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1.  APOL1 genotype and kidney transplantation outcomes from deceased African American donors 
Transplantation  2016;100(1):194-202.
Background
Two apolipoprotein L1 gene (APOL1) renal-risk variants in donors and African American (AA) recipient race are associated with worse allograft survival in deceased-donor kidney transplantation (DDKT) from AA donors. To detect other factors impacting allograft survival from deceased AA kidney donors, APOL1 renal-risk variants were genotyped in additional AA kidney donors.
Methods
APOL1 genotypes were linked to outcomes in 478 newly analyzed DDKTs in the Scientific Registry of Transplant Recipients. Multivariate analyses accounting for recipient age, sex, race, panel reactive antibody level, HLA match, cold ischemia time, donor age, and expanded-criteria donation were performed. These 478 transplantations and 675 DDKTs from a prior report were jointly analyzed.
Results
Fully-adjusted analyses limited to the new 478 DDKTs replicated shorter renal allograft survival in recipients of APOL1-two-renal-risk-variant kidneys (HR 2.00; p=0.03). Combined analysis of 1153 DDKTs from AA donors revealed donor APOL1 high-risk genotype (HR 2.05; p=3×10−4), older donor age (HR 1.18; p=0.05), and younger recipient age (HR 0.70; p=0.001) adversely impacted allograft survival. Although prolonged allograft survival was seen in many recipients of APOL1-two-renal-risk-variant kidneys, follow-up serum creatinine concentrations were higher than in recipients of zero/one APOL1-renal-risk variant kidneys. A competing risk analysis revealed that APOL1 impacted renal allograft survival, but not recipient survival. Interactions between donor age and APOL1 genotype on renal allograft survival were non-significant.
Conclusions
Shorter renal allograft survival is reproducibly observed after DDKT from APOL1-two-renal-risk-variant donors. Younger recipient age and older donor age have independent adverse effects on renal allograft survival.
doi:10.1097/TP.0000000000000969
PMCID: PMC4684443  PMID: 26566060
2.  Plasma FGF23 and Calcified Atherosclerotic Plaque in African Americans with Type 2 Diabetes Mellitus 
American journal of nephrology  2015;42(6):391-401.
Background
Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone implicated in disorders of serum phosphorus concentration and vitamin D. The role of FGF23 in vascular calcification remains controversial.
Methods
Relationships between FGF23 and coronary artery calcified atherosclerotic plaque (CAC), aorto-iliac calcified plaque (CP), carotid artery CP, volumetric bone mineral density (vBMD), albuminuria, and estimated glomerular filtration rate (eGFR) were determined in 545 African Americans with type 2 diabetes (T2D) and preserved kidney function in African American-Diabetes Heart Study participants. Generalized linear models were fitted to test associations between FGF23 and cardiovascular, bone, and renal phenotypes, and change in measurements over time, adjusting for age, sex, African ancestry proportion, BMI, diabetes duration, HbA1c, blood pressure, renin-angiotensin-system inhibitors, statins, calcium supplements, serum calcium, and serum phosphate.
Results
The sample was 56.7% female with mean/SD age 55.6/9.6 years, diabetes duration 10.3/8.2 years, eGFR 90.9/22.1 ml/min/1.73m2, urine albumin:creatinine ratio (UACR) 151/588 (median 13) mg/g, plasma FGF23 161/157 RU/mL, and CAC 637/1179 mg. In fully-adjusted models, FGF23 was negatively associated with eGFR (p<0.0001) and positively associated with UACR (p<0.0001) and CAC (p=0.0006), but not with carotid CP or aortic CP. Baseline FGF23 concentration did not associate with changes in vBMD or CAC after mean 5.1 year follow-up.
Conclusions
Plasma FGF23 concentrations were independently associated with subclinical coronary artery disease, albuminuria, and kidney function in the understudied African American population with T2D. Findings support relationships between FGF23 and vascular calcification, but not bone mineral density, in African Americans lacking advanced nephropathy.
doi:10.1159/000443241
PMCID: PMC4732898  PMID: 26693712
African American; albuminuria; calcified atherosclerotic plaque; FGF23; kidney disease; type 2 diabetes mellitus
3.  Subclinical Atherosclerosis Is Inversely Associated With Gray Matter Volume in African Americans With Type 2 Diabetes 
Diabetes Care  2015;38(11):2158-2165.
OBJECTIVE
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, hypertension, and prior CVD.
RESULTS
Participants were 63.4% female with mean (SD) age of 59.8 years (9.2), diabetes duration of 14.5 years (7.6), HbA1c of 7.95% (1.9), estimated glomerular filtration rate of 86.6 mL/min/1.73 m2 (24.6), and coronary artery CP mass score of 215 mg (502). 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 did not associate with cerebral volumes. Coronary artery CP also associated with poorer global cognitive function on the Montreal Cognitive Assessment.
