Faculty Bibliography
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238
Increasing burden of type 2 diabetes in Navajo youth: The SEARCH for diabetes in youth study
AIM:SEARCH has recently reported that both prevalence and incidence of youth onset type 2 diabetes (YT2D) increased among most US race/ethnic groups in the early 2000s. This study reports on the incidence (2002-2013) and prevalence (2001, 2009) of YT2D in the Navajo Nation among youth age < 20 years from 2001 to 2013. METHODS:SEARCH sought to identify prevalent YT2D cases in 2001 (N = 75) and 2009 (N = 70) and all incident YT2D cases in three periods: 2002 to 2005 (N = 53), 2006 to 2009 (N = 68), and 2010 2013 (N = 90) in Navajo Nation. Denominators were based on the active Indian Health Service user population for eligible health care facilities. Prevalence (per 100 000) and period-specific incidence rates (per 100 000 person-years) were computed for youth aged 10 to 19 years. Changes in prevalence were tested with a two-sided skew-corrected inverted score test, while changes in incidence were tested with Poisson regression. RESULTS:YT2D prevalence was high but stable in 2001 and 2009, overall [146.6 (116.8, 184.0) vs 141.5 (112.0, 178.8), P = .65) and in all subgroups. In contrast, incidence rates increased particularly between the second and third periods overall and in most subgroups by age and by sex. CONCLUSIONS:These data confirm the high burden of YT2D among Navajo youth and suggest an increasing risk in more recent years. However, recent improvements in obesity reduction in this population demonstrate optimism for potential reductions in YT2D in Navajo Nation.
PMCID:6786918
PMID: 31260152
ISSN: 1399-5448
CID: 4318932
APOL1 Kidney Risk Variants and Cardiovascular Disease: An Individual Participant Data Meta-Analysis
BACKGROUND:) are strongly associated with kidney disease in blacks. Kidney disease itself increases the risk of cardiovascular disease, but whether these variants have an independent direct effect on the risk of cardiovascular disease is unclear. Previous studies have had inconsistent results. METHODS:kidney-risk variants with adjudicated cardiovascular disease events and death, independent of kidney measures. The analysis included 21,305 blacks from eight large cohorts. RESULTS:genotype was also not associated with death. There was no difference in adjusted associations by level of kidney function, age, diabetes status, or body-mass index. CONCLUSIONS:kidney-risk variants were not associated with incident cardiovascular disease or death independent of kidney measures.
PMCID:6779370
PMID: 31383730
ISSN: 1533-3450
CID: 4318952
Alternative waist-to-height ratios associated with risk biomarkers in youth with diabetes: comparative models in the SEARCH for Diabetes in Youth Study
BACKGROUND/OBJECTIVES:HtR) can better predict blood pressures and lipid parameters in youth. PARTICIPANTS/METHODS:HtR. RESULTS:HtR (p = 0.003), but otherwise comparisons between alternative WHtR protocols were not significantly different. CONCLUSIONS:Among youth with recently diagnosed diabetes, measurements of WHtR by either waist circumference protocol similarly helped estimate current and prospective cardiometabolic risk biomarkers.
PMID: 30926953
ISSN: 1476-5497
CID: 4318882
Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria
Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.
PMCID:6739370
PMID: 31511532
ISSN: 2041-1723
CID: 4318962
Trends in prevalence of cardiovascular risk factors from 2002 to 2012 among youth early in the course of type 1 and type 2 diabetes. The SEARCH for Diabetes in Youth Study
BACKGROUND:Given diabetes is an important risk factor for cardiovascular disease (CVD), we examined temporal trends in CVD risk factors by comparing youth recently diagnosed with type 1 diabetes (T1D) and type 2 diabetes (T2D) from 2002 through 2012. METHODS:The SEARCH for Diabetes in Youth Study identified youth with diagnosed T1D (n = 3954) and T2D (n = 706) from 2002 to 2012. CVD risk factors were defined using the modified Adult Treatment Panel III criteria for metabolic syndrome: (a) hypertension; (b) high-density lipoprotein cholesterol ≤40 mg/dL; (c) triglycerides ≥110 mg/dL; and (d) waist circumference (WC) >90th percentile. Prevalence of CVD risk factors, stratified by diagnosis year and diabetes type, was reported. Univariate and multivariate logistic models and Poisson regression were fit to estimate the prevalence trends for CVD risk factors individually and in clusters (≥2 risk factors). RESULTS:The prevalence of ≥2 CVD risk factors was higher in youth with T2D than with T1D at each incident year, but the prevalence of ≥2 risk factors did not change across diagnosis years among T1D or T2D participants. The number of CVD risk factors did not change significantly in T1D participants, but increased at an annual rate of 1.38% in T2D participants. The prevalence of hypertension decreased in T1D participants, and high WC increased in T2D participants. CONCLUSION:The increase in number of CVD risk factors including large WC among youth with T2D suggests a need for early intervention to address these CVD risk factors. Further study is needed to examine longitudinal associations between diabetes and CVD.
