cases and 0.8% of controls (P  =  0.77). In a combined analysis with 300 NHAANS participants (n = 500), individuals with urine JCPyV had a 63% lower risk of CKD compared with those without urine JCPyV (odds ratio 0.37; P = 4.6 × 10-6). RNA fluorescence in situ hybridization confirmed the presence of JCPyV genomic DNA and JCPyV messenger RNA (mRNA) in nondiseased kidney. Conclusions:Inverse relationships exist between JCPyV viruria and non-diabetic CKD. Future studies should determine whether renal inflammation associated with CKD is less permissive for JCPyV reactivation/replication or whether JCPyV is a marker of reduced host immune responsiveness that diminishes immune pathologic contributions to CKD.
PMCID:6212725
PMID: 29420808
ISSN: 1460-2385
CID: 4318692
Relationships between cerebral structure and cognitive function in African Americans with type 2 diabetes
BACKGROUND:Relationships between cognitive function and brain structure remain poorly defined in African Americans with type 2 diabetes. METHODS:Cognitive testing and cerebral magnetic resonance imaging in African Americans from the Diabetes Heart Study Memory IN Diabetes (n = 480) and Action to Control Cardiovascular Risk in Diabetes MIND (n = 104) studies were examined for associations. Cerebral gray matter volume (GMV), white matter volume (WMV) and white matter lesion volume (WMLV) and cognitive performance (Mini-mental State Exam [MMSE and 3MSE], Digit Symbol Coding (DSC), Stroop test, and Rey Auditory Verbal Learning Test) were recorded. Multivariable models adjusted for age, sex, BMI, scanner, intracranial volume, education, diabetes duration, HbA1c, LDL-cholesterol, smoking, hypertension and cardiovascular disease assessed associations between cognitive tests and brain volumes by study and meta-analysis. RESULTS:). CONCLUSIONS:In African Americans with diabetes, smaller GMV and increased WMLV associated with poorer performance on tests of global cognitive and executive function. These data suggest that WML burden and gray matter atrophy associate with cognitive performance independent of diabetes-related factors in this population.
PMCID:6138531
PMID: 30042057
ISSN: 1873-460x
CID: 4318792
