Nondiabetic African Americans Research Articles

253-LB: Ethnic Differences in Pancreatic Hormone Secretion in Health and T2D

Purpose: We tested the hypothesis that a critical biologic determinant of T2D disparities is based on ethnicity-related differences in pancreatic islet function. Methods: Utilizing donor tissues from the NIDDK-funded Human Pancreas Analysis Program (HPAP) , we examined both insulin and glucagon secretion from nondiabetic and diabetic Caucasian and African American donor islets. Initially, a physiological amino acid mixture was used to stimulate glucagon secretion, followed by low and high glucose to stimulate insulin secretion and suppress glucagon secretion. During the high glucose step, IBMX (0.1 mM) is added to potentiate secretion of both hormones. Insulin and glucagon concentration in perifusates and islet extracts was measured by radioimmunoassay or ELISA. Statistical comparisons were drawn by repeated measures ANOVA. Results: Comparing nondiabetic islets, we observed overlapping insulin secretion profiles between both ethnicities; however, glucagon secretion was distinctly greater in both nondiabetic African American (+111%) islets compared to nondiabetic Caucasian islets, under all interventions. In T2D, the reduction in insulin secretion was significantly greater in African American T2D donors (high glucose -76%; IBMX -76%) compared to Caucasian T2D donors (high glucose -47%; IBMX -50%) . More strikingly, glucagon secretion in T2D donors was markedly different based on ethnicity. Whereas Caucasian T2D islets exhibited a similar baseline of glucagon secretion compared to Caucasian controls, there was a marked reduction of glucagon secretion overall in African American T2D donors (-70%) compared to their corresponding controls. The largest detected difference was in IBMX-potentiation of glucagon secretion, which is higher in Caucasian T2D donors (+103%) but significantly decreased in African American T2D donors (-76%) . Preliminary analysis of hormone content in a subset of the donor islet preparations revealed no differences according to ethnicity. Conclusions: We propose that ethnicity-related differences in nondiabetic islet function may contribute to the enhanced risk of T2D. Disclosure N. M. Doliba: None. M. Brissova: None. K. H. Kaestner: None. D. A. Stoffers: Other Relationship; Biomarin, Correlagen. J. Roman: None. A. V. Rozo: None. W. Qin: None. C. Liu: None. A. Naji: None. M. R. Rickels: Advisory Panel; Sernova, Corp., Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Consultant; L-Nutra Inc. M. A. Atkinson: None. A. C. Powers: None. Funding This work is supported by 3UC4-112217-01S1 and U01-DK123594-02, UC4-DK-112217, UC4-DK-112232, and U01-DK-123716.

Apolipoprotein L1 Gene Testing Comes of Age.

The landscape in nephrology changed dramatically in 2010 with the discovery of genetic association between two coding renal-risk variants (RRVs) in the apo L1 gene ( APOL1 ) and CKD (1). The APOL1 G1 and G2 nephropathy-associated variants arose <10,000 years ago and are present almost exclusively in individuals with recent African ancestry, those with similar genetic makeup to populations currently residing in Africa. The frequencies of these variants rapidly increased, likely due to positive selection for protection afforded from Trypanosoma brucei rhodesiense infection, a parasite causing African sleeping sickness. Due to the trans-Atlantic slave trade, approximately 39% of African Americans possess one APOL1 RRV and 13% possess two. In contrast, hemoglobin S ( HbS ) gene variants are also common in African Americans; however, <8% inherit one or two HbS variants. Ancestry-based variation in APOL1 contributes to the excess risk of ESKD in African Americans, more rapid failure of transplanted kidneys from African American deceased donors, and higher rates of nephropathy in African American living-kidney donors (2,3). The kidney disease historically attributed to hypertension in nondiabetic African Americans with low-level proteinuria also proved to be APOL1 associated, with biopsy findings including solidified glomerulosclerosis and thyroidization-type tubular atrophy (4). In addition, the APOL1 spectrum of kidney disease includes FSGS, HIV-associated nephropathy (HIVAN), severe lupus nephritis, and sickle cell nephropathy (5). APOL1 RRVs are associated with nephropathy in individuals with recent African ancestry residing in the United States, Africa, Europe, South America, and the Caribbean. Beyond genetic association, APOL1 RRVs were shown to directly cause kidney disease in a transgenic mouse model (6). Recent studies show that APOL1 kidney risk variants do not associate with cardiovascular disease (7,8). Despite the evidence that APOL1 risk variants lead to kidney disease, the precise pathogenic mechanisms are not known. Data suggest a toxic gain …

