Associations of serum and dialysate electrolytes with QT interval and prolongation in incident hemodialysis: the Predictors of Arrhythmic and Cardiovascular Risk in End-Stage Renal Disease (PACE) study.

BACKGROUND: Prolonged QT interval in hemodialysis patients may be associated with sudden cardiac death, however, few studies examined the longitudinal associations of modifiable factors such as serum and dialysate concentrations of calcium, potassium, and magnesium with corrected QT (QTc) prolongation in incident hemodialysis patients. METHODS: In 330 in-center hemodialysis participants from the PACE study who were followed up for one year, we examined the associations of predialysis serum electrolytes (total calcium [Ca], corrected Ca [cCa], ionized Ca [iCa], potassium [K], magnesium [Mg]), dialysate (dCa and dK), and serum-to-dialysate gradient measures with QTc interval and prolongation (≥460 ms in women and ≥ 450 ms in men). RESULTS: At the first study visit, 47% had QTc prolongation. Lower iCa and K were associated with longer QTc interval independent of potential confounders (QTc difference = 8.55[95% CI: 2.13, 14.97] ms for iCa; QTc difference = 9.89[1.58, 18.20] ms for K). Lower iCa was also associated with a higher risk of QTc prolongation. At 1 year of follow-up, 31% had persistent QTc prolongation. In longitudinal analyses, the associations of iCa and K with QTc interval remained significant, and lower K was associated with a higher risk of QTc prolongation while the association of iCa with QTc prolongation was borderline statistically significant. Serum Mg, dCa or dK, and respective gradients were not associated with QTc interval or prolongation. CONCLUSION: Prolonged QTc is very common in incident hemodialysis participants and persists over follow-up. Ionized Ca and K are consistently inversely associated with QTc prolongation, which suggests closer monitoring for a low calcium or potassium level to mitigate risk.

Electrophysiologic Substrate and Risk of Mortality in Incident Hemodialysis.

The single leading cause of mortality on hemodialysis is sudden cardiac death. Whether measures of electrophysiologic substrate independently associate with mortality is unknown. We examined measures of electrophysiologic substrate in a prospective cohort of 571 patients on incident hemodialysis enrolled in the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease Study. A total of 358 participants completed both baseline 5-minute and 12-lead electrocardiogram recordings on a nondialysis day. Measures of electrophysiologic substrate included ventricular late potentials by the signal-averaged electrocardiogram and spatial mean QRS-T angle measured on the averaged beat recorded within a median of 106 days (interquartile range, 78-151 days) from dialysis initiation. The cohort was 59% men, and 73% were black, with a mean±SD age of 55±13 years. Transthoracic echocardiography revealed a mean±SD ejection fraction of 65.5%±12.0% and a mean±SD left ventricular mass index of 66.6±22.3 g/m2.7 During 864.6 person-years of follow-up, 77 patients died; 35 died from cardiovascular causes, of which 15 were sudden cardiac deaths. By Cox regression analysis, QRS-T angle ≥75° significantly associated with increased risk of cardiovascular mortality (hazard ratio, 2.99; 95% confidence interval, 1.31 to 6.82) and sudden cardiac death (hazard ratio, 4.52; 95% confidence interval, 1.17 to 17.40) after multivariable adjustment for demographic, cardiovascular, and dialysis factors. Abnormal signal-averaged electrocardiogram measures did not associate with mortality. In conclusion, spatial QRS-T angle but not abnormal signal-averaged electrocardiogram significantly associates with cardiovascular mortality and sudden cardiac death independent of traditional risk factors in patients starting hemodialysis.

Examination of Potential Modifiers of the Association of APOL1 Alleles with CKD Progression.

