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1.  JC polyoma virus interacts with APOL1 in African Americans with non-diabetic nephropathy 
Kidney international  2013;84(6):10.1038/ki.2013.173.
Individuals with HIV infection and two apolipoprotein L1 gene (APOL1) risk variants frequently develop nephropathy. Here we tested whether non-HIV viral infections influence nephropathy risk via interactions with APOL1 by assessing APOL1 genotypes and presence of urine JC and BK polyoma virus and plasma HHV6 and CMV by quantitative polymerase chain reaction. We analyzed 300 samples from unrelated and related first-degree relatives of African Americans with non-diabetic nephropathy using linear and non-linear mixed models to account for familial relationships. The four groups evaluated were APOL1 0/1 versus 2 risk alleles, with or without nephropathy. Urine JCV and BKV were detected in 90 and 29 patients while HHV6 and CMV were rare. Adjusting for family age at nephropathy, gender and ancestry, presence of JCV genomic DNA in urine and APOL1 risk alleles were significantly negatively associated with elevated serum cystatin C, albuminuria (albumin to creatinine ratio over 30 mg/g), and kidney disease defined as an eGFR under 60 ml/min per 1.73 m2 and/or albuminuria in an additive (APOL1 plus JCV) model. BK viruria was not associated with kidney disease. Thus, African Americans at increased risk for APOL1-associated nephropathy (two APOL1 risk variants) with JC viruria had a lower prevalence of kidney disease, suggesting that JCV interaction with APOL1 genotype may influence kidney disease risk.
doi:10.1038/ki.2013.173
PMCID: PMC3844025  PMID: 23677244
APOL1; BK polyomavirus; HIV; JC polyomavirus; kidney disease; proteinuria
2.  Hypertension and chronic kidney disease: controversies in pathogenesis and treatment 
The relationship between hypertension and chronic kidney disease (CKD) has long been the subject of controversy. The pathogenetic mechanisms of nephropathy in non-diabetic individuals with hypertension, as well as optimal hypertension treatment targets in populations with nephropathy remain important clinical concerns. This manuscript reviews breakthroughs in molecular genetics that have clarified the complex relationship between hypertension and kidney disease, answering the question of which factor comes first. An overview of the potential roles that hyperuricemia plays in the pathogenesis of hypertension and CKD and current blood pressure treatment guidelines in populations with CKD are discussed. The ongoing National Institutes of Health-sponsored Systolic Blood Pressure Intervention Trial (SPRINT) is underway to help answer these important questions. Enrollment of 9,250 hypertensive SPRINT participants will be completed in 2013; important results on ideal blood pressure control targets for reducing nephropathy progression, cardiovascular disease end-points, and preserving cognitive function are expected. As such, many of the controversial aspects of hypertension management will likely be clarified in the near future.
PMCID: PMC4030753  PMID: 23538309
APOL1; blood pressure control; chronic kidney disease; FSGS; hypertension; uric acid
3.  End-Stage Renal Disease in African Americans With Lupus Nephritis Is Associated With APOL1 
Objective
Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) that exhibits familial aggregation and may progress to end-stage renal disease (ESRD). LN is more prevalent among African Americans than among European Americans. This study was undertaken to investigate the hypothesis that the apolipoprotein L1 gene (APOL1) nephropathy risk alleles G1/G2, common in African Americans and rare in European Americans, contribute to the ethnic disparity in risk.
Methods
APOL1 G1 and G2 nephropathy alleles were genotyped in 855 African American SLE patients with LN-ESRD (cases) and 534 African American SLE patients without nephropathy (controls) and tested for association under a recessive genetic model, by logistic regression.
Results
Ninety percent of the SLE patients were female. The mean ± SD age at SLE diagnosis was significantly lower in LN-ESRD cases than in SLE non-nephropathy controls (27.3 ± 10.9 years versus 39.5 ± 12.2 years). The mean ± SD time from SLE diagnosis to development of LN-ESRD in cases was 7.3 ± 7.2 years. The G1/G2 risk alleles were strongly associated with SLE-ESRD, with 25% of cases and 12% of controls having 2 nephropathy alleles (odds ratio [OR] 2.57, recessive model P = 1.49 × 10−9), and after adjustment for age, sex, and ancestry admixture (OR 2.72, P = 6.23 × 10−6). The age-, sex-, and admixture-adjusted population attributable risk for ESRD among patients with G1/G2 polymorphisms was 0.26, compared to 0.003 among European American patients. The mean time from SLE diagnosis to ESRD development was ~2 years earlier among individuals with APOL1 risk genotypes (P = 0.01).