1703-P: Altered DNA-Methylation Modulates Adipose Tissue Gene Expression and Is Associated with Insulin Resistance in African Americans

Altered DNA-methylation has a well-documented mechanistic role in modulating gene expression. However, its contribution in modulating adipose tissue gene expression and insulin sensitivity (SI) in African Americans (AAs) is unknown. To understand the role of differential DNA methylation in determining SI we selected 12 insulin resistant (IR) and 12 insulin sensitive (IS) individuals from a cohort 253 nondiabetic AAs. IR and IS individuals were selected from the extremes of the distribution of SI (1.49±0.69 vs. 8.23±4.48), and expression levels of insulin resistance-associated transcripts in AAGMEx cohort. Reduced representation bisulfite sequencing (RRBS; &amp;gt;30M read) was used to quantify epigenome-wide DNA methylation levels in adipose DNA samples. To determine differentially methylated sites (DMS) linear regressions adjusting for age and sex were used to test for DMS at 774,095 CpG sites (≥ 10X coverage) passing quality control. We identified 8387 hypermethylated and 2532 hypomethylated autosomal DMS in IR individuals (mean methylation difference ≥5% and genomic control corrected-p ≤0.05). Among these DMS, 6414 were annotated to exon, intron or promoter regions of 3923 genes. Highest number of DMS (22, including 20 hypermethylated (5.5-30.2%) DMS) were annotated to PRDM16, a transcription co-factor critical for the development of brown adipocytes. We merged the DMS 3923 genes with 663 differentially expressed transcripts (GC-p≤0.05 and fold change ≥1.2) and identified 123 IR-associated genes with DMS. Genes containing hypermethylated CpG sites and downregulated expression in IR were enriched for long-chain fatty-acyl-CoA biosynthetic process (B-H p=0.0013, includes ELOVL6, ACSF2, ACOT2, FASN, and TECR), and mitochondrion (B-H p=0.0016, 14 genes). In summary, differential DNA-methylation of a subset of genes in adipose tissue modulate expression of transcripts in key biological pathways and may determine insulin sensitivity. Disclosure N.K. Sharma: None. M.E. Comeau: None. C.D. Langefeld: None. S.K. Das: None. Funding American Diabetes Association (1-18-ICTS-113 to S.K.D.); National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases

JC polyoma viruria associates with protection from chronic kidney disease independently from apolipoprotein L1 genotype in African Americans.

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. 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. 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. 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.

Transcriptional Regulatory Mechanisms in Adipose and Muscle Tissue Associated with Composite Glucometabolic Phenotypes.

ObjectiveTissue-specific gene expression is associated with individual metabolic measures. However, these measures may not reflect the true but latent underlying biological phenotype. This study reports gene expression associations with multi-dimensional gluco-metabolic characterizations of obesity, glucose homeostasis, and lipid traits.MethodsFactor analysis was computed using orthogonal rotation to construct composite phenotypes (CPs) from 23 traits in 256 non-diabetic African Americans. Genome-wide transcript expression data from adipose and muscle were tested for association with CPs, and expression quantitative trait loci (eQTL) were identified by association between cis-SNPs and gene expression.ResultsThe factor analysis identified six CPs. The CPs 1 through 6 individually explained 34%, 12%, 9%, 8%, 6% and 5% of the variation in 23 gluco-metabolic traits studied. There were 3994 and 929 CP–associated transcripts identified in adipose and muscle, respectively; CP2 had the largest number of associated transcripts. Pathway analysis identified multiple canonical pathways from the CP-associated transcripts. In adipose and muscle, significant cis-eQTL were identified for 558 and 164 CP-associated transcripts (q-value <0.01), respectively.ConclusionsAdipose and muscle transcripts comprehensively define pathways involved in regulating gluco-metabolic disorders. Cis-eQTLs for CP-associated eGenes may act as primary causal determinants of gluco-metabolic phenotypes by regulating transcription of key genes.

