Characteristics and long-term follow-up of participants with peripheral arterial disease during ALLHAT.

BACKGROUND: Hypertension is a major risk factor for peripheral artery disease (PAD). Little is known about relative efficacy of antihypertensive treatments for preventing PAD. OBJECTIVES: To compare, by randomized treatment groups, hospitalized or revascularized PAD rates and subsequent morbidity and mortality among participants in the Antihypertensive and Lipid-Lower Treatment to Prevent Heart Attack Trial (ALLHAT). DESIGN: Randomized, double-blind, active-control trial in high-risk hypertensive participants. PARTICIPANTS: Eight hundred thirty participants with specified secondary outcome of lower extremity PAD events during the randomized phase of ALLHAT. INTERVENTIONS/EVENTS: In-trial PAD events were reported during ALLHAT (1994-2002). Post-trial mortality data through 2006 were obtained from administrative databases. Mean follow-up was 8.8 years. MAIN MEASURES: Baseline characteristics and intermediate outcomes in three treatment groups, using the Kaplan-Meier method to calculate cumulative event rates and post-PAD mortality rates, Cox proportional hazards regression model for hazard ratios and 95 % confidence intervals, and multivariate Cox regression models to examine risk differences among treatment groups. KEY RESULTS: Following adjustment for baseline characteristics, neither participants assigned to the calcium-channel antagonist amlodipine nor to the ACE-inhibitor lisinopril showed a difference in risk of clinically advanced PAD compared with those in the chlorthalidone arm (HR, 0.86; 95 % CI, 0.72-1.03 and HR, 0.98; 95 % CI, 0.83-1.17, respectively). Of the 830 participants with in-trial PAD events, 63 % died compared to 34 % of those without PAD; there were no significant treatment group differences for subsequent nonfatal myocardial infarction, coronary revascularizations, strokes, heart failure, or mortality. CONCLUSIONS: Neither amlodipine nor lisinopril showed superiority over chlorthalidone in reducing clinically advanced PAD risk. These findings reinforce the compelling need for comparative outcome trials examining treatment of PAD in high-risk hypertensive patients. Once PAD develops, cardiovascular event and mortality risk is high, regardless of type of antihypertensive treatment.

Expression of the renin-angiotensin system in a human placental cell line.

BACKGROUND: The renin-angiotensin system (RAS) is present in human placental tissue and participates in regulation of maternal-fetal blood flow during pregnancy. RAS expression in placental tissue is regulated by various hormones and is altered in various disease conditions. An in vitro system is needed to further investigate regulation of the placental RAS. To this end, we studied RAS expression in the human placenta-derived cell line, CRL-7548. METHODS: CRL-7548 cells were cultured in plastic plates. Total RNA was extracted, reverse transcribed, and amplified by polymerase chain reaction (PCR) with specific primers. Angiotensin II peptide in the culture media was measured by radioimmunoassay. Renin activity was detected by radioimmunoassay measuring angiotensin I generated. Angiotensin receptor type I was detected by Western blot. RESULTS: Specific mRNA for angiotensin, renin, angiotensin converting enzyme, and angiotensin receptor type I was detected by real-time PCR. Renin activity was detected in the placental cell lysate, and angiotensin II peptide, the final product of the RAS system, was detected in cell culture media by radioimmunoassay. Angiotensin receptor type I was identified as a 41 kDa protein in cell lysates by Western blot. CONCLUSIONS: These results demonstrate that all necessary components of the classic RAS are expressed in the human placental cell line CRL-7548. This cell line may prove useful as an in vitro system for studying RAS regulation in the placenta.

The use of dietary supplements and their association with blood pressure in a large Midwestern cohort.

BACKGROUND: There have been numerous studies assessing the association of diet and blood pressure but little is known about the association between less commonly used nutritional supplements and blood pressured. The purpose of this study was to quantify the use of dietary supplements and their potential association with blood pressure in a large population-based cohort of adults in the Midwest. METHODS: The Personalized Medicine Research Project cohort was the population source for the current study. The current study includes subjects with Dietary History Questionnaire (DHQ) data available as well as at least one clinical blood pressure measurement recorded in their electronic medical record. After excluding extreme outlying measurements, median systolic and diastolic blood pressure measurements were calculated for each individual and were compared for subjects who did and did not report taking one of a list of 37 different supplements listed on the DHQ more than once per week over the previous 12 months. RESULTS: 9,732 subjects had both blood pressure and DHQ data available. They ranged in age from 18 to 98 years (mean 56 years) and 3,625 (37%) were male. Nine of 37 supplements showed evidence for association with blood pressure: coenzyme Q10, fish oil, iron, bilberry, echinacea, evening primrose oil, garlic, goldenseal and milk thistle. With the exception of the mineral iron, mean systolic and diastolic blood pressures were higher for users of the specific supplements than non-users. CONCLUSIONS: These results should not be interpreted as causal, nor can the direction of the association be assumed to be correct because the temporality of the association is unknown. We hope the observed significant associations will foster future research to evaluate blood pressure effects of dietary supplements.