BACKGROUND AND OBJECTIVES: Common apolipoprotein L1 (APOL1) variants are associated with increased risk of progressive CKD; however, not all individuals with high-risk APOL1 variants experience CKD progression. Identification of factors contributing to heterogeneity has important scientific and clinical implications. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using multivariable Cox models, we analyzed data from 693 participants in the African American Study of Kidney Disease and Hypertension to identify factors that modify the association between APOL1 genotypes and CKD progression (doubling of serum creatinine or incident ESRD). RESULTS: Participant mean age was 54 years old, median GFR was 49 ml/min per 1.73 m(2), and 23% had the APOL1 high-risk genotype (two copies of the high-risk allele). Over a mean follow-up of 7.8 years, 288 (42%) participants experienced CKD progression. As previously reported, the high-risk genotype was associated with higher risk of CKD progression compared with the low-risk genotype (hazard ratio [HR], 1.88; 95% confidence interval [95% CI], 1.46 to 2.41). Although we found some suggestion that obesity (HR, 1.48; 95% CI, 1.05 to 2.08 and HR, 2.44; 95% CI, 1.66 to 3.57 for body mass index ≥ 30 versus <30 kg/m(2); P interaction =0.04) and increased urinary excretion of urea nitrogen (HR, 1.43; 95% CI, 0.98 to 2.09 versus HR, 2.33; 95% CI, 1.65 to 3.30 for urine urea nitrogen ≥ 8 versus <8 g/d; P interaction =0.04) were associated with lower APOL1-associated risk for CKD progression, these findings were not robust in sensitivity analyses with alternative cut points. No other sociodemographic (e.g., education and income), clinical (e.g., systolic BP and smoking), or laboratory (e.g., net endogenous acid production, urinary sodium and potassium excretions, 25-hydroxy vitamin D, intact parathyroid hormone, or fibroblast growth factor 23) variables modified the association between APOL1 and CKD progression (P interaction >0.05 for each). CONCLUSIONS: Sociodemographic factors and common risk factors for CKD progression do not seem to alter APOL1-related CKD progression. Additional investigation is needed to identify nontraditional factors that may affect the association between APOL1 and progressive CKD.

Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND).

Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.

APOL1 Genotype and Glomerular and Tubular Kidney Injury in Women With HIV.

BACKGROUND: APOL1 genotype is associated with advanced kidney disease in African Americans, but the pathogenic mechanisms are unclear. Here, associations of APOL1 genotype with urine biomarkers of glomerular and tubular injury and kidney function decline were evaluated. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: 431 human immunodeficiency virus (HIV)-infected African American women enrolled in Women's Interagency HIV Study (WIHS). PREDICTOR: APOL1 genotype. OUTCOMES: Albumin-creatinine ratio (ACR), 4 tubular injury biomarkers (interleukin 18 [IL-18], kidney injury molecule 1 [KIM-1], neutrophil gelatinase-associated lipocalin [NGAL], and α1-microglobulin [A1M]), and kidney function estimated using the CKD-EPI cystatin C equation. MEASUREMENTS: Participants were genotyped for APOL1 single-nucleotide polymorphisms rs73885319 (G1 allele) and rs71785313 (G2 allele). Urine biomarkers were measured using stored samples from 1999-2000. Cystatin C was measured using serum collected at baseline and 4- and 8-year follow-ups. RESULTS: At baseline, ACRs were higher among 47 women with 2 APOL1 risk alleles versus 384 women with 0/1 risk allele (median, 24 vs 11mg/g; P<0.001). Compared with women with 0/1 risk allele, women with 2 risk alleles had 104% higher ACRs (95% CI, 29-223mg/g) and 2-fold greater risk of ACR>30 (95% CI, 1.17-3.44) mg/g after multivariable adjustment. APOL1 genotype showed little association with urine IL-18:Cr ratio, KIM-1:Cr ratio, and NGAL:Cr ratio (estimates of -5% [95% CI, -24% to 18%], -20% [95% CI, -36% to -1%], and 10% [95% CI, -26% to 64%], respectively) or detectable urine A1M (prevalence ratio, 1.13; 95% CI, 0.65-1.97) in adjusted analyses. Compared with women with 0/1 allele, women with 2 risk alleles had faster eGFR decline, by 1.2 (95% CI, 0.2 to 2.2) mL/min/1.73m(2) per year, and 1.7- and 3.4-fold greater rates of incident chronic kidney disease (95% CI, 1.1 to 2.5) and 10% annual eGFR decline (95% CI, 1.7 to 6.7), respectively, with minimal attenuation after adjustment for glomerular and tubular injury biomarker levels. LIMITATIONS: Results may not be generalizable to men. CONCLUSIONS: Among HIV-infected African American women, APOL1-associated kidney injury appears to localize to the glomerulus, rather than the tubules.

Relative performance of gene- and pathway-level methods as secondary analyses for genome-wide association studies.