Conclusion
APOL1 G1/G2 alleles strongly impact the risk of LN-ESRD in African Americans, as well as the time to progression to ESRD. The high frequency of these alleles in African Americans with near absence in European Americans explains an important proportion of the increased risk of LN-ESRD in African Americans.
doi:10.1002/art.38220
PMCID: PMC4002759  PMID: 24504811
5.  Genotypic variation and outcomes in kidney transplantation: donor and recipient effects 
Kidney international  2013;84(3):431-433.
The genetic composition of a donor impacts long term allograft survival after kidney transplantation. Effects of the recipient’s genetic make-up, particularly variation in immune response pathway genes are less certain. A report in this issue of Kidney International reveals improved graft survival in transplant recipients with lower copy numbers of the complement 4 gene (C4) after receipt of deceased donor kidneys. Genomics breakthroughs in nephrology and immunology will likely revolutionize the field of transplant medicine.
doi:10.1038/ki.2013.167
PMCID: PMC3761401  PMID: 23989355
6.  Admixture Mapping of Coronary Artery Calcified Plaque in African Americans with Type 2 Diabetes 
Background
The presence and severity of coronary artery calcified plaque (CAC) differs markedly between individuals of African and European descent, suggesting that admixture mapping (AM) may be informative for identifying genetic variants associated with subclinical cardiovascular disease (CVD).
Methods and Results
AM of CAC was performed in 1,040 unrelated African Americans with type 2 diabetes mellitus from the African American-Diabetes Heart Study (AA-DHS), Multi-Ethnic Study of Atherosclerosis (MESA), and Family Heart Study (FamHS) using the Illumina custom ancestry informative marker (AIM) panel. All cohorts obtained computed tomography scanning of the coronary arteries using identical protocols. For each AIM, the probability of inheriting 0, 1, and 2 copies of a European-derived allele was determined. Linkage analysis was performed by testing for association between each AIM using these probabilities and CAC, accounting for global ancestry, age, gender and study. Markers on 1p32.3 in the GLIS1 gene (rs6663966, LOD=3.7), 1q32.1 near CHIT1 (rs7530895, LOD=3.1), 4q21.2 near PRKG2 (rs1212373, LOD=3.0) and 11q25 in the OPCML gene (rs6590705, LOD=3.4) had statistically significant LOD scores, while markers on 8q22.2 (rs6994682, LOD=2.7), 9p21.2 (rs439314, LOD=2.7), and 13p32.1 (rs7492028, LOD=2.8) manifested suggestive evidence of linkage. These regions were uniformly characterized by higher levels of European ancestry associating with higher levels or odds of CAC. Findings were replicated in 1,350 AAs without diabetes and 2,497 diabetic European Americans from MESA and the Diabetes Heart Study.
Conclusions
Fine mapping these regions will likely identify novel genetic variants that contribute to CAC and clarify racial differences in susceptibility to subclinical CVD.
doi:10.1161/CIRCGENETICS.112.964114
PMCID: PMC3578054  PMID: 23233742
ancestry; cardiovascular disease risk factors; type 2 diabetes; admixture mapping
7.  APOL1 Risk Variants, Race, and Progression of Chronic Kidney Disease 
The New England journal of medicine  2013;369(23):2183-2196.
BACKGROUND
Among patients in the United States with chronic kidney disease, black patients are at increased risk for end-stage renal disease, as compared with white patients.
METHODS
In two studies, we examined the effects of variants in the gene encoding apolipoprotein L1 (APOL1) on the progression of chronic kidney disease. In the African American Study of Kidney Disease and Hypertension (AASK), we evaluated 693 black patients with chronic kidney disease attributed to hypertension. In the Chronic Renal Insufficiency Cohort (CRIC) study, we evaluated 2955 white patients and black patients with chronic kidney disease (46% of whom had diabetes) according to whether they had 2 copies of high-risk APOL1 variants (APOL1 high-risk group) or 0 or 1 copy (APOL1 low-risk group). In the AASK study, the primary outcome was a composite of end-stage renal disease or a doubling of the serum creatinine level. In the CRIC study, the primary outcomes were the slope in the estimated glomerular filtration rate (eGFR) and the composite of end-stage renal disease or a reduction of 50% in the eGFR from baseline.
RESULTS
In the AASK study, the primary outcome occurred in 58.1% of the patients in the APOL1 high-risk group and in 36.6% of those in the APOL1 low-risk group (hazard ratio in the high-risk group, 1.88; P<0.001). There was no interaction between APOL1 status and trial interventions or the presence of baseline proteinuria. In the CRIC study, black patients in the APOL1 high-risk group had a more rapid decline in the eGFR and a higher risk of the composite renal outcome than did white patients, among those with diabetes and those without diabetes (P<0.001 for all comparisons).