CONCLUSIONS
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.
doi:10.2337/dc15-1035
PMCID: PMC4613911  PMID: 26370382
4.  Genome-Wide Interaction with Insulin Secretion Loci Reveals Novel Loci for Type 2 Diabetes in African Americans 
PLoS ONE  2016;11(7):e0159977.
Type 2 diabetes (T2D) is the result of metabolic defects in insulin secretion and insulin sensitivity, yet most T2D loci identified to date influence insulin secretion. We hypothesized that T2D loci, particularly those affecting insulin sensitivity, can be identified through interaction with insulin secretion loci. To test this hypothesis, single nucleotide polymorphisms (SNPs) associated with acute insulin response to glucose (AIRg), a dynamic measure of first-phase insulin secretion, were identified in African Americans from the Insulin Resistance Atherosclerosis Family Study (IRASFS; n = 492 subjects). These SNPs were tested for interaction, individually and jointly as a genetic risk score (GRS), using genome-wide association study (GWAS) data from five cohorts (ARIC, CARDIA, JHS, MESA, WFSM; n = 2,725 cases, 4,167 controls) with T2D as the outcome. In single variant analyses, suggestively significant (Pinteraction<5×10−6) interactions were observed at several loci including LYPLAL1 (rs10746381), CHN2 (rs7796525), and EXOC1 (rs4289500). Notable AIRg GRS interactions were observed with SAMD4A (rs11627203) and UTRN (rs17074194). These data support the hypothesis that additional genetic factors contributing to T2D risk can be identified by interactions with insulin secretion loci.
doi:10.1371/journal.pone.0159977
PMCID: PMC4957757  PMID: 27448167
5.  Association analysis of the reticulon 1 gene (RTN1) in end-stage kidney disease 
American journal of nephrology  2015;42(4):259-264.
Background
The reticulon 1 gene (RTN1) encodes reticulons, endoplasmic reticulum stress proteins recently implicated in kidney disease progression.
Methods
RTN1 single nucleotide polymorphisms (SNPs) were tested for association with type 2 diabetes-associated (T2D) end-stage kidney disease (ESKD) in African Americans (AAs) and European Americans (EAs), and AAs with non-diabetic ESKD. RTN1 SNPs that were associated with T2D-ESKD in AA cases compared to non-nephropathy controls were identified from a discovery genome-wide association study (N=1,797), then tested for replication in 1,847 additional AA T2D-ESKD cases and controls.
Results
Three intronic RTN1 variants were nominally associated with T2D-ESKD in both discovery and replication analyses: rs1952034, rs12431381, and rs12434215 (additive models); combined T2D-ESKD (discovery+replication) p-values were 0.015-3.0×10−4 (odds ratios [ORs] 0.67-0.77; minor alleles protective). In addition, rs12434215 was weakly associated with T2D-ESKD in 557 EA T2D-ESKD cases contrasted with 753 EA non-nephropathy controls (p=0.019; OR=0.69, dominant model). Nominal association extended to non-diabetic causes of ESKD in 1,459 additional AA cases (rs12431381 and rs12434215 p-values=0.014–0.015; OR=0.77). An all-cause ESKD association analysis contrasted the 3,594 AA ESKD cases with 1,489 AA non-nephropathy controls and detected association with rs12434215 (p=6.7×10−4, OR=0.73) and rs12431381 (p=7.5×10−4, OR=0.75) in dominant models. Of the three SNPs, only rs12434215 was weakly associated with T2D per se when contrasting T2D non-nephropathy cases with non-diabetic controls (additive model p=0.032 AAs; p=0.048 EAs).
Conclusions
These results suggest evidence of genetic association between common variants in RTN1 and ESKD in AAs and EAs.
doi:10.1159/000441199
PMCID: PMC4651726  PMID: 26496126
African Americans; chronic kidney disease; diabetes; diabetic kidney disease; genetics; reticulon 1
6.  Associations between Anxiety and Depression Symptoms and Cognitive Testing and Neuroimaging in Type 2 Diabetes 
Structured Abstract
Aims
Anxiety, depression, accelerated cognitive decline, and increased risk of dementia are observed in individuals with type 2 diabetes. Anxiety and depression may contribute to lower performance on cognitive tests and differences in neuroimaging observed in individuals with type 2 diabetes.
Methods
These relationships were assessed in 655 European Americans with type 2 diabetes from 504 Diabetes Heart Study families. Participants completed cognitive testing, brain magnetic resonance imaging, the Brief Symptom Inventory Anxiety subscale, and the Center for Epidemiologic Studies Depression-10.
Results
In analyses adjusted for age, sex, educational attainment, and use of psychotropic medications, individuals with comorbid anxiety and depression symptoms had lower performance on all cognitive testing measures assessed (p≤0.005). Those with both anxiety and depression also had increased white matter lesion volume (p=0.015), decreased gray matter cerebral blood flow (p=4.43 × 10−6), decreased gray matter volume (p=0.002), increased white and gray matter mean diffusivity (p≤0.001), and decreased white matter fractional anisotropy (p=7.79 × 10−4). These associations were somewhat attenuated upon further adjustment for health status related covariates.