Estimating the efficacy of pharmacogenomics over a lifetime.

It is well known that common variants in specific genes influence drug metabolism and response, but it is currently unknown what fraction of patients are given prescriptions over a lifetime that could be contraindicated by their pharmacogenomic profiles. To determine the clinical utility of pharmacogenomics over a lifetime in a general patient population, we sequenced the genomes of 300 deceased Marshfield Clinic patients linked to lifelong medical records. Genetic variants in 33 pharmacogenes were evaluated for their lifetime impact on drug prescribing using extensive electronic health records. Results show that 93% of the 300 deceased patients carried clinically relevant variants. Nearly 80% were prescribed approximately three medications on average that may have been impacted by these variants. Longitudinal data suggested that the optimal age for pharmacogenomic testing was prior to age 50, but the optimal age is greatly influenced by the stability of the population in the healthcare system. This study emphasizes the broad clinical impact of pharmacogenomic testing over a lifetime and demonstrates the potential application of genomic medicine in a general patient population for the advancement of precision medicine.

Validating cuffless continuous blood pressure monitoring devices.

Cuff-based home blood pressure (BP) devices, which have been the standard for BP monitoring for decades, are limited by physical discomfort, convenience, and their ability to capture BP variability and patterns between intermittent readings. In recent years, cuffless BP devices, which do not require cuff inflation around a limb, have entered the market, offering the promise of continuous beat-to-beat measurement of BP. These devices take advantage of a variety of principles to determine BP, including (1) pulse arrival time, (2) pulse transit time, (3) pulse wave analysis, (4) volume clamping, and (5) applanation tonometry. Because BP is calculated indirectly, these devices require calibration with cuff-based devices at regular intervals. Unfortunately, the pace of regulation of these devices has failed to match the speed of innovation and direct availability to patient consumers. There is an urgent need to develop a consensus on standards by which cuffless BP devices can be tested for accuracy. In this narrative review, we describe the landscape of cuffless BP devices, summarize the current status of validation protocols, and provide recommendations for an ideal validation process for these devices.

Long-term follow-up of participants with heart failure in the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT).

BACKGROUND: In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double-blind, practice-based, active-control, comparative effectiveness trial in high-risk hypertensive participants, risk of new-onset heart failure (HF) was higher in the amlodipine (2.5-10 mg/d) and lisinopril (10-40 mg/d) arms compared with the chlorthalidone (12.5-25 mg/d) arm. Similar to other studies, mortality rates following new-onset HF were very high (≥50% at 5 years), and were similar across randomized treatment arms. After the randomized phase of the trial ended in 2002, outcomes were determined from administrative databases. METHODS AND RESULTS: With the use of national databases, posttrial follow-up mortality through 2006 was obtained on participants who developed new-onset HF during the randomized (in-trial) phase of ALLHAT. Mean follow-up for the entire period was 8.9 years. Of 1761 participants with incident HF in-trial, 1348 died. Post-HF all-cause mortality was similar across treatment groups, with adjusted hazard ratios (95% confidence intervals) of 0.95 (0.81-1.12) and 1.05 (0.89-1.25), respectively, for amlodipine and lisinopril compared with chlorthalidone, and 10-year adjusted rates of 86%, 87%, and 83%, respectively. All-cause mortality rates were also similar among those with reduced ejection fractions (84%) and preserved ejection fractions (81%), with no significant differences by randomized treatment arm. CONCLUSIONS: Once HF develops, risk of death is high and consistent across randomized treatment groups. Measures to prevent the development of HF, especially blood pressure control, must be a priority if mortality associated with the development of HF is to be addressed. Clinical Trial Registration- http://www.clinicaltrials.gov. Unique identifier: NCT00000542.

Cardiovascular risk assessment: addition of CKD and race to the Framingham equation.