Genetic regulation of adipose tissue transcript expression is involved in modulating serum triglyceride and HDL-cholesterol

Dyslipidemia is a major contributor to the increased cardiovascular disease and mortality associated with obesity and type 2 diabetes. We hypothesized that variation in expression of adipose tissue transcripts is associated with serum lipid concentrations in African Americans (AAs), and common genetic variants regulate expression levels of these transcripts. Fasting serum lipid levels, genome-wide transcript expression profiles of subcutaneous adipose tissue, and genome-wide SNP genotypes were analyzed in a cohort of non-diabetic AAs (N=250). Serum triglyceride (TRIG) and high density lipoprotein-cholesterol (HDL-C) levels were associated (FDR<0.01) with expression level of 1021 and 1875 adipose tissue transcripts, respectively, but none associated with total cholesterol or LDL-C levels. Serum HDL-C-associated transcripts were enriched for salient biological pathways, including branched-chain amino acid degradation, and oxidative phosphorylation. Genes in immuno-inflammatory pathways were activated among individuals with higher serum TRIG levels. We identified significant cis-regulatory SNPs (cis-eSNPs) for 449 serum lipid-associated transcripts in adipose tissue. The cis-eSNPs of 12 genes were nominally associated (p<0.001) with serum lipid level in genome wide association studies in Global Lipids Genetics Consortium (GLGC) cohorts. Allelic effect direction of cis-eSNPs on expression of MARCH2, BEST1 and TMEM258 matched with effect direction of these SNP alleles on serum TRIG or HDL-C levels in GLGC cohorts. These data suggest that expressions of serum lipid-associated transcripts in adipose tissue are dependent on common cis-eSNPs in African Americans. Thus, genetically-mediated transcriptional regulation in adipose tissue may play a role in reducing HDL-C and increasing TRIG in serum.

Mapping adipose and muscle tissue expression quantitative trait loci in African Americans to identify genes for type 2 diabetes and obesity.

Relative to European Americans, type 2 diabetes (T2D) is more prevalent in African Americans (AAs). Genetic variation may modulate transcript abundance in insulin-responsive tissues and contribute to risk; yet, published studies identifying expression quantitative trait loci (eQTLs) in African ancestry populations are restricted to blood cells. This study aims to develop a map of genetically regulated transcripts expressed in tissues important for glucose homeostasis in AAs, critical for identifying the genetic etiology of T2D and related traits. Quantitative measures of adipose and muscle gene expression, and genotypic data were integrated in 260 non-diabetic AAs to identify expression regulatory variants. Their roles in genetic susceptibility to T2D, and related metabolic phenotypes, were evaluated by mining GWAS datasets. eQTL analysis identified 1971 and 2078 cis-eGenes in adipose and muscle, respectively. Cis-eQTLs for 885 transcripts including top cis-eGenes CHURC1, USMG5, and ERAP2 were identified in both tissues. 62.1% of top cis-eSNPs were within ±50kb of transcription start sites and cis-eGenes were enriched for mitochondrial transcripts. Mining GWAS databases revealed association of cis-eSNPs for more than 50 genes with T2D (e.g. PIK3C2A, RBMS1, UFSP1), gluco-metabolic phenotypes (e.g. INPP5E, SNX17, ERAP2, FN3KRP), and obesity (e.g. POMC, CPEB4). Integration of GWAS meta-analysis data from AA cohorts revealed the most significant association for cis-eSNPs of ATP5SL and MCCC1 genes, with T2D and BMI, respectively. This study developed the first comprehensive map of adipose and muscle tissue eQTLs in AAs (publically accessible at https://mdsetaa.phs.wakehealth.edu ) and identified genetically regulated transcripts for delineating genetic causes of T2D, and related metabolic phenotypes.

Associations between Markers of Glucose and Insulin Function and Cognitive Function in Healthy African American Elders.