Conclusions
Comorbid anxiety and depression symptoms were associated with cognitive performance and brain structure in a European American cohort with type 2 diabetes.
doi:10.1016/j.jdiacomp.2015.09.010
PMCID: PMC4698057  PMID: 26476474
Type 2 diabetes; anxiety; depression; cognition; magnetic resonance imaging
7.  Selecting SNPs informative for African, American Indian and European Ancestry: application to the Family Investigation of Nephropathy and Diabetes (FIND) 
BMC Genomics  2016;17:325.
Background
The presence of population structure in a sample may confound the search for important genetic loci associated with disease. Our four samples in the Family Investigation of Nephropathy and Diabetes (FIND), European Americans, Mexican Americans, African Americans, and American Indians are part of a genome- wide association study in which population structure might be particularly important. We therefore decided to study in detail one component of this, individual genetic ancestry (IGA). From SNPs present on the Affymetrix 6.0 Human SNP array, we identified 3 sets of ancestry informative markers (AIMs), each maximized for the information in one the three contrasts among ancestral populations: Europeans (HAPMAP, CEU), Africans (HAPMAP, YRI and LWK), and Native Americans (full heritage Pima Indians). We estimate IGA and present an algorithm for their standard errors, compare IGA to principal components, emphasize the importance of balancing information in the ancestry informative markers (AIMs), and test the association of IGA with diabetic nephropathy in the combined sample.
Results
A fixed parental allele maximum likelihood algorithm was applied to the FIND to estimate IGA in four samples: 869 American Indians; 1385 African Americans; 1451 Mexican Americans; and 826 European Americans. When the information in the AIMs is unbalanced, the estimates are incorrect with large error. Individual genetic admixture is highly correlated with principle components for capturing population structure. It takes ~700 SNPs to reduce the average standard error of individual admixture below 0.01. When the samples are combined, the resulting population structure creates associations between IGA and diabetic nephropathy.
Conclusions
The identified set of AIMs, which include American Indian parental allele frequencies, may be particularly useful for estimating genetic admixture in populations from the Americas. Failure to balance information in maximum likelihood, poly-ancestry models creates biased estimates of individual admixture with large error. This also occurs when estimating IGA using the Bayesian clustering method as implemented in the program STRUCTURE. Odds ratios for the associations of IGA with disease are consistent with what is known about the incidence and prevalence of diabetic nephropathy in these populations.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-016-2654-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s12864-016-2654-x
PMCID: PMC4855449  PMID: 27142425
Individual genetic ancestry; Population structure; SNP; Diabetic nephropathy
8.  Re-sequencing of the APOL1-APOL4 and MYH9 gene regions in African Americans does not identify additional risks for CKD progression 
American journal of nephrology  2015;42(2):99-106.
Background
APOL1 G1 and G2 nephropathy risk variants are associated with non-diabetic end-stage kidney disease (ESKD) in African Americans (AAs) 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.
Methods
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.
Results
Sequencing identified 3246 non-coding single nucleotide polymorphisms (SNPs), 55 coding SNPs, and 246 insertion/deletions (InDels). No new coding variations were identified. Eleven variants, including a rare APOL3 Gln58Ter null variant (rs11089781), were genotyped in a replication panel of 1571 AA ESKD cases and 1334 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; 1139 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 (FIND) did not replicate this association.
Conclusion
Additional common variants in the APOL1-APOL4-MYH9 region do not contribute significantly to ESKD risk beyond the APOL1 G1 and G2 alleles.
doi:10.1159/000439448
PMCID: PMC4589514  PMID: 26343748
African Americans; APOL1; kidney disease; FSGS; genetics; DNA sequencing
9.  Montreal Cognitive Assessment and Modified Mini Mental State Examination in African Americans 
Journal of Aging Research  2015;2015:872018.
Background. Sparse data limit the interpretation of Montreal Cognitive Assessment (MoCA) scores, particularly in minority populations. Additionally, there are no published data on how MoCA scores compare to the widely used Modified Mini Mental State Examination (3MSE). We provide performance data on the MoCA in a large cohort of African Americans and compare 3MSE and MoCA scores, providing a “crosswalk” for interpreting scores. Methods. Five hundred and thirty African Americans with type 2 diabetes were enrolled in African American-Diabetes Heart Study-MIND, a cross-sectional study of cognition and structural and functional brain imaging. After excluding participants with possible cognitive impairment (n = 115), mean (SD) MoCA and 3MSE scores are presented stratified by age and education. Results. Participant mean age was 58.2 years (range: 35-83); 61% were female; and 64.9% had >12 years of education. Mean (SD) 3MSE and MoCA scores were 86.9 (8.2) and 19.8 (3.8), respectively. 93.5% of the cohort had a “positive” screen on the MoCA, scoring <26 (education-adjusted), compared with 47.5% on the 3MSE (cut-point < 88). A 3MSE score of 88 corresponded to a MoCA score of 20 in this population. Conclusion. The present data suggest the need for caution when applying proposed MoCA cutoffs to African Americans.