BACKGROUND: Despite the success of genome-wide association studies (GWAS), there still remains "missing heritability" for many traits. One contributing factor may be the result of examining one marker at a time as opposed to a group of markers that are biologically meaningful in aggregate. To address this problem, a variety of gene- and pathway-level methods have been developed to identify putative biologically relevant associations. A simulation was conducted to systematically assess the performance of these methods. Using genetic data from 4,500 individuals in the Wellcome Trust Case Control Consortium (WTCCC), case-control status was simulated based on an additive polygenic model. We evaluated gene-level methods based on their sensitivity, specificity, and proportion of false positives. Pathway-level methods were evaluated on the relationship between proportion of causal genes within the pathway and the strength of association. RESULTS: The gene-level methods had low sensitivity (20-63%), high specificity (89-100%), and low proportion of false positives (0.1-6%). The gene-level program VEGAS using only the top 10% of associated single nucleotide polymorphisms (SNPs) within the gene had the highest sensitivity (28.6%) with less than 1% false positives. The performance of the pathway-level methods depended on their reliance upon asymptotic distributions or if significance was estimated in a competitive manner. The pathway-level programs GenGen, GSA-SNP and MAGENTA had the best performance while accounting for potential confounders. CONCLUSIONS: Novel genes and pathways can be identified using the gene and pathway-level methods. These methods may provide valuable insight into the "missing heritability" of traits and provide biological interpretations to GWAS findings.

Rationale and design for the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease (PACE) study.

BACKGROUND: Sudden cardiac death occurs commonly in the end-stage renal disease population receiving dialysis, with 25% dying of sudden cardiac death over 5 years. Despite this high risk, surprisingly few prospective studies have studied clinical- and dialysis-related risk factors for sudden cardiac death and arrhythmic precursors of sudden cardiac death in end-stage renal disease. METHODS/DESIGN: We present a brief summary of the risk factors for arrhythmias and sudden cardiac death in persons with end-stage renal disease as the rationale for the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease (PACE) study, a prospective cohort study of patients recently initiated on chronic hemodialysis, with the overall goal to understand arrhythmic and sudden cardiac death risk. Participants were screened for eligibility and excluded if they already had a pacemaker or an automatic implantable cardioverter defibrillator. We describe the study aims, design, and data collection of 574 incident hemodialysis participants from the Baltimore region in Maryland, U.S.A.. Participants were recruited from 27 hemodialysis units and underwent detailed clinical, dialysis and cardiovascular evaluation at baseline and follow-up. Cardiovascular phenotyping was conducted on nondialysis days with signal averaged electrocardiogram, echocardiogram, pulse wave velocity, ankle, brachial index, and cardiac computed tomography and angiography conducted at baseline. Participants were followed annually with study visits including electrocardiogram, pulse wave velocity, and ankle brachial index up to 4 years. A biorepository of serum, plasma, DNA, RNA, and nails were collected to study genetic and serologic factors associated with disease. DISCUSSION: Studies of modifiable risk factors for sudden cardiac death will help set the stage for clinical trials to test therapies to prevent sudden cardiac death in this high-risk population.

Genome-wide association analysis of plasma B-type natriuretic peptide in blacks: the Jackson Heart Study.

BACKGROUND: Numerous experimental studies suggest that B-type natriuretic peptide (BNP) is cardioprotective; however, in clinical studies, higher plasma BNP concentrations have been associated with incident cardiovascular disease and higher left ventricular mass. Genetic association studies may allow us to determine the true causal directions without confounding by compensatory mechanisms. METHODS AND RESULTS: We performed a meta-analysis of 2 genome-wide association results from a total of 2790 blacks. We assumed an additive genetic model in an association analysis of imputed 2.5 million single-nucleotide polymorphism dosages with residuals generated from multivariable-adjusted logarithmically transformed BNP controlling for relevant covariates and population stratification. Two loci were genome-wide significant, a candidate gene locus NPPB (rs198389, P=1.18×10(-09)) and a novel missense variant in the KLKB1 locus (rs3733402, P=1.75×10(-11)) that explained 0.4% and 1.9% of variation in log BNP concentration, respectively. The observed increase in BNP concentration was proportional to the number of effect allele copies, and an average of 8.1 pg/mL increase was associated with 2 allele copies. In a companion study, single-nucleotide polymorphisms in this loci were cross-checked with genome-wide association results for the aldosterone/renin ratio in individuals of European ancestry, and rs3733402 was genome-wide significant (P<5.0×10(-8)), suggesting possible shared genetic architecture for these 2 pathways. Other statistically significant relations for these single-nucleotide polymorphisms included the following: rs198389 with systolic blood pressure in blacks (COGENT consortium) and rs198389 and rs3733402 with left ventricular mass in whites (EchoGEN consortium). CONCLUSIONS: These findings improve our knowledge of the genetic basis of BNP variation in blacks, demonstrate a possible shared allelic architecture for BNP with aldosterone-renin ratio, and motivate further studies of underlying mechanisms.