Glucose and insulin are important moderators of cognitive function. African Americans have poorer glycemic control across the glycemic spectrum and are at increased risk for type 2 diabetes and poor cognitive health. It is unclear which glucoregulatory markers predict cognitive function in this at-risk population. The purpose of this study was to examine the association between cognitive function and common markers of glucoregulation in non-diabetic African Americans elders. Thirty-four, community-dwelling African Americans, aged 50-75 years completed cognitive testing and blood collection as part of a health screening assessment. Cognitive outcomes were composite scores derived from neuropsychological tests of executive function and verbal memory. Linear regression was used to examine relationships between cognitive composite scores and fasting blood levels of glucose, insulin, and hemoglobin A1C, with adjustments for age, education, body mass index, and antihypertensive medication use. Fasting plasma glucose was negatively associated with executive function (β=-0.41, p=0.03). There was a trend of an association between fasting plasma glucose and verbal memory (β=-0.34, p=0.06). Fasting insulin and hemoglobin A1c were not associated with cognitive function. High non-diabetic fasting glucose levels were associated with poorer executive function and verbal memory. These results provide preliminary support for proactive glucose control in older African Americans even before glycemic criteria for type 2 diabetes are met. Our findings suggests that high-normal FPG levels may represent an early red-flag to signify increased risk of cognitive impairment or decline.

APOL1 associations with nephropathy, atherosclerosis, and all-cause mortality in African Americans with type 2 diabetes

Albuminuria and reduced eGFR associate with two apolipoprotein L1 gene (APOL1) variants in non-diabetic African Americans. Whether APOL1 associates with subclinical atherosclerosis and survival remains unclear. To determine this, 717 African American-Diabetes Heart Study participants underwent computed tomography to determine coronary artery, carotid artery, and aorta calcified atherosclerotic plaque mass scores in addition to the urine albumin:creatinine ratio (UACR), eGFR, and C-reactive protein. Associations between mass scores and APOL1 were assessed adjusting for age, gender, African ancestry, BMI, HbA1c, smoking, hypertension, use of statins and ACE inhibitors, albuminuria, and eGFR. Participants were 58.9% female with mean age 56.5 years, eGFR 89.5 ml/min/1.73m2, UACR 169.6 mg/g, coronary artery, carotid artery and aorta calcified plaque mass scores of 610, 171 and 5378, respectively. In fully adjusted models, APOL1 risk variants were significantly associated with lower levels of carotid artery calcified plaque (β −0.42, SE 0.18, dominant model), and marginally lower coronary artery plaque (β −0.36, SE 0.21; dominant model), but not with aorta calcified plaque, C-reactive protein, UACR, or eGFR. After a mean follow-up of 5.0 years, 89 participants died. APOL1 nephropathy risk variants were significantly associated with improved survival (hazard ratio 0.67 for 1 copy; 0.44 for 2 copies). Thus, APOL1 nephropathy variants associate with lower levels of subclinical atherosclerosis and reduced risk of death in African Americans with type 2 diabetes mellitus.

Apolipoprotein L1 gene variants associate with prevalent kidney but not prevalent cardiovascular disease in the Systolic Blood Pressure Intervention Trial

Apolipoprotein L1 gene (APOL1) G1 and G2 coding variants are strongly associated with chronic kidney disease (CKD) in African Americans. Here APOL1 association was tested with baseline estimated glomerular filtration rate (eGFR), urine albumin:creatinine ratio (UACR), and prevalent cardiovascular disease (CVD) in 2,571 African Americans from the Systolic Blood Pressure Intervention Trial (SPRINT), a trial assessing effects of systolic blood pressure reduction on renal and CVD outcomes. Logistic regression models that adjusted for potentially important confounders tested for association between APOL1 risk variants and baseline clinical CVD (myocardial infarction, coronary or carotid artery revascularization) and CKD (eGFR under 60 ml/min/1.73m2 and/or UACR over 30 mg/g). African American SPRINT participants were 45.3% female with mean (median) age of 64.3 (63) years, mean arterial pressure 100.7 (100) mmHg, eGFR 76.3 (77.1) ml/min/1.73m2, UACR 49.9 (9.2) mg/g, and 8.2% had clinical CVD. APOL1 (recessive inheritance) was positively associated with CKD (odds ratio 1.37, 95% confidence interval 1.08–1.73) and log UACR estimated slope [β] 0.33) and negatively associated with eGFR (β −3.58), all significant. APOL1 risk variants were not significantly associated with prevalent CVD (1.02, 0.82–1.27). Thus, SPRINT data show that APOL1 risk variants are associated with mild CKD but not prevalent CVD in African American with a UACR under 1000 mg/g.