doi:10.1155/2015/872018
PMCID: PMC4649096  PMID: 26618003
10.  GENOME-WIDE INTERACTION WITH SELECTED TYPE 2 DIABETES LOCI REVEALS NOVEL LOCI FOR TYPE 2 DIABETES IN AFRICAN AMERICANS 
Type 2 diabetes (T2D) is the result of metabolic defects in insulin secretion and insulin sensitivity, yet most T2D loci identified to date influence insulin secretion. We hypothesized that T2D loci, particularly those affecting insulin sensitivity, can be identified through interaction with known T2D loci implicated in insulin secretion. To test this hypothesis, single nucleotide polymorphisms (SNPs) nominally associated with acute insulin response to glucose (AIRg), a dynamic measure of first-phase insulin secretion, and previously associated with T2D in genome-wide association studies (GWAS) were identified in African Americans from the Insulin Resistance Atherosclerosis Family Study (IRASFS; n=492 subjects). These SNPs were tested for interaction, individually and jointly as a genetic risk score (GRS), using GWAS data from five cohorts (ARIC, CARDIA, JHS, MESA, WFSM; n=2,725 cases, 4,167 controls) with T2D as the outcome. In single variant analyses, suggestively significant (Pinteraction < 5×10−6) interactions were observed at several loci including DGKB (rs978989), CDK18 (rs12126276), CXCL12 (rs7921850), HCN1 (rs6895191), FAM98A (rs1900780), and MGMT (rs568530). Notable beta-cell GRS interactions included two SNPs at the DGKB locus (rs6976381; rs6962498). These data support the hypothesis that additional genetic factors contributing to T2D risk can be identified by interactions with insulin secretion loci.
PMCID: PMC5146756  PMID: 27896979
11.  Genetic associations of leptin-related polymorphisms with systemic lupus erythematosus 
Clinical immunology (Orlando, Fla.)  2015;161(2):157-162.
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.
doi:10.1016/j.clim.2015.09.007
PMCID: PMC4658308  PMID: 26385092
systemic lupus erythematosus; leptin pathway; gene polymorphisms
12.  Electrochemical skin conductance in diabetic kidney disease 
American journal of nephrology  2015;41(6):438-447.
Background
There is a need to identify patients with diabetic kidney disease (DKD) using non-invasive, cost-effective screening tests. Sudoscan®, a device using electrochemical skin conductance (ESC) to measure sweat gland dysfunction, is valuable for detecting peripheral neuropathy. ESC was tested for association with DKD (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73m2) in 383 type 2 diabetes mellitus (T2D)-affected patients; diagnostic thresholds were determined in 540 patients.
Methods
Relationships between ESC with eGFR and urine albumin:creatinine ratio (UACR) were assessed in 202 European Americans (EA) and 181 African Americans (AA) with T2D.
Results
In 92 EA DKD cases and 110 T2D non-nephropathy controls, respectively, mean(SD) ages were 68.9(9.8) and 61.1(10.8) years, HbA1c 7.4(1.2) and 7.4(1.3)%, eGFR 29.5(12.2) and 87.7(14.1) ml/min/1.73m2, and UACR 1227(1710) and 7.6(5.9) mg/g. In 57 AA cases and 124 controls, respectively, mean (SD) ages were 64.0(12.0) and 59.5(9.7) years, HbA1c 7.4(1.3) and 7.6 (1.7)%, eGFR 29.7(13.3) and 90.2(16.2) ml/min/1.73m2, and UACR 1172(1564) and 7.8(7.1) mg/g. Mean(SD) ESC (μS) was lower in cases than controls (EA: case/control hands 49.3(18.5)/62.4(16.2); feet 62.2(18.0)/73.4(13.9), both p<5.8×10−7; AA: case/control hands 39.8(19.0)/48.5(17.1); feet 53.2(21.3)/63.5(19.4), both p≤0.01). Adjusting for age, sex, BMI and HbA1c, hands and feet ESC associated with eGFR <60 ml/min/1.73m2 (p≤7.2×10−3), UACR >30 mg/g (p≤7.0×10−3), UACR >300 mg/g (p≤8.1×10−3), and continuous traits eGFR and UACR (both p≤5.0×10−9). HbA1c values were not useful for risk stratification.
