[Show abstract][Hide abstract] ABSTRACT: Background:
Despite evidence of an association between variants at the apolipoprotein L1 gene (APOL1) locus and a spectrum of related kidney diseases, underlying biological mechanisms remain unknown. An earlier preliminary study published by our group showed that an APOL1 variant (rs73885319) modified the association between high-density lipoprotein cholesterol (HDLC) and estimated glomerular filtration rate (eGFR) in African Americans. To further understand this relationship, we evaluated the interaction in two additional large cohorts of African Americans for a total of 3,592 unrelated individuals from the Howard University Family Study (HUFS), the Natural History of APOL1-Associated Nephropathy Study (NHAAN), and the Atherosclerosis Risk in Communities Study (ARIC). The association between HDLC and eGFR was determined using linear mixed models, and the interaction between rs73885319 genotype and HDLC was evaluated using a multiplicative term.
Among individuals homozygous for the risk genotype, a strong inverse HDLC-eGFR association was observed, with a positive association in others (p for the interaction of the rs73885319 × HDLC =0.0001). The interaction was similar in HUFS and NHAAN, and attenuated in ARIC. Given that ARIC participants were older, we investigated an age effect; age was a significant modifier of the observed interaction. When older individuals were excluded, the interaction in ARIC was similar to that in the other studies.
Based on these findings, it is clear that the relationship between HDLC and eGFR is strongly influenced by the APOL1 rs73885319 kidney risk genotype. Moreover, the degree to which this variant modifies the association may depend on the age of the individual. More detailed physiological studies are warranted to understand how rs73885319 may affect the relationship between HDLC and eGFR in individuals with and without disease and across the lifespan.
[Show abstract][Hide abstract] ABSTRACT: Leptin is abnormally elevated in the plasma of patients with systemic lupus erythematosus (SLE), where it is thought to promote and/or sustain pro-inflammatory responses. Whether this association could reflect an increased genetic susceptibility to develop SLE is not known, and studies of genetic associations with leptin-related polymorphisms in SLE patients have been so far inconclusive. Here we genotyped DNA samples from 15,706 SLE patients and healthy matched controls from four different ancestral groups, to correlate polymorphisms of genes of the leptin pathway to risk for SLE. It was found that although several SNPs showed weak associations, those associations did not remain significant after correction for multiple testing. These data do not support associations between defined leptin-related polymorphisms and increased susceptibility to develop SLE.
[Show abstract][Hide abstract] ABSTRACT: Objectives:
Relative to European Americans, African Americans manifest lower levels of computed tomography-based calcified atherosclerotic plaque (CP), a measure of subclinical cardiovascular disease (CVD). Potential relationships between CP and cerebral structure are poorly defined in the African American population. We assessed associations among glycemic control, inflammation, and CP with cerebral structure on MRI and with cognitive performance in 268 high-risk African Americans with type 2 diabetes.
Research design and methods:
Associations among hemoglobin A1c (HbA1c), C-reactive protein (CRP), and CP in coronary arteries, carotid arteries, and the aorta with MRI volumetric analysis (white matter volume, gray matter volume [GMV], cerebrospinal fluid volume, and white matter lesion volume) were assessed using generalized linear models adjusted for age, sex, African ancestry proportion, smoking, BMI, use of statins, HbA1c level, hypertension, and prior CVD.
Participants were 63.4% female with mean (SD) age of 59.8 years (9.2 years), diabetes duration of 14.5 years (7.6 years), HbA1c level of 7.95% (1.9%), estimated glomerular filtration rate of 86.7 mL/min/1.73 m(2) (24.6 mL/min/1.73 m(2)), and coronary artery CP mass score of 215 mg (502 mg). In fully adjusted models, GMV was inversely associated with coronary artery CP (parameter estimate [β] -0.47 [SE 0.15], P = 0.002; carotid artery CP (β -1.92 [SE 0.62], P = 0.002; and aorta CP [β -0.10 [SE 0.03] P = 0.002); whereas HbA1c and CRP levels did not associate with cerebral volumes. Coronary artery CP also associated with poorer global cognitive function on the Montreal Cognitive Assessment.
Subclinical atherosclerosis was associated with smaller GMV and poorer cognitive performance in African Americans with diabetes. Cardioprotective strategies could preserve GMV and cognitive function in high-risk African Americans with diabetes.
Diabetes care 09/2015; DOI:10.2337/dc15-1035 · 8.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
In African Americans (AAs), APOL1 G1 and G2 nephropathy risk variants are associated with non-diabetic end-stage kidney disease (ESKD) in an autosomal recessive pattern. Additional risk and protective genetic variants may be present near the APOL1 loci, since earlier age ESKD is observed in some AAs with one APOL1 renal-risk variant, and because the adjacent gene MYH9 is associated with nephropathy in populations lacking G1 and G2 variants.
Re-sequencing was performed across a ∼275 kb region encompassing the APOL1-APOL4 and MYH9 genes in 154 AA cases with non-diabetic ESKD and 38 controls without nephropathy who were heterozygous for a single APOL1 G1 or G2 risk variant.
Sequencing identified 3,246 non-coding single nucleotide polymorphisms (SNPs), 55 coding SNPs, and 246 insertion/deletions. No new coding variations were identified. Eleven variants, including a rare APOL3 Gln58Ter null variant (rs11089781), were genotyped in a replication panel of 1,571 AA ESKD cases and 1,334 controls. After adjusting for APOL1 G1 and G2 risk effects, these variations were not significantly associated with ESKD. In subjects with <2 APOL1 G1 and/or G2 alleles (849 cases; 1,139 controls), the APOL3 null variant was nominally associated with ESKD (recessive model, OR 1.81; p = 0.026); however, analysis in 807 AA cases and 634 controls from the Family Investigation of Nephropathy and Diabetes did not replicate this association.
Additional common variants in the APOL1-APOL4-MYH9 region do not contribute significantly to ESKD risk beyond the APOL1 G1 and G2 alleles.
American Journal of Nephrology 09/2015; 42(2):99-106. DOI:10.1159/000439448 · 2.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.
[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 · 6.21 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: 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: 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; 88(3). DOI:10.1038/ki.2015.105 · 8.56 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 · 8.56 Impact Factor