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Clin. Pract. (2014) 11(2), 139–143 ISSN 2044-9038 part of Parsa A, Kao WH, Xie D et al.; AASK Study Investigators; CRIC Study Investigators. APOL1 risk variants, race and progression of chronic kidney disease. N. Engl. J. Med. 369(23), 2183–2196 (2013). For decades, it has been observed that African–Americans experience a more rapid progression of chronic kidney disease (CKD) in virtually every etiology of kidney disease. This has been ascribed to more severe hypertension, poor risk factor control and noncompliance. Heretofore, a search for genetic determinants among African–Americans has been unrevealing. High-density lipoprotein cholesterol particles contain major apolipoproteins A-I and A-II, and minor apolipoproteins, including A-IV, A-V, C-I, C-II, C-III, D, E, F, H, J, L, M, O and P. Polymorphisms of these apolipoproteins have been associated with changes in reverse cholesterol transport function, oxidation and now, most recently, altered catabolism. High-density lipoprotein is filtered in the glomerulus and then catabolized by the proximal tubular cells. A mutant form of apo-L has been described in African–Americans that may have a protective effect against trypanosomes. APOL1 polymorphisms have a prevalence of approximately 30 and 2% among African–Americans and Caucasians, respectively. In this paper, data from two clinical studies, one exclusively in nondiabetic African–Americans with hypertension (AASK) and the other in patients screened for CKD (CRIC), variants in the gene for APOL1 were assessed according to whether they had two high-risk APOL1 variants (APOL1 high-risk group) or 0 or 1 copy (APOL1 low-risk group) [1]. In both studies, among those with and without diabetes, there was a more rapid progression of CKD, including the need for dialysis, in African–Americans with two alleles containing mutant variants of the APOL1 gene. This and other studies suggest that APOL1 variants are associated with a 50–100% increased risk of rapid progression of CKD and may be related to a toxic or adverse process invoked by proximal tubular cell catabolism of this apoprotein. So, in summary, APOL1 genetic abnormalities appear to be a major genetic basis for the difference between rates of progression of CKD between African–Americans and Caucasians.

APOL1 and Progression of Nondiabetic Nephropathy

African Americans are disproportionately affected by most common causes of nephropathy and develop ESRD at rates approximately 3.5 times higher than those in European Americans.[1][1] Population ancestry-based disparities in nondiabetic nephropathy have recently been attributed to two variants in

Neighborhood Disadvantage, Neighborhood Safety and Cardiometabolic Risk Factors in African Americans: Biosocial Associations in the Jackson Heart Study

ObjectiveWe examined associations between neighborhood socioeconomic disadvantage, perceived neighborhood safety and cardiometabolic risk factors, adjusting for health behaviors and socioeconomic status (SES) among African Americans.MethodsStudy participants were non-diabetic African Americans (n = 3,909) in the baseline examination (2000–2004) of the Jackson Heart Study. We measured eight risk factors: the metabolic syndrome, its five components, insulin resistance and cardiovascular inflammation. We assessed neighborhood socioeconomic disadvantage with US Census 2000 data. We assessed perceived neighborhood safety, health behaviors and SES via survey. We used generalized estimating equations to estimate associations with a random intercept model for neighborhood effects.ResultsAfter adjustment for health behaviors and SES, neighborhood socioeconomic disadvantage was associated with the metabolic syndrome in women (PR 1.13, 95% CI 1.01, 1.27). Lack of perceived safety was associated with elevated glucose (OR 1.36, 95% CI 1.03, 1.80) and waist circumference (PR 1.06, 95% CI 1.02, 1.11) among women, and with elevated glucose (PR 1.30, 95% CI 1.02, 1.66) and insulin resistance (PR 1.25, 95% CI 1.08, 1.46) among men.ConclusionsNeighborhood socioeconomic disadvantage and perceived safety should be considered as targets for intervention to reduce cardiometabolic risks among African Americans.