Conclusions
ESC measured using Sudoscan® is strongly associated with DKD in AA and EA. ESC is a useful screening test to identify DKD in patients with T2D.
doi:10.1159/000437342
PMCID: PMC4560993  PMID: 26228248
African Americans; albuminuria; diabetes mellitus; electrochemical skin conductance; European Americans; kidney disease
13.  The Spectrum of MYH9-Associated Nephropathy 
Causes of the excess incidence rates of chronic kidney disease in the African American population have long been under study. Recently, polymorphisms in the nonmuscle myosin heavy chain 9 gene (MYH9) have been associated with nondiabetic kidney diseases in African- and European-derived populations. Risk variants in MYH9 contribute to approximately 70% of nondiabetic forms of ESRD in African Americans and 40 to 45% of all ESRD in this ethnic group, with lesser effects in European Americans. It is clear that MYH9 polymorphisms have a significant impact on the incidence rates of kidney disease in African Americans. This article describes the current spectrum of biopsy-proven MYH9-associated kidney diseases, along with potential effects of MYH9 on ethnic differences in clinical outcome. MYH9 risk variants exhibit the most impressive association with any common complex kidney disease yet identified.
doi:10.2215/CJN.08721209
PMCID: PMC4890964  PMID: 20299374
14.  Apolipoprotein L1 gene variants in deceased organ donors are associated with renal allograft failure 
Apolipoprotein L1 gene (APOL1) nephropathy variants in African American deceased kidney donors were associated with shorter renal allograft survival in a prior single-center report. APOL1 G1 and G2 variants were genotyped in newly accrued DNA samples from African American deceased donors of kidneys recovered and/or transplanted in Alabama and North Carolina. APOL1 genotypes and allograft outcomes in subsequent transplants from 55 U.S. centers were linked, adjusting for age, sex and race/ethnicity of recipients, HLA match, cold ischemia time, panel reactive antibody levels, and donor type. For 221 transplantations from kidneys recovered in Alabama, there was a statistical trend toward shorter allograft survival in recipients of two-APOL1-nephropathy-variant kidneys (hazard ratio [HR] 2.71; p=0.06). For all 675 kidneys transplanted from donors at both centers, APOL1 genotype (HR 2.26; p=0.001) and African American recipient race/ethnicity (HR 1.60; p=0.03) were associated with allograft failure. Kidneys from African American deceased donors with two APOL1 nephropathy variants reproducibly associate with higher risk for allograft failure after transplantation. These findings warrant consideration of rapidly genotyping deceased African American kidney donors for APOL1 risk variants at organ recovery and incorporation of results into allocation and informed-consent processes.
doi:10.1111/ajt.13223
PMCID: PMC4784684  PMID: 25809272
15.  Deceased donor multidrug resistance protein 1 and caveolin 1 gene variants may influence allograft survival in kidney transplantation 
Kidney international  2015;88(3):584-592.
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 1,233 resultant kidney transplantations, adjusting for recipient age, sex, ethnicity, cold ischemia time, PRA, HLA 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.
doi:10.1038/ki.2015.105
PMCID: PMC4556550  PMID: 25853335
African American; allograft failure; ABCB1; APOL1; CAV1; kidney transplantation
16.  Baseline Characteristics of African Americans in the Systolic Blood Pressure Intervention Trial (SPRINT) 
The Systolic Blood Pressure Intervention Trial (SPRINT) will compare treatment to a systolic blood pressure goal of <120 mmHg to treatment to the currently recommended goal of <140 mmHg for effects on incident cardiovascular, renal, and neurologic outcomes including cognitive decline.
Objectives
The objectives of this analysis are to compare baseline characteristics of African American (AA) and non-AA SPRINT participants and explore factors associated with uncontrolled blood pressure (BP) by race.
Methods
SPRINT enrolled 9,361 hypertensive participants over age 50. This cross-sectional analysis examines sociodemographics, baseline characteristics, and study measures among AAs compared to non-AAs.
Results
AAs made up 31% of participants. AAs (compared to non-AAs) were younger and less frequently male, had less education, and were more likely uninsured or covered by Medicaid. In addition, AAs scored lower on the cognitive screening test when compared to non-AAs. Multivariable logistic regression analysis found BP control rates to <140/90 mmHg were higher for AAs who were male, had higher number of chronic diseases, were on diuretic treatment, and had better medication adherence.
Conclusion
SPRINT is well poised to examine the effects of SBP targets on clinical outcomes as well as predictors influencing BP control in AAs.
doi:10.1016/j.jash.2015.06.012
PMCID: PMC4573272  PMID: 26320890
Hypertension; Clinical Trials; and African Americans
17.  Cerebral Structural Changes in Diabetic Kidney Disease: African American–Diabetes Heart Study MIND 
Diabetes Care  2014;38(2):206-212.
OBJECTIVE
Albuminuria and reduced kidney function are associated with cognitive impairment. Relationships between nephropathy and cerebral structural changes remain poorly defined, particularly in African Americans (AAs), a population at higher risk for both cognitive impairment and diabetes than European Americans. We examined the relationship between urine albumin:creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), and cerebral MRI volumes in 263 AAs with type 2 diabetes.
RESEARCH DESIGN AND METHODS
Cross-sectional associations between renal parameters and white matter (WM), gray matter (GM), hippocampal, and WM lesion (WML) volumes were assessed using generalized linear models adjusted for age, education, sex, BMI, hemoglobin A1c (HbA1c) level, and hypertension.