The association between APOL1 risk alleles and longitudinal kidney function differs by HIV viral suppression status.

BACKGROUND: Existing data suggest that human immunodeficiency virus (HIV)-infected African Americans carrying 2 copies of the APOL1 risk alleles have greater risk of kidney disease than noncarriers. We sought to determine whether HIV RNA suppression mitigates APOL1-related kidney function decline among African Americans enrolled in the Multicenter AIDS Cohort Study. METHODS: We genotyped HIV-infected men for the G1 and G2 risk alleles and ancestry informative markers. Mixed-effects models were used to estimate the annual rate of estimated glomerular filtration rate (eGFR) decline, comparing men carrying 2 (high-risk) vs 0-1 risk allele (low-risk). Effect modification by HIV suppression status (defined as HIV type 1 RNA level <400 copies/mL for >90% of follow-up time) was evaluated using interaction terms and stratified analyses. RESULTS: Of the 333 African American men included in this study, 54 (16%) carried the APOL1 high-risk genotype. Among HIV-infected men with unsuppressed viral loads, those with the high-risk genotype had a 2.42 mL/minute/1.73 m(2) (95% confidence interval [CI], -3.52 to -1.32) faster annual eGFR decline than men with the low-risk genotype. This association was independent of age, comorbid conditions, baseline eGFR, ancestry, and HIV-related factors. In contrast, the rate of decline was similar by APOL1 genotype among men with sustained viral suppression (-0.16 mL/minute/1.73 m(2)/year; 95% CI, -.59 to .27; P for interaction <.001). CONCLUSIONS: Unsuppressed HIV-infected African Americans with the APOL1 high-risk genotype experience an accelerated rate of kidney function decline; HIV suppression with antiretroviral therapy may reduce these deleterious renal effects.

Estimating time to ESRD using kidney failure risk equations: results from the African American Study of Kidney Disease and Hypertension (AASK).

BACKGROUND: Planning for renal replacement therapy, such as referral for arteriovenous fistula placement and transplantation, often is guided by level of estimated glomerular filtration rate (eGFR). The use of risk equations might enable more accurate estimation of time to end-stage renal disease (ESRD), thus improving patient care. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: 1,094 participants in the African American Study of Kidney Disease and Hypertension (AASK) cohort. PREDICTOR: Age, sex, urine protein-creatinine ratio ≥ 1g/g, APOL1 high-risk status, and 3-year antecedent eGFR decline. OUTCOME: Cumulative incidence of ESRD from 5 different starting points: eGFR of 30 and 15mL/min/1.73m(2) and 1-year ESRD risk of 5%, 10%, and 20%, estimated by a published 4-variable kidney failure risk equation. RESULTS: 566 participants developed eGFR of 30mL/min/1.73m(2), 244 developed eGFR of 15mL/min/1.73m(2), and 437, 336, and 259 developed 1-year ESRD risks of 5%, 10%, and 20%, respectively. The 1-year cumulative incidence of ESRD was 4.3% from eGFR of 30mL/min/1.73m(2), 49.0% from eGFR of 15mL/min/1.73m(2), 6.7% from 5% ESRD risk, 15.0% from 10% ESRD risk, and 29% from 20% ESRD risk. From eGFR of 30mL/min/1.73m(2), there were several risk factors that predicted ESRD risk. From eGFR of 15mL/min/1.73m(2), only level of proteinuria did; median time to ESRD was 9 and 19 months in those with higher and lower proteinuria, respectively. Median times were less variable from corresponding ESRD risk thresholds. For example, median times to ESRD from 20% ESRD risk were 22 and 25 months among those with higher and lower proteinuria, respectively. LIMITATIONS: Relatively homogeneous population of African Americans with hypertensive kidney disease. CONCLUSIONS: Results of the present study suggest the potential benefit of incorporating kidney failure risk equations into clinical care, with selection of a specific threshold guided by its intended use.