CONCLUSIONS
Renal risk variants in APOL1 were associated with the higher rates of end-stage renal disease and progression of chronic kidney disease that were observed in black patients as compared with white patients, regardless of diabetes status. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.)
doi:10.1056/NEJMoa1310345
PMCID: PMC3969022  PMID: 24206458
8.  Polymorphisms in the Selenoprotein S gene and subclinical cardiovascular disease in the Diabetes Heart Study 
Acta diabetologica  2012;50(3):391-399.
Selenoprotein S (SelS), has previously been associated with a range of inflammatory markers, particularly in the context of cardiovascular disease (CVD). The aim of this study was to examine the role of SELS genetic variants in risk for subclinical CVD and mortality in individuals with type 2 diabetes mellitus (T2DM). The association between 10 polymorphisms tagging SELS and coronary (CAC), carotid (CarCP) and abdominal-aortic calcified plaque (AACP), carotid intima media thickness (IMT) and other known CVD risk factors was examined in 1220 European Americans from the family-based Diabetes Heart Study. The strongest evidence of association for SELS SNPs was observed for CarCP; rs28665122 (5′ region; β=0.329, p=0.044), rs4965814 (intron 5; β=0.329, p=0.036), rs28628459 (3′ region; β=0.331, p=0.039) and rs7178239 (downstream; β=0.375, p=0.016) were all associated. In addition, rs12917258 (intron 5) was associated with CAC (β =−0.230, p=0.032) and rs4965814, rs28628459 and rs9806366 were all associated with self reported history of prior CVD (p=0.020–0.043). These results suggest a potential role for the SELS region in the development subclinical CVD in this sample enriched for T2DM. Further understanding the mechanisms underpinning these relationships may prove important in predicting and managing CVD complications in T2DM.
doi:10.1007/s00592-012-0440-z
PMCID: PMC3597768  PMID: 23161441
genetics; atherosclerosis; calcified plaque; diabetes mellitus
9.  Genetic Analysis of Adiponectin Variation and its Association with Type 2 Diabetes in African Americans 
Obesity (Silver Spring, Md.)  2013;21(12):10.1002/oby.20419.
Objective
Adiponectin is an adipocytokine that has been implicated in a variety of metabolic disorders, including T2D and cardiovascular disease. Studies evaluating genetic variants in ADIPOQ have been contradictory when testing association with T2D in different ethnic groups.
Design and Methods
In this study, 18 SNPs in ADIPOQ were tested for association with plasma adiponectin levels and diabetes status. SNPs were examined in two independent African-American cohorts (nmax=1116) from the Insulin Resistance Atherosclerosis Family Study (IRASFS) and the African American-Diabetes Heart Study (AA-DHS).
Results
Five polymorphisms were nominally associated with plasma adiponectin levels in the meta-analysis (p=0.035–1.02x10−6) including a low frequency arginine to cysteine mutation (R55C) which reduced plasma adiponectin levels to <15% of the mean. Variants were then tested for association with T2D in a meta-analysis of these and the Wake Forest T2D Case-Control study (n=3233 T2D, 2645 non-T2D). Association with T2D was not observed (p≥0.08), suggesting limited influence of ADIPOQ variants on T2D risk.
Conclusions
Despite identification of variants associated with adiponectin levels, a detailed genetic analysis of ADIPOQ revealed no association with T2D risk. This puts into question the role of adiponectin in T2D pathogenesis: whether low adiponectin levels are truly causal for or rather a consequence.
doi:10.1002/oby.20419
PMCID: PMC3690163  PMID: 23512866
10.  GENETICS IN KIDNEY DISEASE IN 2013 
Nature reviews. Nephrology  2013;10(2):69-70.
In 2013, substantial progress was made in uncovering the genetic basis of a variety of kidney and urological disorders, including congenital and developmental diseases. The new findings will lead to an increased understanding of the pathophysiology of these diseases, improved risk prediction and the development of novel therapies.
doi:10.1038/nrneph.2013.259
PMCID: PMC4003456  PMID: 24296626
11.  Usefulness of Biventricular Volume as a Predictor of Mortality in Patients with Diabetes Mellitus (From the Diabetes Heart Study) 
The American journal of cardiology  2013;111(8):1152-1158.