RESULTS
Participants had a mean (SD) age of 60.2 years (9.7 years), and 62.7% were female. Mean diabetes duration was 14.3 years (8.9 years), HbA1c level was 8.2% (2.2%; 66 mmol/mol), eGFR was 86.0 mL/min/1.73 m2 (23.2 mL/min/1.73 m2), and UACR was 155.8 mg/g (542.1 mg/g; median 8.1 mg/g). Those with chronic kidney disease (CKD) (eGFR <60 mL/min/1.73 m2 or UACR >30 mg/g) had smaller GM and higher WML volumes. Higher UACR was significantly associated with higher WML volume and greater atrophy (larger cerebrospinal fluid volumes), and smaller GM and hippocampal WM volumes. A higher eGFR was associated with larger hippocampal WM volumes. Consistent with higher WML volumes, participants with CKD had significantly poorer processing speed and working memory. These findings were independent of glycemic control.
CONCLUSIONS
We found albuminuria to be a better marker of cerebral structural changes than eGFR in AAs with type 2 diabetes. Relationships between albuminuria and brain pathology may contribute to poorer cognitive performance in patients with mild CKD.
doi:10.2337/dc14-1231
PMCID: PMC4302263  PMID: 25205141
18.  Structural and functional assessment of the brain in European Americans with mild-to-moderate kidney disease: Diabetes Heart Study-MIND 
Nephrology Dialysis Transplantation  2015;30(8):1322-1329.
Background
Advanced chronic kidney disease (CKD) is associated with altered cerebral structure and function. Relationships between mild-to-moderate CKD and brain morphology and cognitive performance were evaluated in European Americans (EAs).
Methods
A total of 478 EAs with estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m2 and urine albumin:creatinine ratio (UACR) < 300 mg/g, most with type 2 diabetes (T2D), were included. Measures of total intracranial volume (TICV), cerebrospinal fluid volume, total white matter volume (TWMV), total gray matter volume (TGMV), total white matter lesion volume (TWMLV), hippocampal white matter volume (HWMV) and hippocampal gray matter volume (HGMV) were obtained with magnetic resonance imaging. Cognitive testing included memory (Rey Auditory Visual Learning Test), global cognition (Modified Mini-Mental State Examination) and executive function (Stroop Task, Semantic Fluency, Digit Symbol Substitution Test). Associations with CKD were assessed using log-transformed eGFR and UACR, adjusted for age, sex, body mass index, smoking, hemoglobin A1c, blood pressure, diabetes duration, cardiovascular disease and education.
Results
Participants were 55.2% female, 78.2% had T2D; mean ± SD age 67.6 ± 9.0 years, T2D duration 16.4 ± 6.5 years, eGFR 92.0 ± 22.3 mL/min/1.73 m2 and UACR 23.8 ± 39.6 mg/g. In adjusted models, eGFR was negatively associated with TICV only in participants with T2D [parameter estimate (β): −72.2, P = 0.002]. In non-diabetic participants, inverse relationships were observed between eGFR and HGMV (β: −1.0, P = 0.03) and UACR and normalized TWMLV (β: −0.2, P = 0.03). Kidney function and albuminuria did not correlate with cognitive testing.
Conclusions
In EAs with mild CKD enriched for T2D, brain structure and cognitive performance were generally not impacted. Longitudinal studies are necessary to determine when cerebral structural changes and cognitive dysfunction develop with progressive CKD in EAs.
doi:10.1093/ndt/gfv030
PMCID: PMC4513893  PMID: 25722384
albuminuria; brain; cognitive function; kidney disease; magnetic resonance imaging
19.  Analysis of a Cardiovascular Disease Genetic Risk Score in the Diabetes Heart Study 
Acta diabetologica  2015;52(4):743-751.
Aims
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 (GWAS) 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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1007/s00592-015-0720-5
PMCID: PMC4506855  PMID: 25700702
Type 2 diabetes; mortality; coronary artery calcification; genetic risk score
20.  Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function 
