[Show abstract][Hide abstract] ABSTRACT: Vitamin D binding protein (DBP) is an important determinant of bioavailable vitamin D (BAVD) and may provide clues to racial variation in osteoporosis and atherosclerosis.
Assess relationships between DBP, BAVD, 25-hydroxyvitamin D (25OHD), and 1,25 di-hydroxyvitamin D (1,25OH2D) with kidney, bone, adipose, and atherosclerosis phenotypes in African Americans with type 2 diabetes.
Cross-sectional (N=545) and longitudinal (N=288; mean 5.1±0.9 year follow-up) relationships between vitamin D concentrations with renal phenotypes, vertebral bone mineral density (BMD), aorto-iliac, coronary artery, and carotid artery calcified plaque (CP), and adipose tissue volumes.
African American-Diabetes Heart Study.
Participants were 56.7% female with mean±SD age 55.6±9.6 years, diabetes duration 10.3±8.2 years, and eGFR 90.9±22.1 ml/min/1.73m(2).
Associations tested between vitamin D and aforementioned phenotypes adjusting for age, sex, African ancestry proportion, diabetes duration, statins, smoking, changes in eGFR, BMI, hemoglobin A1c, and blood pressure.
1,25OH2D was inversely associated with change in coronary artery CP (parameter estimate [β] -0.005, SE 0.002; p=0.037), with a trend for change in carotid artery CP (β -0.007, SE 0.004; p=0.074). Further adjustment for renin-aldosterone-system blockade revealed inverse association between 1,25OH2D and change in albuminuria (β -0.004, SE 0.002; p=0.037). DBP, BAVD, and 25OHD did not associate significantly with changes in albuminuria, CP, or BMD. BAVD was inversely associated with visceral, subcutaneous, intermuscular, and pericardial adipose volumes.
In contrast to BAVD and 25OHD, only 1,25OH2D levels were significantly and inversely associated with changes in subclinical atherosclerosis and albuminuria in African Americans, suggesting potential beneficial effects.
The Journal of Clinical Endocrinology and Metabolism 07/2015; DOI:10.1210/jc.2015-2167 · 6.31 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: Variants in donor multidrug resistance protein 1 (ABCB1) and caveolin 1 (CAV1) genes are associated with renal allograft failure after transplantation in Europeans. Here we assessed transplantation outcomes of kidneys from 368 African American (AA) and 314 European American (EA) deceased donors based on 38 single-nucleotide polymorphisms (SNPs) spanning ABCB1 and 16 SNPs spanning CAV1, including previously associated index and haplotype-tagging SNPs. Tests for association with time to allograft failure were performed for the 1233 resultant kidney transplantations, adjusting for recipient age, sex, ethnicity, cold ischemia time, panel reactive antibody, human leukocyte antigen match, expanded-criteria donation, and APOL1-nephropathy variants in AA donors. Interaction analyses between APOL1 with ABCB1 and CAV1 were performed. In a meta-analysis of all transplantations, ABCB1 index SNP rs1045642 was associated with time to allograft failure and other ABCB1 SNPs were nominally associated, but not CAV1 SNPs. ABCB1 SNP rs1045642 showed consistent effects with the 558 transplantations from EA donors, but not with the 675 transplantations from AA donors. ABCB1 SNP rs956825 and CAV1 SNP rs6466583 interacted with APOL1 in transplants from AA donors. Thus, the T allele at ABCB1 rs1045642 is associated with shorter renal allograft survival for kidneys from American donors. Interactions between ABCB1 and CAV1 with APOL1 may influence allograft failure for transplanted kidneys from AA donors.Kidney International advance online publication, 8 April 2015; doi:10.1038/ki.2015.105.
Kidney International 04/2015; DOI:10.1038/ki.2015.105 · 8.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Kidney International aims to inform the renal researcher and practicing nephrologists on all aspects of renal research. Clinical and basic renal research, commentaries, The Renal Consult, Nephrology sans Frontieres, minireviews, reviews, Nephrology Images, Journal Club. Published weekly online and twice a month in print.
Kidney International 04/2015; 87(4):671-673. DOI:10.1038/ki.2015.16 · 8.52 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: A classic T-cell phenotype in systemic lupus erythematosus (SLE) is the downregulation and replacement of the CD3ζ chain that alters T-cell receptor signaling. However, genetic associations with SLE in the human CD247 locus that encodes CD3ζ are not well established and require replication in independent cohorts. Our aim was therefore to examine, localize and validate CD247-SLE association in a large multiethnic population. We typed 44 contiguous CD247 single-nucleotide polymorphisms (SNPs) in 8922 SLE patients and 8077 controls from four ethnically distinct populations. The strongest associations were found in the Asian population (11 SNPs in intron 1, 4.99 × 10(-4)<P<4.15 × 10(-2)), where we further identified a five-marker haplotype (rs12141731-rs2949655-rs16859085-rs12144621-rs858554; G-G-A-G-A; Phap=2.12 × 10(-5)) that exceeded the most associated single SNP rs858554 (minor allele frequency in controls=13%; P=4.99 × 10(-4), odds ratio=1.32) in significance. Imputation and subsequent association analysis showed evidence of association (P<0.05) at 27 additional SNPs within intron 1. Cross-ethnic meta-analysis, assuming an additive genetic model adjusted for population proportions, showed five SNPs with significant P-values (1.40 × 10(-3)<P<3.97 × 10(-2)), with one (rs704848) remaining significant after Bonferroni correction (Pmeta=2.66 × 10(-2)). Our study independently confirms and extends the association of SLE with CD247, which is shared by various autoimmune disorders and supports a common T-cell-mediated mechanism.Genes and Immunity advance online publication, 8 January 2015; doi:10.1038/gene.2014.73.
Genes and Immunity 01/2015; 16(2). DOI:10.1038/gene.2014.73 · 3.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report the rare occurrence of donor-derived myeloid sarcoma in two kidney transplant patients who received organs from a single deceased donor. There was no evidence of preexisting hematologic malignancy in the donor at the time of organ recovery. Both recipients developed leukemic involvement that appeared to be limited to the transplanted organ. Fluorescence in situ hybridization (FISH) and molecular genotyping analyses confirmed that the malignant cells were of donor origin in each patient. Allograft nephrectomy and immediate withdrawal of immunosuppression were performed in both cases; systemic chemotherapy was subsequently administered to one patient. Both recipients were in remission at least one year following the diagnosis of donor-derived myeloid sarcoma. These cases suggest that restoration of the immune system after withdrawal of immunosuppressive therapy and allograft nephrectomy may be sufficient to control HLA-mismatched donor-derived myeloid sarcoma without systemic involvement.
[Show abstract][Hide abstract] 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.