Both rare and common variants in PCSK9 influence plasma low-density lipoprotein cholesterol level in American Indians.

CONTEXT: Elevated LDL cholesterol (LDL-C) is an important risk factor for atherosclerosis and cardiovascular disease. Variants in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene have been associated not only with plasma LDL-C concentration, but also with ischemic heart disease. Little is known about the genetic architecture of PCSK9 and its influence on LDL-C in American Indians. OBJECTIVE: We aimed to investigate the genetic architecture in the 1p32 region encompassing PCSK9 and its influence on LDL-C in American Indians. DESIGN: The Strong Heart Family Study (SHFS) is a family-based genetic study. PARTICIPANTS: Two thousand four hundred fifty eight American Indians from Arizona, Oklahoma, North Dakota, and South Dakota, who were genotyped by Illumina MetaboChip. RESULTS: We genotyped 486 SNPs in a 3.9 Mb region at chromosome 1p32 encompassing PCSK9 in 2458 American Indians. We examined the association between these SNPs and LDL-C. For common variants (MAF ≥ 1%), meta-analysis across the three geographic regions showed common variants in PCSK9 were significantly associated with higher LDL-C. The most significant SNP rs12067569 (MAF = 1.7 %, ß = 16.9 ± 3.7, P = 5.9 × 10(-6)) was in complete LD (r(2) = 1) with a nearby missense SNP, rs505151 (E670G) (ß = 15.0 ± 3.6, P = 3.6 × 10(-5)). For rare variants (MAF < 1%), rs11591147 (R46L, MAF = 0.9%) was associated with lower LDL-C (ß = - 31.1 ± 7.1, P = 1.4 × 10(-5)). The mean (SD) of LDL-C was 76.9 (7.8) and 107.4 (1.0) mg/dL for those with and without the R46L mutation, respectively. One person who was homozygous for R46L had LDL-C levels of 11 mg/dL. In one family, 6 out of 8 members carrying the R46L mutation had LDL-C levels below the lower 10% percentile of LDL-C among all study participants. CONCLUSIONS: Both rare and common variants in PCSK9 influence plasma LDL-C levels in American Indians. Follow-up studies may disclose the influence of these mutations on the risk of CVD and responses to cholesterol-lowering medications.

Polygenic overlap between kidney function and large artery atherosclerotic stroke.

BACKGROUND AND PURPOSE: Epidemiological studies show strong associations between kidney dysfunction and risk of ischemic stroke (IS), the mechanisms of which are incompletely understood. We investigated whether these associations may reflect shared heritability because of a common polygenic basis and whether this differed for IS subtypes. METHODS: Polygenic models were derived using genome-wide association studies meta-analysis results for 3 kidney traits: estimated glomerular filtration rate using serum creatinine (eGFRcrea: n=73 998), eGFR using cystatin C (eGFRcys: n=22 937), and urinary albumin to creatinine ratio (n=31 580). For each, single nucleotide polymorphisms passing 10 P value thresholds were used to form profile scores in 4561 IS cases and 7094 controls from the United Kingdom, Germany, and Australia. Scores were tested for association with IS and its 3 aetiological subtypes: large artery atherosclerosis, cardioembolism, and small vessel disease. RESULTS: Polygenic scores correlating with higher eGFRcrea were associated with reduced risk of large artery atherosclerosis, with 5 scores reaching P<0.05 (peak P=0.004) and all showing the epidemiologically expected direction of effect. A similar pattern was observed for polygenic scores reflecting higher urinary albumin to creatinine ratio, of which 3 associated with large artery atherosclerosis (peak P=0.01) and all showed the expected directional association. One urinary albumin to creatinine ratio-based score also associated with small vessel disease (P=0.03). The global pattern of results was unlikely to have occurred by chance (P=0.02). CONCLUSIONS: This study suggests possible polygenic correlation between renal dysfunction and IS. The shared genetic components may be specific to stroke subtypes, particularly large artery atherosclerotic stroke. Further study of the genetic relationships between these disorders seems merited.

Association of levels of fasting glucose and insulin with rare variants at the chromosome 11p11.2-MADD locus: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.