Endothelial dysfunction: The contribution of diabetes mellitus to the risk factor burden in a high risk population

Background: Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality in Western societies and are rapidly becoming a worldwide health problem. African-Americans have increased morbidity and mortality rates from CVD. Our study aimed to assess the effects of the CVD risk factors burden alone versus with diabetes mellitus in a high riskCVDpopulation. Methods: The two study groups consisted of thirty seven diabetics and thirty seven non-diabetic African-Americans aged ≥55 years without clinical atherosclerosis having similar cardiovascular risk factors (age, hypertension, hypercholesterolemia, smoking, and body mass index) except for diabetes mellitus. Brachial artery flow-mediated dilation (FMD), Nitroglycerin-mediated dilatation (NMD) and carotid intima-media thickness (IMT) were recorded in all subjects. Results: Endothelial function as assessed by the brachial artery FMD was significantly impaired in the diabetic group compared to the non-diabetic group (7.8 ± 5 vs 3.3 ± 4; p = 0.0001). There were no differences in neither Nitroglycerin-mediated dilatation (NMD) nor carotid intima-media thickness (IMT) in the diabetic and non-diabetic groups. Conclusion: The contribution of diabetes to the development of endothelial dysfunction in subjects with clustering of CVD risk factors may be early as indicated by significant functional changes preceeding structural vascular changes..

933 IMPACT OF DIABETES ON VASCULAR HEALTH

Background: Hypertension (HTN) and Diabetes (DM) constitute a potent duet for the development of atherosclerotic and hypertensive-renal cardiovascular diseases. Increase pulse pressure (PP), a marker of vascular health, is observed in some hypertensive subjects with DM. We investigate the impact of DM on vascular structure and function as reflected by carotid intima media thickness (IMT), brachial flow mediated dilatation (FMD) and the mechanism of a disproportionate increase in systolic and decrease in diastolic pressure resulting in an increase PP. Methods: We studied diabetic and non-diabetic African-Americans aged ≥ 55 years without clinical CVD and matched for age, gender, smoking, BMI, LDL, TG. Ischemic endothelial FMD was measured after testing for vascular dilatation with nitroglycerin, NMD. Differences in parameters are compared using the t-test.Conclusion: The significantly greater PP, a marker of vascular stiffness, and the diminished FMD, an index of vascular health in diabetics may indicate the onset of CVD before the development of clinical symptoms and/or signs.

Genome-wide association study identifies novel loci association with fasting insulin and insulin resistance in African Americans

Insulin resistance (IR) is a key determinant of type 2 diabetes (T2D) and other metabolic disorders. This genome-wide association study (GWAS) was designed to shed light on the genetic basis of fasting insulin (FI) and IR in 927 non-diabetic African Americans. 5 396 838 single-nucleotide polymorphisms (SNPs) were tested for associations with FI or IR with adjustments for age, sex, body mass index, hypertension status and first two principal components. Genotyped SNPs (n = 12) with P < 5 × 10(-6) in African Americans were carried forward for de novo genotyping in 570 non-diabetic West Africans. We replicated SNPs in or near SC4MOL and TCERG1L in West Africans. The meta-analysis of 1497 African Americans and West Africans yielded genome-wide significant associations for SNPs in the SC4MOL gene: rs17046216 (P = 1.7 × 10(-8) and 2.9 × 10(-8) for FI and IR, respectively); and near the TCERG1L gene with rs7077836 as the top scoring (P = 7.5 × 10(-9) and 4.9 × 10(-10) for FI and IR, respectively). In silico replication in the MAGIC study (n = 37 037) showed weak but significant association (adjusted P-value of 0.0097) for rs34602777 in the MYO5A gene. In addition, we replicated previous GWAS findings for IR and FI in Europeans for GCKR, and for variants in four T2D loci (FTO, IRS1, KLF14 and PPARG) which exert their action via IR. In summary, variants in/near SC4MOL, and TCERG1L were associated with FI and IR in this cohort of African Americans and were replicated in West Africans. SC4MOL is under-expressed in an animal model of T2D and plays a key role in lipid biosynthesis, with implications for the regulation of energy metabolism, obesity and dyslipidemia. TCERG1L is associated with plasma adiponectin, a key modulator of obesity, inflammation, IR and diabetes.