Individuals with type 2 diabetes mellitus (DM) are at increased risk of cardiovascular disease (CVD) and mortality. Beyond traditional CVD risk factors, novel measures reflecting additional aspects of disease pathophysiology, such as biventricular volume (BiVV), may be useful for risk stratification. This study examined the relationship between BiVV and risk for mortality in European Americans with type 2 DM from the Diabetes Heart Study. BiVV was calculated from 771 non-contrast computed tomography scans performed to image coronary artery calcified plaque (CAC). Relationships between BiVV and traditional CVD risk factors were examined. Cox proportional hazards regression was performed to determine risk for mortality (all-cause and CVD-mortality) associated with increasing BiVV. Area under the curve analysis was used to assess BiVV utility in risk prediction models. During 8.4 ± 2.4 years (mean ± SD) of follow-up, 23% of the sample were deceased. In unadjusted analyses, BiVV was significantly associated with increasing body mass index, height, CAC, history of hypertension and prior myocardial infarction (p<0.0001–0.012). BiVV was significantly associated with all-cause (HR: 2.45; CI: 1.06–5.67; p=0.036) and CVD-mortality (HR: 4.36; CI: 1.36–14.03; p=0.014) in models adjusted for other known CVD risk factors. Area under the curve increased from 0.76 to 0.78 (p=0.04) and 0.74 to 0.77 (p=0.02) for all-cause and CVD-mortality on inclusion of BiVV. In conclusion, in the absence of echocardiography or other noninvasive imaging modalities to assess ventricular volumes, or when such methods are contra-indicated, BiVV from computed tomography may be considered as a tool for stratification of high-risk individuals, such as those with type 2 DM.
doi:10.1016/j.amjcard.2012.12.044
PMCID: PMC3618594  PMID: 23351459
cardiovascular disease; heart size; diabetes; risk-prediction
12.  Analysis of common and coding variants with cardiovascular disease in the diabetes heart study 
Background
Type 2 diabetes mellitus (T2DM) is a major cardiovascular disease (CVD) risk factor. Identification of genetic risk factors for CVD is important to understand disease risk. Two recent genome-wide association study (GWAS) meta-analyses in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium detected CVD-associated loci.
Methods
Variants identified in CHARGE were tested for association with CVD phenotypes, including vascular calcification, and conventional CVD risk factors, in the Diabetes Heart Study (DHS) (n = 1208; >80% T2DM affected). This included 36 genotyped or imputed single nucleotide polymorphisms (SNPs) from DHS GWAS data. 28 coding SNPs from 14 top CHARGE genes were also identified from exome sequencing resources and genotyped, along with 209 coding variants from the Illumina HumanExome BeadChip genotype data in the DHS were also tested. Genetic risk scores (GRS) were calculated to evaluate the association of combinations of variants with CVD measures.
Results
After correction for multiple comparisons, none of the CHARGE SNPs were associated with vascular calcification (p < 0.0014). Multiple SNPs showed nominal significance with calcification, including rs599839 (PSRC1, p = 0.008), rs646776 (CELSR2, p = 0.01), and rs17398575 (PIK3CG, p = 0.009). Additional COL4A2 and CXCL12 SNPs were nominally associated with all-cause or CVD-cause mortality. Three SNPs were significantly or nominally associated with serum lipids: rs3135506 (Ser19Trp, APOA5) with triglycerides (TG) (p = 5×10−5), LDL (p = 0.00070), and nominally with high density lipoprotein (HDL) (p = 0.0054); rs651821 (5′UTR, APOA5) with increased TGs (p = 0.0008); rs13832449 (splice donor, APOC3) associated with decreased TGs (p = 0.0015). Rs45456595 (CDKN2A, Gly63Arg), rs5128 (APOC3, 3′UTR), and rs72650673 (SH2B3, Glu400Lys) were nominally associated with history of CVD, subclinical CVD, or CVD risk factors (p < 0.010). From the exome chip, rs3750103 (CHN2, His204Arg/His68Arg) with carotid intima-medial thickness (IMT) (p = 3.9×10−5), and rs61937878 (HAL, Val549Met) with infra-renal abdominal aorta CP (AACP) (p = 7.1×10−5). The unweighted GRS containing coronary artery calcified plaque (CAC) SNPs was nominally associated with history of prior CVD (p = 0.033; OR = 1.09). The weighted GRS containing SNPs was associated with CAC and myocardial infarction (MI) was associated with history of MI (p = 0.026; OR = 1.15).