BACKGROUND: Common variation at the 11p11.2 locus, encompassing MADD, ACP2, NR1H3, MYBPC3, and SPI1, has been associated in genome-wide association studies with fasting glucose and insulin (FI). In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study, we sequenced 5 gene regions at 11p11.2 to identify rare, potentially functional variants influencing fasting glucose or FI levels. METHODS AND RESULTS: Sequencing (mean depth, 38×) across 16.1 kb in 3566 individuals without diabetes mellitus identified 653 variants, 79.9% of which were rare (minor allele frequency <1%) and novel. We analyzed rare variants in 5 gene regions with FI or fasting glucose using the sequence kernel association test. At NR1H3, 53 rare variants were jointly associated with FI (P=2.73×10(-3)); of these, 7 were predicted to have regulatory function and showed association with FI (P=1.28×10(-3)). Conditioning on 2 previously associated variants at MADD (rs7944584, rs10838687) did not attenuate this association, suggesting that there are >2 independent signals at 11p11.2. One predicted regulatory variant, chr11:47227430 (hg18; minor allele frequency=0.00068), contributed 20.6% to the overall sequence kernel association test score at NR1H3, lies in intron 2 of NR1H3, and is a predicted binding site for forkhead box A1 (FOXA1), a transcription factor associated with insulin regulation. In human HepG2 hepatoma cells, the rare chr11:47227430 A allele disrupted FOXA1 binding and reduced FOXA1-dependent transcriptional activity. CONCLUSIONS: Sequencing at 11p11.2-NR1H3 identified rare variation associated with FI. One variant, chr11:47227430, seems to be functional, with the rare A allele reducing transcription factor FOXA1 binding and FOXA1-dependent transcriptional activity.

Explaining the racial difference in AKI incidence.

African Americans face higher risk of AKI than Caucasians. The extent to which this increased risk is because of differences in clinical, socioeconomic, or genetic risk factors is unknown. We evaluated 10,588 African-American and Caucasian participants in the Atherosclerosis Risk in Communities study, a community-based prospective cohort of middle-aged individuals. Participants were followed from baseline study visit (1996-1999) to first hospitalization for AKI (defined by billing code), ESRD, death, or December 31, 2010. African-American participants were slightly younger (61.7 versus 63.1 years, P<0.001), were more often women (64.5% versus 53.2%, P<0.001), and had higher baseline eGFR compared with Caucasians. Annual family income, education level, and prevalence of health insurance were lower among African Americans than Caucasians. The unadjusted incidence of hospitalized AKI was 7.4 cases per 1000 person-years among African Americans and 5.8 cases per 1000 person-years among Caucasians (P=0.002). The elevated risk of AKI among African Americans persisted after adjustment for demographics, cardiovascular risk factors, kidney markers, and time-varying number of hospitalizations (adjusted hazard ratio, 1.20; 95% confidence interval [95% CI], 1.01 to 1.43; P=0.04); however, accounting for differences in income and/or insurance by race attenuated the association (P>0.05). High-risk APOL1 variants did not associate with AKI among African Americans (demographic-adjusted hazard ratio, 1.07; 95% CI, 0.69 to 1.65; P=0.77). In summary, the higher risk of AKI among African Americans may be related to disparities in socioeconomic status.

The pharmacogenetics of type 2 diabetes: a systematic review.