PMCID:6785186
PMID: 30903717
ISSN: 1399-5448
CID: 4318872
Estimating prevalence of type I and type II diabetes using incidence rates: the SEARCH for diabetes in youth study
PURPOSE/OBJECTIVE:Most surveillance efforts in childhood diabetes have focused on incidence, whereas prevalence is rarely reported. This study aimed to assess whether a mathematical illness-death model accurately estimated future prevalence from baseline prevalence and incidence rates in children. METHODS:SEARCH for Diabetes in Youth is an ongoing population-based surveillance study of prevalence and incidence of diabetes and its complications among youth in the United States. We used age-, sex-, and race/ethnicity-specific SEARCH estimates of the prevalence of type I and type II diabetes in 2001 and incidence from 2002 to 2008. These data were used in a partial differential equation to estimate prevalence in 2009 with 95% bootstrap confidence intervals. Model-based prevalence was compared with the observed prevalence in 2009. RESULTS:Most confidence intervals for the difference between estimated and observed prevalence included zero, indicating no evidence for a difference between the two methods. The width of confidence intervals indicated high precision for the estimated prevalence when considering all races/ethnicities. In strata with few cases, precision was reduced. CONCLUSIONS:Future prevalence of type I and type II diabetes in youth may be accurately estimated from baseline prevalence and incidence. Diabetes surveillance could benefit from potential cost savings of this method.
PMCID:6785183
PMID: 31383511
ISSN: 1873-2585
CID: 4318942
A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure
Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.
PMID: 31127295
ISSN: 1460-2083
CID: 3967142
Plasma apoM and S1P levels are inversely associated with mortality in African Americans with type 2 diabetes mellitus
apoM is a minor HDL apolipoprotein and carrier for sphingosine-1-phosphate (S1P). HDL apoM and S1P concentrations are inversely associated with atherosclerosis progression in rodents. We evaluated associations between plasma concentrations of S1P, plasma concentrations of apoM, and HDL apoM levels with prevalent subclinical atherosclerosis and mortality in the African American-Diabetes Heart Study participants (N = 545). Associations between plasma S1P, plasma apoM, and HDL apoM with subclinical atherosclerosis and mortality were assessed using multivariate parametric, nonparametric, and Cox proportional hazards models. At baseline, participants' median (25th percentile, 75th percentile) age was 55 (49, 62) years old and their coronary artery calcium (CAC) mass score was 26.5 (0.0, 346.5). Plasma S1P, plasma apoM, and HDL apoM were not associated with CAC. After 64 (57.6, 70.3) months of follow-up, 81 deaths were recorded. Higher concentrations of plasma S1P [odds ratio (OR) = 0.14, P = 0.01] and plasma apoM (OR = 0.10, P = 0.02), but not HDL apoM (P = 0.89), were associated with lower mortality after adjusting for age, sex, statin use, CAC, kidney function, and albuminuria. We conclude that plasma S1P and apoM concentrations are inversely and independently associated with mortality, but not CAC, in African Americans with type 2 diabetes after accounting for conventional risk factors.
PMCID:6672033
PMID: 31133557
ISSN: 1539-7262
CID: 4318922
Nephropathy Progression in African Americans With a Family History of ESKD: Implications for Clinical Trials in APOL1-Associated Nephropathy [Letter]
PMID: 31076172
ISSN: 1523-6838
CID: 4318912
JC Viruria Is Associated With Reduced Risk of Diabetic Kidney Disease
PURPOSE/OBJECTIVE:African Americans who shed JC polyomavirus (JCV) in their urine have reduced rates of nondiabetic chronic kidney disease (CKD). We assessed the associations between urinary JCV and urine BK polyomavirus (BKV) with CKD in African Americans with diabetes mellitus. METHODS:African Americans with diabetic kidney disease (DKD) and controls lacking nephropathy from the Family Investigation of Nephropathy and Diabetes Consortium (FIND) and African American-Diabetes Heart Study (AA-DHS) had urine tested for JCV and BKV using quantitative PCR. Of the 335 individuals tested, 148 had DKD and 187 were controls. RESULTS:JCV viruria was detected more often in the controls than in the patients with DKD (FIND: 46.6% vs 32.2%; OR, 0.52; 95% CI, 0.29 to 0.93; P = 0.03; AA-DHS: 30.4% vs 26.2%; OR, 0.63; 95% CI, 0.27 to 1.48; P = 0.29). A joint analysis adjusted for age, sex, and study revealed that JC viruria was inversely associated with DKD (OR, 0.56; 95% CI, 0.35 to 0.91; P = 0.02). Statistically significant relationships between BKV and DKD were not observed. MAIN CONCLUSIONS/CONCLUSIONS:The results from the present study extend the inverse association between urine JCV and nondiabetic nephropathy in African Americans to DKD. These results imply that common pathways likely involving the innate immune system mediate coincident chronic kidney injury and restriction of JCV replication. Future studies are needed to explore causative pathways and characterize whether the absence of JC viruria can serve as a biomarker for DKD in the African American population.
PMCID:6489692
PMID: 30715336
ISSN: 1945-7197
CID: 4318862