Conclusions
Genetic risk factors for subclinical CVD in the general population (CHARGE) were modestly associated with T2DM-related risk factors and CVD outcomes in the DHS.
doi:10.1186/1475-2840-13-77
PMCID: PMC4021556  PMID: 24725463
Coronary artery calcified plaque; Type 2 diabetes mellitus; Cardiovascular disease; Genetic risk score
13.  The Role of Copy Number Variation in African Americans with Type 2 Diabetes-Associated End Stage Renal Disease 
This study investigated the association of copy number variants (CNVs) in type 2 diabetes (T2D) and T2D-associated end-stage renal disease (ESRD) in African Americans. Using the Affymetrix 6.0 array, >900,000 CNV probes spanning the genome were interrogated in 965 African Americans with T2D-ESRD and 1029 non-diabetic African American controls. Previously identified and novel CNVs were separately analyzed and were evaluated for insertion/deletion status and then used as predictors in a logistic regression model to test for association. One common CNV insertion on chromosome 1 was significantly associated with T2D-ESRD (p=6.17×10−5, OR=1.63) after multiple comparison correction. This CNV region encompasses the genes AMY2A and AMY2B, which encode amylase isoenzymes produced by the pancreas. Additional common and novel CNVs approaching significance with disease were also detected. These exploratory results require further replication but suggest the involvement of the AMY2A/AMY2B CNV in T2D and/or T2D-ESRD, and indicate that CNVs may contribute to susceptibility for these diseases.
doi:10.4172/1747-0862.1000061
PMCID: PMC3973178  PMID: 24707315
Copy number variation; African Americans; Diabetic nephropathy; End-stage renal disease; Genome-wide association study; Type 2 diabetes
14.  Coronary Calcium Score Predicts Cardiovascular Mortality in Diabetes 
Diabetes Care  2013;36(4):972-977.
OBJECTIVE
In type 2 diabetes mellitus (T2DM), it remains unclear whether coronary artery calcium (CAC) provides additional information about cardiovascular disease (CVD) mortality beyond the Framingham Risk Score (FRS) factors.
RESEARCH DESIGN AND METHODS
A total of 1,123 T2DM participants, ages 34–86 years, in the Diabetes Heart Study followed up for an average of 7.4 years were separated using baseline computed tomography scans of CAC (0–9, 10–99, 100–299, 300–999, and ≥1,000). Logistic regression was performed to examine the association between CAC and CVD mortality adjusting for FRS. Areas under the curve (AUC) with and without CAC were compared. Net reclassification improvement (NRI) compared FRS (model 1) versus FRS+CAC (model 2) using 7.4-year CVD mortality risk categories 0% to <7%, 7% to <20%, and ≥20%.
RESULTS
Overall, 8% of participants died of cardiovascular causes during follow-up. In multivariate analysis, the odds ratios (95% CI) for CVD mortality using CAC 0–9 as the reference group were, CAC 10–99: 2.93 (0.74–19.55); CAC 100–299: 3.17 (0.70–22.22); CAC 300–999: 4.41(1.15–29.00); and CAC ≥1,000: 11.23 (3.24–71.00). AUC (95% CI) without CAC was 0.70 (0.67–0.73), AUC with CAC was 0.75 (0.72–0.78), and NRI was 0.13 (0.07–0.19).
CONCLUSIONS
In T2DM, CAC predicts CVD mortality and meaningfully reclassifies participants, suggesting clinical utility as a risk stratification tool in a population already at increased CVD risk.
doi:10.2337/dc12-1548
PMCID: PMC3609509  PMID: 23230101
15.  Insights into the Genetic Architecture of Diabetic Nephropathy 
Current Diabetes Reports  2012;12(4):423-431.
Diabetic nephropathy (DN) is a devastating complication of type 1 and type 2 diabetes and leads to increased morbidity and premature mortality. Susceptibility to DN has an inherent genetic basis as evidenced by familial aggregation and ethnic-specific prevalence rates. Progress in identifying the underlying genetic architecture has been arduous with the realization that a single locus of large effect does not exist, unlike in predisposition to non-diabetic nephropathy in individuals with African ancestry. Numerous risk variants have been identified, each with a nominal effect, and they collectively contribute to disease. These results have identified loci targeting novel pathways for disease susceptibility. With continued technological advances and development of new analytic methods, additional genetic variants and mechanisms (e.g., epigenetic variation) will be identified and help to elucidate the pathogenesis of DN. These advances will lead to early detection and development of novel therapeutic strategies to decrease the incidence of disease.
doi:10.1007/s11892-012-0279-2
PMCID: PMC3389140  PMID: 22573336
Nephropathy; Type 2 diabetes; Albuminuria; Kidney; Genetics; Association
16.  A Critical Evaluation of Glycated Protein Parameters in Advanced Nephropathy: A Matter of Life or Death 
Diabetes Care  2012;35(7):1621-1624.