OBJECTIVE: We performed a systematic review to identify which genetic variants predict response to diabetes medications. RESEARCH DESIGN AND METHODS: We performed a search of electronic databases (PubMed, EMBASE, and Cochrane Database) and a manual search to identify original, longitudinal studies of the effect of diabetes medications on incident diabetes, HbA1c, fasting glucose, and postprandial glucose in prediabetes or type 2 diabetes by genetic variation. Two investigators reviewed titles, abstracts, and articles independently. Two investigators abstracted data sequentially and evaluated study quality independently. Quality evaluations were based on the Strengthening the Reporting of Genetic Association Studies guidelines and Human Genome Epidemiology Network guidance. RESULTS: Of 7,279 citations, we included 34 articles (N = 10,407) evaluating metformin (n = 14), sulfonylureas (n = 4), repaglinide (n = 8), pioglitazone (n = 3), rosiglitazone (n = 4), and acarbose (n = 4). Studies were not standalone randomized controlled trials, and most evaluated patients with diabetes. Significant medication-gene interactions for glycemic outcomes included 1) metformin and the SLC22A1, SLC22A2, SLC47A1, PRKAB2, PRKAA2, PRKAA1, and STK11 loci; 2) sulfonylureas and the CYP2C9 and TCF7L2 loci; 3) repaglinide and the KCNJ11, SLC30A8, NEUROD1/BETA2, UCP2, and PAX4 loci; 4) pioglitazone and the PPARG2 and PTPRD loci; 5) rosiglitazone and the KCNQ1 and RBP4 loci; and 5) acarbose and the PPARA, HNF4A, LIPC, and PPARGC1A loci. Data were insufficient for meta-analysis. CONCLUSIONS: We found evidence of pharmacogenetic interactions for metformin, sulfonylureas, repaglinide, thiazolidinediones, and acarbose consistent with their pharmacokinetics and pharmacodynamics. While high-quality controlled studies with prespecified analyses are still lacking, our results bring the promise of personalized medicine in diabetes one step closer to fruition.

Genome-wide association study identifies common loci influencing circulating glycated hemoglobin (HbA1c) levels in non-diabetic subjects: the Long Life Family Study (LLFS).

OBJECTIVE: Glycated hemoglobin (HbA1c) is a stable index of chronic glycemic status and hyperglycemia associated with progressive development of insulin resistance and frank diabetes. It is also associated with premature aging and increased mortality. To uncover novel loci for HbA1c that are associated with healthy aging, we conducted a genome-wide association study (GWAS) using non-diabetic participants in the Long Life Family Study (LLFS), a study with familial clustering of exceptional longevity in the US and Denmark. METHODS: A total of 4088 non-diabetic subjects from the LLFS were used for GWAS discoveries, and a total of 8231 non-diabetic subjects from the Atherosclerosis Risk in Communities Study (ARIC, in the MAGIC Consortium) and the Health, Aging, and Body Composition Study (HABC) were used for GWAS replications. HbA1c was adjusted for age, sex, centers, 20 principal components, without and with BMI. A linear mixed effects model was used for association testing. RESULTS: Two known loci at GCK rs730497 (or rs2908282) and HK1 rs17476364 were confirmed (p<5e-8). Of 25 suggestive (5e-8

Biomarkers of vascular calcification and mortality in patients with ESRD.

BACKGROUND: Vascular calcification is common among patients undergoing dialysis and is associated with mortality. Factors such as osteoprotegerin (OPG), osteopontin (OPN), bone morphogenic protein-7 (BMP-7), and fetuin-A are involved in vascular calcification. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: OPG, OPN, BMP-7, and fetuin-A were measured in blood samples from 602 incident dialysis patients recruited from United States dialysis centers between 1995 and 1998 as part of the Choices for Healthy Outcomes In Caring for ESRD Study. Their association with all-cause and cardiovascular mortality were assessed using Cox proportional hazards models adjusted for demographic characteristics, comorbidity, serum phosphate, and calcium. An interaction with diabetes was tested because of its known association with vascular calcification. Predictive accuracy of selected biomarkers was explored by C-statistics in nested models with training and validation subcohorts. RESULTS: Higher OPG and lower fetuin-A levels were associated with higher mortality over up to 13 years of follow-up (median, 3.4 years). The adjusted hazard ratios (HR) for highest versus lowest tertile were 1.49 (95% confidence interval [95% CI], 1.08 to 2.06) for OPG and 0.69 (95% CI, 0.52 to 0.92) for fetuin-A. In stratified models, the highest tertile of OPG was associated with higher mortality among patients without diabetes (HR, 2.42; 95% CI, 1.35 to 4.34), but not patients with diabetes (HR, 1.26; 95% CI, 0.82 to 1.93; P for interaction=0.001). In terms of cardiovascular mortality, higher fetuin-A was associated with lower risk (HR, 0.85 per 0.1 g/L: 95% CI, 0.75 to 0.96). In patients without diabetes, higher OPG was associated with greater risk (HR for highest versus lowest tertile, 2.91; 95% CI, 1.06 to 7.99), but not in patients with diabetes or overall. OPN and BMP-7 were not independently associated with outcomes overall. The addition of OPG and fetuin-A did not significantly improve predictive accuracy of mortality. CONCLUSIONS: OPG and fetuin-A may be risk factors for all-cause and cardiovascular mortality in patients undergoing dialysis, but do not improve risk prediction.