The new era of APOL1-associated glomerulosclerosis

The association between apolipoprotein L1 gene (APOL1)variants and non-diabetic chronic kidney disease (CKD)has dramatically altered the landscape in nephrology [1,2]. The pathogenesis of glomerulosclerosis is now betterunderstood, providing the possibility of novel treatmentsand hope for millions with, and at risk of, CKD worldwide[3, 4]. The article by Tzur et al. [5] in the current issue ofNephrology Dialysis Transplantation provides importantnew information in this fast moving field. To put this paperin perspective, it is appropriate to review how APOL1has revolutionized our understanding of non-diabeticglomerulosclerosis.Relative to European Americans (EAs), nephrologistshave observed ‘different renal responses’ to systemic hyper-tension and Type 2 diabetes mellitus in African Americans(AAs) [6]. This vague phenomenon was widely applied toexplain the higher incidence rates of common forms ofend-stage renal disease (ESRD) in AAs compared to EAs.The hypothesis that mild–moderate essential hypertensionwas the proximate cause of ‘hypertensive kidney disease’or arteriolar nephrosclerosis in non-diabetic AAs with low-level proteinuria was deeply ingrained in the literature,despite strong evidence to the contrary [3, 7, 8]. Higher ratesof non-diabetic nephropathy in AAs, relative to EAs, werealso ascribed to differences in socioeconomic status andenvironment between population groups.Three important developments led to identification ofAPOL1 and variants in the adjacent non-muscle myosinheavy chain 9 gene (MYH9), as initiating factors for mostcases of ‘hypertension-attributed’ nephropathy in those withAfrican ancestry, as well as a spectrum of related kidneydiseases in AAs, Hispanic Americans (HAs), Europeansand EAs. The first development was recognition of markedfamilial aggregation of kidney disease. In AA families, clus-tering of disparate forms of ESRD was often present. Thisobservation suggested the presence of an overarching kidneyfailure susceptibility gene inherited independently from sys-temic disorders, such as hypertension, HIV infection, diabe-tes and systemic lupus erythematosus [9–13]. The seconddevelopment was a series of molecular genetic advances,particularly admixture mapping (also called mapping by ad-mixture linkage disequilibrium; MALD) [14]. MALD is apowerful genome-wide method useful to detect associatedgenes in admixed populations, where ancestral populationshave markedly different disease frequencies. AAs are anadmixed population with ~80% African and 20% Europeanancestry, while kidney disease is far more common inAfricans than Europeans. MALD detected linkage betweengenetic markers on Chromosome 22q containing the MYH9and APOL1 genes with focal segmental glomerulosclerosis(FSGS) and HIV-associated collapsing glomerulopathy inAAs [15, 16]. The third development was broad geneticscreening for MYH9 and APOL1 polymorphisms, whosevariants were strongly associated with the clearly definedFSGS phenotype, in large numbers of AAs and HAs withcommon complex forms of ESRD [1, 2, 17]. These sequen-tial developments led to the realization that FSGS,HIV-associated nephropathy, arteriolar nephrosclerosis andhypertension-attributed ESRD were members of a single dis-ease spectrum [18]. This spectrum has expanded to includesickle cell nephropathy [19] and C1q-associated collapsingglomerulopathy [20].It is now apparent that many patients with African an-cestry and ESRD attributed to diabetes or lupus had beenmisdiagnosed, they actually have APOL1-associated FSGS(with coexisting diabetes or lupus) [21, 22]. APOL1 geno-typing has been used to ‘genetically dissect’ cases withdiabetes and ESRD, enriching for those with diabeticnephropathy by removing those with two APOL1 risk var-iants likely with FSGS. This allowed for detection of dia-betic nephropathy genes [23, 24]. Variation in APOL1 isstrongly associated with the kidney disease that has histor-ically been labeled ‘hypertensive’ or arteriolar nephroscle-rosis, as in the African American Study of Kidney Diseaseand Hypertension (AASK) [25]. The strongest APOL1 as-sociation was present in AASK participants with higherbaseline proteinuria and progressive nephropathy [26].Aggressive hypertension control and universal use ofangiotensin-converting enzyme inhibitors failed to reliablyhalt nephropathy progression in AASK, strongly supportingnephropathy initiation from mechanisms other than hyper-tension. It appears that AASK patients predominantly hadfocal global glomerulosclerosis (FGGS) with interstitial and

Genome-wide associated loci influencing interleukin (IL)-10, IL-1Ra, and IL-6 levels in African Americans