Chronic kidney disease remains as one of the major complications for individuals with diabetes and contributes to considerable morbidity. Individuals subjected to dialysis therapy, half of whom are diabetic, experience a mortality of ∼20% per year. Understanding factors related to mortality remains a priority. Outside of dialysis units, A1C is unquestioned as the “gold standard” for glycemic control. In the recent past, however, there is evidence in large cohorts of diabetic dialysis patients that A1C at both the higher and lower levels was associated with mortality. Given the unique conditions associated with the metabolic dysregulation in dialysis patients, there is a critical need to identify accurate assays to monitor glycemic control to relate to cardiovascular endpoints. In this two-part point-counterpoint narrative, Drs. Freedman and Kalantar-Zadeh take opposing views on the utility of A1C in relation to cardiovascular disease and survival and as to consideration of use of other short-term markers in glycemia. In the narrative below, Dr. Freedman suggests that glycated albumin may be the preferred glycemic marker in dialysis subjects. In the counterpoint narrative following Dr. Freedman’s contribution, Dr. Kalantar-Zadeh defends the use of A1C as the unquestioned gold standard for glycemic management in dialysis subjects.
—William T. Cefalu, MD Editor in Chief, Diabetes Care
doi:10.2337/dc12-0027
PMCID: PMC3379614  PMID: 22723586
17.  Apolipoprotein L1 gene variants associate with hypertension-attributed nephropathy and the rate of kidney function decline in African Americans 
Kidney international  2012;83(1):114-120.
Despite intensive anti-hypertensive therapy there was a high incidence of renal end-points in participants of the African American Study of Kidney Disease and Hypertension (AASK) cohort. To better understand this, coding variants in the apolipoprotein L1 (APOL1) and the non-muscle myosin heavy chain 9 (MYH9) genes were evaluated for an association with hypertension-attributed nephropathy and clinical outcomes in a case-control study. Clinical data and DNA were available for 675 AASK participant cases and 618 African American non-nephropathy control individuals. APOL1 G1 and G2, and MYH9 E1 variants along with 44 ancestry informative markers were genotyped with allele frequency differences between cases and controls analyzed by logistic regression multivariable models adjusting for ancestry, age, and gender. In recessive models, APOL1 risk variants were significantly associated with kidney disease in all cases compared to controls with an odds ratio of 2.57. In AASK cases with more advanced disease, such as a baseline urine protein to creatinine ratio over 0.6 g/g or a serum creatinine over 3 mg/dL during follow-up, the association was strengthened with odds ratios of 6.29 and 4.61, respectively. APOL1 risk variants were consistently associated with renal disease progression across medication classes and blood pressure targets. Thus, kidney disease in AASK participants was strongly associated with APOL1 renal risk variants.
doi:10.1038/ki.2012.263
PMCID: PMC3484228  PMID: 22832513
18.  Transferability and Fine Mapping of Type 2 Diabetes Loci in African Americans 
Diabetes  2013;62(3):965-976.
Type 2 diabetes (T2D) disproportionally affects African Americans (AfA) but, to date, genetic variants identified from genome-wide association studies (GWAS) are primarily from European and Asian populations. We examined the single nucleotide polymorphism (SNP) and locus transferability of 40 reported T2D loci in six AfA GWAS consisting of 2,806 T2D case subjects with or without end-stage renal disease and 4,265 control subjects from the Candidate Gene Association Resource Plus Study. Our results revealed that seven index SNPs at the TCF7L2, KLF14, KCNQ1, ADCY5, CDKAL1, JAZF1, and GCKR loci were significantly associated with T2D (P < 0.05). The strongest association was observed at TCF7L2 rs7903146 (odds ratio [OR] 1.30; P = 6.86 × 10−8). Locus-wide analysis demonstrated significant associations (Pemp < 0.05) at regional best SNPs in the TCF7L2, KLF14, and HMGA2 loci as well as suggestive signals in KCNQ1 after correction for the effective number of SNPs at each locus. Of these loci, the regional best SNPs were in differential linkage disequilibrium (LD) with the index and adjacent SNPs. Our findings suggest that some loci discovered in prior reports affect T2D susceptibility in AfA with similar effect sizes. The reduced and differential LD pattern in AfA compared with European and Asian populations may facilitate fine mapping of causal variants at loci shared across populations.
doi:10.2337/db12-0266
PMCID: PMC3581206  PMID: 23193183
19.  Evaluation of Candidate Nephropathy Susceptibility Genes in a Genome-Wide Association Study of African American Diabetic Kidney Disease 
PLoS ONE  2014;9(2):e88273.