Pattaro, Cristian | Teumer, Alexander | Gorski, Mathias | Chu, Audrey Y. | Li, Man | Mijatovic, Vladan | Garnaas, Maija | Tin, Adrienne | Sorice, Rossella | Li, Yong | Taliun, Daniel | Olden, Matthias | Foster, Meredith | Yang, Qiong | Chen, Ming-Huei | Pers, Tune H. | Johnson, Andrew D. | Ko, Yi-An | Fuchsberger, Christian | Tayo, Bamidele | Nalls, Michael | Feitosa, Mary F. | Isaacs, Aaron | Dehghan, Abbas | d’Adamo, Pio | Adeyemo, Adebowale | Dieffenbach, Aida Karina | Zonderman, Alan B. | Nolte, Ilja M. | van der Most, Peter J. | Wright, Alan F. | Shuldiner, Alan R. | Morrison, Alanna C. | Hofman, Albert | Smith, Albert V. | Dreisbach, Albert W. | Franke, Andre | Uitterlinden, Andre G. | Metspalu, Andres | Tonjes, Anke | Lupo, Antonio | Robino, Antonietta | Johansson, Åsa | Demirkan, Ayse | Kollerits, Barbara | Freedman, Barry I. | Ponte, Belen | Oostra, Ben A. | Paulweber, Bernhard | Krämer, Bernhard K. | Mitchell, Braxton D. | Buckley, Brendan M. | Peralta, Carmen A. | Hayward, Caroline | Helmer, Catherine | Rotimi, Charles N. | Shaffer, Christian M. | Müller, Christian | Sala, Cinzia | van Duijn, Cornelia M. | Saint-Pierre, Aude | Ackermann, Daniel | Shriner, Daniel | Ruggiero, Daniela | Toniolo, Daniela | Lu, Yingchang | Cusi, Daniele | Czamara, Darina | Ellinghaus, David | Siscovick, David S. | Ruderfer, Douglas | Gieger, Christian | Grallert, Harald | Rochtchina, Elena | Atkinson, Elizabeth J. | Holliday, Elizabeth G. | Boerwinkle, Eric | Salvi, Erika | Bottinger, Erwin P. | Murgia, Federico | Rivadeneira, Fernando | Ernst, Florian | Kronenberg, Florian | Hu, Frank B. | Navis, Gerjan J. | Curhan, Gary C. | Ehret, George B. | Homuth, Georg | Coassin, Stefan | Thun, Gian-Andri | Pistis, Giorgio | Gambaro, Giovanni | Malerba, Giovanni | Montgomery, Grant W. | Eiriksdottir, Gudny | Jacobs, Gunnar | Li, Guo | Wichmann, H.-Erich | Campbell, Harry | Schmidt, Helena | Wallaschofski, Henri | Völzke, Henry | Brenner, Hermann | Kroemer, Heyo K. | Kramer, Holly | Lin, Honghuang | Leach, I. Mateo | Ford, Ian | Guessous, Idris | Rudan, Igor | Prokopenko, Inga | Borecki, Ingrid | Heid, Iris M. | Kolcic, Ivana | Persico, Ivana | Jukema, J. Wouter | Wilson, James F. | Felix, Janine F. | Divers, Jasmin | Lambert, Jean-Charles | Stafford, Jeanette M. | Gaspoz, Jean-Michel | Smith, Jennifer A. | Faul, Jessica D. | Wang, Jie Jin | Ding, Jingzhong | Hirschhorn, Joel N. | Attia, John | Whitfield, John B. | Chalmers, John | Viikari, Jorma | Coresh, Josef | Denny, Joshua C. | Karjalainen, Juha | Fernandes, Jyotika K. | Endlich, Karlhans | Butterbach, Katja | Keene, Keith L. | Lohman, Kurt | Portas, Laura | Launer, Lenore J. | Lyytikäinen, Leo-Pekka | Yengo, Loic | Franke, Lude | Ferrucci, Luigi | Rose, Lynda M. | Kedenko, Lyudmyla | Rao, Madhumathi | Struchalin, Maksim | Kleber, Marcus E. | Cavalieri, Margherita | Haun, Margot | Cornelis, Marilyn C. | Ciullo, Marina | Pirastu, Mario | de Andrade, Mariza | McEvoy, Mark A. | Woodward, Mark | Adam, Martin | Cocca, Massimiliano | Nauck, Matthias | Imboden, Medea | Waldenberger, Melanie | Pruijm, Menno | Metzger, Marie | Stumvoll, Michael | Evans, Michele K. | Sale, Michele M. | Kähönen, Mika | Boban, Mladen | Bochud, Murielle | Rheinberger, Myriam | Verweij, Niek | Bouatia-Naji, Nabila | Martin, Nicholas G. | Hastie, Nick | Probst-Hensch, Nicole | Soranzo, Nicole | Devuyst, Olivier | Raitakari, Olli | Gottesman, Omri | Franco, Oscar H | Polasek, Ozren | Gasparini, Paolo | Munroe, Patricia B. | Ridker, Paul M. | Mitchell, Paul | Muntner, Paul | Meisinger, Christa | Smit, Johannes H. | Kovacs, Peter | Wild, Philipp S. | Froguel, Philippe | Rettig, Rainer | Magi, Reedik | Biffar, Reiner | Schmidt, Reinhold | Middelberg, Rita PS | Carroll, Robert J. | Penninx, Brenda W. | Scott, Rodney J. | Katz, Ronit | Sedaghat, Sanaz | Wild, Sarah H. | Kardia, Sharon L.R. | Ulivi, Sheila | Hwang, Shih-Jen | Enroth, Stefan | Kloiber, Stefan | Trompet, Stella | Stengel, Benedicte | Hancock, Stephen J. | Turner, Stephen T. | Rosas, Sylvia E. | Stracke, Sylvia | Harris, Tamara B. | Zeller, Tanja | Zemunik, Tatijana | Lehtimäki, Terho | Illig, Thomas | Aspelund, Thor | Nikopensius, Tiit | Esko, Tonu | Tanaka, Toshiko | Gyllensten, Ulf | Völker, Uwe | Emilsson, Valur | Vitart, Veronique | Aalto, Ville | Gudnason, Vilmundur | Chouraki, Vincent | Chen, Wei-Min | Igl, Wilmar | März, Winfried | Koenig, Wolfgang | Lieb, Wolfgang | Loos, Ruth J. F. | Liu, Yongmei | Snieder, Harold | Pramstaller, Peter P. | Parsa, Afshin | O’Connell, Jeffrey R. | Susztak, Katalin | Hamet, Pavel | Tremblay, Johanne | de Boer, Ian H. | Böger, Carsten A. | Goessling, Wolfram | Chasman, Daniel I. | Köttgen, Anna | Kao, WH Linda | Fox, Caroline S.