Interleukins (ILs) are key mediators of the immune response and inflammatory process. Plasma levels of IL-10, IL-1Ra, and IL-6 are associated with metabolic conditions, show large inter-individual variations, and are under strong genetic control. Therefore, elucidation of the genetic variants that influence levels of these ILs provides useful insights into mechanisms of immune response and pathogenesis of diseases. We conducted a genome-wide association study (GWAS) of IL-10, IL-1Ra, and IL-6 levels in 707 non-diabetic African Americans using 5,396,780 imputed and directly genotyped single nucleotide polymorphisms (SNPs) with adjustment for gender, age, and body mass index. IL-10 levels showed genome-wide significant associations (p < 5 × 10(-8)) with eight SNPs, the most significant of which was rs5743185 in the PMS1 gene (p = 2.30 × 10(-10)). We tested replication of SNPs that showed genome-wide significance in 425 non-diabetic individuals from West Africa, and successfully replicated rs17365948 in the YWHAZ gene (p = 0.02). IL-1Ra levels showed suggestive associations with two SNPs in the ASB3 gene (p = 2.55 × 10(-7)), ten SNPs in the IL-1 gene family (IL1F5, IL1F8, IL1F10, and IL1Ra, p = 1.04 × 10(-6) to 1.75 × 10(-6)), and 23 SNPs near the IL1A gene (p = 1.22 × 10(-6) to 1.63 × 10(-6)). We also successfully replicated rs4251961 (p = 0.009); this SNP was reported to be associated with IL-1Ra levels in a candidate gene study of Europeans. IL-6 levels showed genome-wide significant association with one SNP (RP11-314E23.1; chr6:133397598; p = 8.63 × 10(-9)). To our knowledge, this is the first GWAS on IL-10, IL-1Ra, and IL-6 levels. Follow-up of these findings may provide valuable insight into the pathobiology of IL actions and dysregulations in inflammation and human diseases.

Target Organ Damage in African American Hypertension: Role of APOL1

Apolipoprotein L1 (APOL1) gene association studies and results of the African American Study of Kidney Disease and Hypertension are disproving the longstanding concept that mild to moderate essential hypertension contributes substantially to end-stage renal disease susceptibility in African Americans. APOL1 coding variants underlie a spectrum of kidney diseases, including that attributed to hypertension (labeled arteriolar or hypertensive nephrosclerosis), focal segmental glomerulosclerosis, and HIV-associated nephropathy. APOL1 nephropathy risk variants persist because of protection afforded from the parasite that causes African sleeping sickness. This breakthrough will lead to novel treatments for hypertensive African Americans with low-level proteinuria, for whom effective therapies are lacking. Furthermore, APOL1 nephropathy risk variants contribute to racially variable allograft survival rates after kidney transplantation and assist in detecting nondiabetic forms of nephropathy in African Americans with diabetes. Discovery of APOL1-associated nephropathy was a major success of the genetics revolution, demonstrating that secondary hypertension is typically present in nondiabetic African Americans with nephropathy.

Ethnic differences in glucose disposal, hepatic insulin sensitivity, and endogenous glucose production among African American and European American women

Intravenous glucose tolerance tests have demonstrated lower whole-body insulin sensitivity (SI) among African Americans (AA) compared with European Americans (EA). Whole-body SI represents both insulin-stimulated glucose disposal, primarily by skeletal muscle, and insulin's suppression of endogenous glucose production (EGP) by liver. A mathematical model was recently introduced that allows for distinction between disposal and hepatic SI. The purpose of this study was to examine specific indexes of SI among AA and EA women to determine whether lower whole-body SI in AA may be attributed to insulin action at muscle, liver, or both. Participants were 53 nondiabetic, premenopausal AA and EA women. Profiles of EGP and indexes of Disposal SI and Hepatic SI were calculated by mathematical modeling and incorporation of a stable isotope tracer ([6,6-2H2]glucose) into the intravenous glucose tolerance test. Body composition was assessed by dual-energy x-ray absorptiometry. After adjustment for percentage fat, both Disposal SI and Hepatic SI were lower among AA (P = .009 for both). Time profiles for serum insulin and EGP revealed higher peak insulin response and corresponding lower EGP among AA women compared with EA. Indexes from a recently introduced mathematical model suggest that lower whole-body SI among nondiabetic AA women is due to both hepatic and peripheral components. Despite lower Hepatic SI, AA displayed lower EGP, resulting from higher postchallenge insulin levels. Future research is needed to determine the physiological basis of lower insulin sensitivity among AA and its implications for type 2 diabetes mellitus risk.