Type 2 diabetes (T2D)-associated end-stage kidney disease (ESKD) is a complex disorder resulting from the combined influence of genetic and environmental factors. This study contains a comprehensive genetic analysis of putative nephropathy loci in 965 African American (AA) cases with T2D-ESKD and 1029 AA population-based controls extending prior findings. Analysis was based on 4,341 directly genotyped and imputed single nucleotide polymorphisms (SNPs) in 22 nephropathy candidate genes. After admixture adjustment and correction for multiple comparisons, 37 SNPs across eight loci were significantly associated (1.6E-05
doi:10.1371/journal.pone.0088273
PMCID: PMC3923777  PMID: 24551085
Nephrology Dialysis Transplantation  2012;27(4):1288-1291.
doi:10.1093/ndt/gfr812
PMCID: PMC3315674  PMID: 22302261
African American; APOL1; end-stage renal disease; FSGS; hypertensive nephrosclerosis
Kidney international  2012;82(7):805-811.
Familial aggregation of non-diabetic end stage renal disease (ESRD) is found in African Americans and variants in the apolipoprotein L1 gene (APOL1) contribute to this risk. To detect genetic associations with milder forms of nephropathy in high-risk families, analyses were performed using generalized estimating equations to assess relationships between kidney disease phenotypes and APOL1 variants in 786 relatives of 470 families. Adjusting for familial correlations, 23.1, 46.7, and 30.2 percent of genotyped relatives possessed two, one, or no APOL1 risk variants, respectively. Relatives with two compared to one or no risk variants had statistically indistinguishable median systolic blood pressure, urine albumin to creatinine ratio, estimated GFR (MDRD equation) and serum cystatin C levels. After adjusting for age, gender, age at ESRD in families, and African ancestry, significant associations were detected between APOL1 with overt proteinuria and estimated GFR (CKD-EPI equation), with a trend toward significance for quantitative albuminuria. Thus, relatives of African Americans with non-diabetic ESRD are enriched for APOL1 risk variants. After adjustment, two APOL1 risk variants weakly predict mild forms of kidney disease. Second hits appear necessary for the initiation of APOL1-associated nephropathy.
doi:10.1038/ki.2012.217
PMCID: PMC3443536  PMID: 22695330
African American; APOL1; end-stage renal disease; FSGS; kidney; screening
Circulation research  2012;112(2):318-326.
Rationale
Hypertension (HTN) affects ~30% of adults in industrialized countries and is the major risk factor for cardiovascular disease.
Objective
We sought to study the genetic effect of coding and conserved non-coding variants in syndromic HTN genes on systolic (SBP) and diastolic (DBP) blood pressure to assess their overall impact on essential hypertension (EH).
Methods and Results
We resequenced 11 genes (AGT, CYP11B1, CYP17A1, HSD11B2, NR3C1, NR3C2, SCNN1A, SCNN1B, SCNN1G, WNK1 and WNK4) in 560 European (EA) and African (AA) ancestry GenNet participants with extreme SBP. We investigated genetic associations of 2,535 variants with BP in 19,997 EAs and 6,069 AAs in three types of analyses. First, we studied the combined effects of all variants in GenNet. Second, we studied 1000 Genomes imputed polymorphic variants in 9,747 EA and 3,207 AA ARIC subjects. Lastly, we genotyped 37 missense and common noncoding variants in 6,591 EAs and 6,521 individuals (3,659 EA/2,862 AA) from the CLUE and FBPP studies. None of the variants individually reached significant false-discovery rates (FDR≤0.05) for SBP and DBP. However, upon pooling all coding and non-coding variants we identified at least 5 loci (AGT, CYP11B1, NR3C2, SCNN1G and WNK1), with higher association at evolutionary conserved sites.
Conclusions
Both rare and common variants at these genes affect BP in the general population with modest effects sizes (<0.05 standard deviation units) and much larger sample sizes are required to assess the impact of individual genes. Collectively, conserved noncoding variants affect BP to a greater extent than missense mutations.
doi:10.1161/CIRCRESAHA.112.276725
PMCID: PMC3548950  PMID: 23149595
essential hypertension; blood pressure; population genetics; sequencing; genotype
Current Hypertension Reports  2012;14(1):21-28.