Nature communications  2016;7:10023.
Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, nineteen associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biologic pathways.
doi:10.1038/ncomms10023
PMCID: PMC4735748  PMID: 26831199
21.  Response to “JC polyoma virus and kidney disease” 
Kidney international  2014;85(5):1242-1243.
doi:10.1038/ki.2014.40
PMCID: PMC4143177  PMID: 24786886
22.  Kidney disease and cognitive function: African American-Diabetes Heart Study MIND 
American journal of nephrology  2014;40(3):200-207.
Aims
Albuminuria and reduced estimated glomerular filtration rate (eGFR) associate with poorer cognitive performance in European-ancestry populations with advanced nephropathy; relationships in African Americans (AAs) with type 2 diabetes (T2D) are less clear. Tests of cognitive performance, urine albumin:creatinine ratio (UACR), and CKD-EPI eGFR were measured in unrelated AAs with T2D to determine relationships.
Methods
Cross-sectional analysis of 263 unrelated AAs with T2D recruited in the African American-Diabetes Heart Study (AA-DHS) MIND. Global cognitive function (mini-mental state exam [3MSE] and Montreal Cognitive Assessment [MoCA]), memory (Rey Auditory Verbal Learning Test [RAVLT]), executive function (Stroop, verbal fluency for animals, and Digit Symbol Copy [DSC]), UACR, and eGFR were determined. Relationships between cognitive tests and renal parameters were assessed using multivariate models, adjusted for age, gender, body mass index, hemoglobin A1c, level of education, hypertension, and LDL cholesterol.
Results
Participants had a mean±SD age of 60.2±9.7 years, 62.7% were female, T2D duration was 14.3±8.9 years, eGFR 86.0±23.2 ml/min/1.73m2, and UACR 155.8±542.1 (median 8.1) mg/g. In adjusted models, higher UACR was associated with worse 3MSE (p=0.014), MoCA (p=0.0089), DSC (p=0.0004), Stroop performance time (p=0.003), Stroop errors (p=0.032), and Stroop interference (p=0.026). Higher eGFR was associated with better performance on DSC (p=0.0071).
Conclusions
In AAs with T2D, albuminuria and eGFR were associated with cognitive function, even in mild kidney disease. These data stress the need for interventions to prevent cognitive decline well before the late stages of kidney disease.
doi:10.1159/000367669
PMCID: PMC4216628  PMID: 25323981
albuminuria; glomerular filtration rate; cognition; type 2 diabetes; African Americans; kidney disease
23.  Should kidney donors be genotyped for APOL1 risk alleles? 
Kidney international  2015;87(4):671-673.
doi:10.1038/ki.2015.16
PMCID: PMC4382897  PMID: 25826538
African American; APOL1; FSGS; kidney donor; chronic kidney disease; outcomes
24.  The impact of APOL1, CAV1, and ABCB1 gene variants on outcomes in kidney transplantation: donor and recipient effects 
Dramatic improvements have been seen in short term kidney allograft survival over recent decades with introduction of more potent immunosuppressant medications and regimens. Unfortunately improvements in long term graft survival have lagged behind. The genomics revolution is providing new insights regarding the potential impact of kidney donor genotypes on long term graft survival. Variation in the donor apolipoprotein L1 (APOL1), caveolin 1 (CAV1), and multi-drug resistance 1 encoding P-glycoprotein genes (ABCB1) are all associated with graft survival after kidney transplantation. Although the precise mechanisms whereby these donor gene variants confer risk for graft loss have yet to be determined, these findings provide novel opportunities for modifying interactive environmental factors and optimizing kidney allocation with the ultimate goal of improving long term graft survival rates.
doi:10.1007/s00467-013-2531-7
PMCID: PMC3809028  PMID: 23748364
ABCB1; APOL1; CAV1; genetics; kidney disease; transplantation
25.  Genetic Association of CD247 (CD3ζ) with SLE in a Large-Scale Multiethnic Study 
Genes and immunity  2015;16(2):142-150.
A classic T-cell phenotype in Systemic lupus erythematosus (SLE) is the downregulation and replacement of the CD3ζ chain that alters TCR 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 multi-ethnic population. We typed 44 contiguous CD247 SNPs in 8 922 SLE patients and 8 077 controls from four ethnically distinct populations. The strongest associations were found in the Asian population (11 SNPs in intron 1, 4.99×10−4
doi:10.1038/gene.2014.73
PMCID: PMC4371129  PMID: 25569266

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