Association of a cystatin C gene variant with cystatin C levels, CKD, and risk of incident cardiovascular disease and mortality.

BACKGROUND: Carriers of the T allele of the single-nucleotide polymorphism rs13038305 tend to have lower cystatin C levels and higher cystatin C-based estimated glomerular filtration rate (eGFRcys). Adjusting for this genetic effect on cystatin C concentrations may improve GFR estimation, reclassify cases of chronic kidney disease (CKD), and strengthen risk estimates for cardiovascular disease (CVD) and mortality. STUDY DESIGN: Observational. SETTING & POPULATION: 4 population-based cohorts: Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health (CHS), Framingham Heart (FHS), and Health, Aging, and Body Composition (Health ABC) studies. PREDICTORS: We estimated the association of rs13038305 with eGFRcys and serum creatinine-based eGFR (eGFRcr) and performed longitudinal analyses of the associations of eGFRcys with mortality and cardiovascular events following adjustment for rs13038305. OUTCOMES: We assessed reclassification by genotype-adjusted eGFRcys across CKD categories: <45, 45-59, 60-89, and ≥ 90 mL/min/1.73 m(2). We compared mortality and CVD outcomes in those reclassified to a worse eGFRcys category with those unaffected. Results were combined using fixed-effect inverse-variance meta-analysis. RESULTS: In 14,645 participants, each copy of the T allele of rs13038305 (frequency, 21%) was associated with a 6.4% lower cystatin C concentration, 5.5-mL/min/1.73 m(2) higher eGFRcys, and 36% [95% CI, 29%-41%] lower odds of CKD. Associations with CVD (HR, 1.17; 95% CI, 1.14-1.20) and mortality (HR, 1.22; 95% CI, 1.19-1.24) per 10-mL/min/1.73 m(2) lower eGFRcys were similar with or without rs13038305 adjustment. 1,134 (7.7%) participants were reclassified to a worse CKD category following rs13038305 adjustment, and rates of CVD and mortality were higher in individuals who were reclassified. However, the overall net reclassification index was not significant for either outcome, at 0.009 (95% CI, -0.003 to 0.022) for mortality and 0.014 (95% CI, 0.0 to 0.028) for CVD. LIMITATIONS: rs13038305 explains only a small proportion of cystatin C variation. CONCLUSIONS: Statistical adjustment can correct a genetic bias in GFR estimates based on cystatin C in carriers of the T allele of rs13038305 and result in changes in disease classification. However, on a population level, the effects on overall reclassification of CKD status are modest.

A genome-wide search for linkage of estimated glomerular filtration rate (eGFR) in the Family Investigation of Nephropathy and Diabetes (FIND).

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.

Association of SERPINA9 gene variants with carotid artery atherosclerosis: the Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study.

The SNP rs11628722 in the SERPINA9 gene was previously associated with incident ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) study. Centerin, the protein encoded by SERPINA9, is involved in maturation and maintenance of naïve B cells, which play a role in atherogenesis. We investigated whether 21 tag SNPs in the SERPINA9 gene are associated with features of carotid artery atherosclerotic plaque measured by magnetic resonance imaging (MRI). Carotid MRI data were obtained from 1,282 European Americans and 341 African Americans of the ARIC Carotid MRI study, which recruited participants from ARIC by a stratified sampling plan that over-sampled participants with carotid intima-media thickening. Five MRI measures, focused on carotid wall volume, wall thickness, and lipid core, were analyzed. Genetic associations between the MRI measurements and each of the 21 SNPs were analyzed in linear regression models with adjustment for sample weights and traditional risk factors. Rs11628722 was tested a priori. In African Americans, rs11628722 was significantly associated with carotid wall volume (p < 0.05). Among the other 20 SNPs, adjusted for multiple testing, rs4905204, which encodes an Ala to Val amino acid change, was significantly associated with maximum wall thickness (p < 0.000625) and suggestively associated with total wall volume (p < 0.0026) in European Americans. In conclusion, SNPs in the SERPINA9 gene showed race-specific associations with characteristics of carotid atherosclerotic plaques. Replications in other populations are needed to validate findings of this study and to establish the SERPINA9 gene as a candidate in the etiology of carotid atherosclerosis.