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 by 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.
doi:10.1007/s11906-011-0237-4
PMCID: PMC3253170  PMID: 22068337
African American; African sleeping sickness; Arteriolar nephrosclerosis; APOL1; Chronic kidney disease; Dialysis; End-stage renal disease; ESRD: Focal segmental glomerulosclerosis; Genetics; Glomerulosclerosis; Hypertension; Hypertensive nephrosclerosis; Kidney disease; Kidney donors; MYH9; Nondiabetic nephropathy; Racial differences; Trypanosoma brucei rhodesiense; Transplantation
Background
African Americans (AAs) have increased susceptibility to non-diabetic nephropathy relative to European Americans.
Study Design
Follow-up of a pooled genome-wide association study (GWAS) in AA dialysis patients with nondiabetic nephropathy; novel gene-gene interaction analyses.
Setting & Participants
Wake Forest sample: 962 AA nondiabetic nephropathy cases; 931 non-nephropathy controls. Replication sample: 668 Family Investigation of Nephropathy and Diabetes (FIND) AA nondiabetic nephropathy cases; 804 non-nephropathy controls.
Predictors
Individual genotyping of top 1420 pooled GWAS-associated single nucleotide polymorphisms (SNPs) and 54 SNPs in six nephropathy susceptibility genes.
Outcomes
APOL1 genetic association and additional candidate susceptibility loci interacting with, or independently from, APOL1.
Results
The strongest GWAS associations included two non-coding APOL1 SNPs, rs2239785 (odds ratio [OR], 0.33; dominant; p = 5.9 × 10−24) and rs136148 (OR, 0.54; additive; p = 1.1 × 10−7) with replication in FIND (p = 5.0 × 10−21 and 1.9 × 10−05, respectively). Rs2239785 remained significantly associated after controlling for the APOL1 G1 and G2 coding variants. Additional top hits included a CFH SNP(OR from meta-analysis in above 3367 AA cases and controls, 0.81; additive; p = 6.8 × 10−4). The 1420 SNPs were tested for interaction with APOL1 G1 and G2 variants. Several interactive SNPs were detected, the most significant was rs16854341 in the podocin gene (NPHS2) (p = 0.0001).
Limitations
Non-pooled GWAS have not been performed in AA nondiabetic nephropathy.
Conclusions
This follow-up of a pooled GWAS provides additional and independent evidence that APOL1 variants contribute to nondiabetic nephropathy in AAs and identified additional associated and interactive non-diabetic nephropathy susceptibility genes.
doi:10.1053/j.ajkd.2011.09.020
PMCID: PMC3259209  PMID: 22119407
African American; APOL1; CFH; end-stage renal disease; FIND; FSGS; hypertension
PLoS ONE  2013;8(12):e81888.
Objective
Estimated glomerular filtration rate (eGFR), a measure of kidney function, is heritable, suggesting that genes influence renal function. Genes that influence eGFR have been identified through genome-wide association studies. However, family-based linkage approaches may identify loci that explain a larger proportion of the heritability. This study used genome-wide linkage and association scans to identify quantitative trait loci (QTL) that influence eGFR.
Methods
Genome-wide linkage and sparse association scans of eGFR were performed in families ascertained by probands with advanced diabetic nephropathy (DN) from the multi-ethnic Family Investigation of Nephropathy and Diabetes (FIND) study. This study included 954 African Americans (AA), 781 American Indians (AI), 614 European Americans (EA) and 1,611 Mexican Americans (MA). A total of 3,960 FIND participants were genotyped for 6,000 single nucleotide polymorphisms (SNPs) using the Illumina Linkage IVb panel. GFR was estimated by the Modification of Diet in Renal Disease (MDRD) formula.
Results
The non-parametric linkage analysis, accounting for the effects of diabetes duration and BMI, identified the strongest evidence for linkage of eGFR on chromosome 20q11 (log of the odds [LOD] = 3.34; P = 4.4×10−5) in MA and chromosome 15q12 (LOD = 2.84; P = 1.5×10−4) in EA. In all subjects, the strongest linkage signal for eGFR was detected on chromosome 10p12 (P = 5.5×10−4) at 44 cM near marker rs1339048. A subsequent association scan in both ancestry-specific groups and the entire population identified several SNPs significantly associated with eGFR across the genome.
Conclusion
The present study describes the localization of QTL influencing eGFR on 20q11 in MA, 15q21 in EA and 10p12 in the combined ethnic groups participating in the FIND study. Identification of causal genes/variants influencing eGFR, within these linkage and association loci, will open new avenues for functional analyses and development of novel diagnostic markers for DN.
doi:10.1371/journal.pone.0081888
PMCID: PMC3866106  PMID: 24358131

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