BACKGROUND/AIMS: The value of the Framingham equation in predicting cardiovascular risk in African Americans and patients with chronic kidney disease (CKD) is unclear. The purpose of the study was to evaluate whether the addition of CKD and race to the Framingham equation improves risk stratification in hypertensive patients. METHODS: Participants in the ALLHAT were studied. Those randomized to doxazosin, older than 74 years, and those with a history of coronary heart disease were excluded. Two risk stratification models were developed using Cox proportional hazards models in a two-thirds developmental sample. The first model included the traditional Framingham risk factors. The second model included the traditional risk factors plus CKD, defined by estimated glomerular filtration rate categories, and stratification by race (black vs non-black). The primary outcome was a composite of fatal coronary heart disease, nonfatal myocardial infarction, coronary revascularization, and hospitalized angina. RESULTS: There were a total of 19,811 eligible subjects. In the validation cohort, there was no difference in C-statistics between the Framingham equation and the ALLHAT model including CKD and race. This was consistent across subgroups by race and sex and among those with CKD. One exception was among Non-Black women where the C-statistic was higher for the Framingham equation (0.68 vs 0.65, P = .02). In addition, net reclassification improvement was not significant for any subgroup based on race and sex, ranging from -5.5% to 4.4%. CONCLUSION: The addition of CKD status and stratification by race does not improve risk prediction in high-risk hypertensive patients.

Palliative medicine referral in patients undergoing continuous renal replacement therapy for acute kidney injury.

BACKGROUND: Referral patterns for palliative medicine consultation (PMC) by intensivists for patients requiring continuous renal replacement therapy (CRRT) have not been studied. METHODS: We retrospectively analyzed clinical data on patients who received CRRT in a tertiary referral center between 1999 and 2006 to determine timeliness and effectiveness of PMC referrals and mortality rate as a surrogate for safety among patients receiving CRRT for acute kidney injury. RESULTS: Over one-fifth (21.1%) of the 230 CRRT patients studied were referred for PMC (n = 55). PMC was requested on average after median of 15 hospital and 13 intensive care unit (ICU) days. Multivariate regression analysis revealed no association between mortality risk and PMC. Total hospital length of stay for patients who died after PMC referral was 18.5 (95% CI = 15-25) days compared with 12.5 days (95% CI = 9-17) for patients who died without PMC referral. ICU care for patients who died and received PMC was longer than for patients with no PMC [11.5 (95% CI = 9-15) days vs. 7.0 (95% CI = 6-9) days, p < 0.01]. CRRT duration was longer for patients who died and received PMC referral than for those without PMC [5.5 (95% CI = 4-8) vs. 3.0 (95% CI = 3-4) days; p < 0.01]. CONCLUSIONS: PMC was safe, but referrals were delayed and ineffective in optimizing the utilization of intensive care in patients receiving CRRT. A proactive, "triggered" referral process will likely be necessary to improve timeliness of PMC and reduce duration of non-beneficial life-sustaining therapies.

Does early initiation of continuous renal replacement therapy affect outcome: experience in a tertiary care center.

BACKGROUND: Acute kidney injury (AKI) requiring dialysis commonly occurs in critically ill patients and is associated with high mortality. Factors impacting outcomes of individuals with AKI who underwent continuous renal replacement therapy (CRRT), including early versus late initiation and duration of CRRT, were examined. METHODS: Survival and recovery of renal function for patients with AKI in the intensive care unit were retrospectively examined over a 7-year period. Factors associated with mortality and renal recovery were analyzed based on severity of illness as defined by Cleveland Clinic Foundation (CCF) score. Univariate and multivariate logistic regression analysis with backward elimination was performed to determine the most significant risk factors. RESULTS: Of patients who underwent CRRT, 230/330 met inclusion criteria. During index admission 112/230 (48.7%) patients died. Median survival was 15.5 days [95% confidence interval (12.0, 18.0)]. Among survivors, renal recovery occurred in 84/118 (71.2%). Renal recovery overall was observed in 90/230 subjects (39.13%). A higher baseline CCF score correlated with higher mortality and lower probability of renal recovery. Patients initiated on CRRT > 6 days after AKI diagnosis had significantly higher mortality compared with those initiated earlier (odds ratio = 11.66, p = 0.0305). Patients receiving CRRT >10 days had a higher mortality rate compared with those with shorter exposure (71.3% vs. 45.5%, respectively, p = 0.012). CONCLUSIONS: CRRT remains an important dialysis modality in hemodynamically unstable patients with AKI. Mortality in these patients continues to be high. Renal recovery is high in survivors. Delay in initiation and length of CRRT exposure may portend poorer prognosis.

Medical records-based chronic kidney disease phenotype for clinical care and "big data" observational and genetic studies.

Chronic Kidney Disease (CKD) represents a slowly progressive disorder that is typically silent until late stages, but early intervention can significantly delay its progression. We designed a portable and scalable electronic CKD phenotype to facilitate early disease recognition and empower large-scale observational and genetic studies of kidney traits. The algorithm uses a combination of rule-based and machine-learning methods to automatically place patients on the staging grid of albuminuria by glomerular filtration rate ("A-by-G" grid). We manually validated the algorithm by 451 chart reviews across three medical systems, demonstrating overall positive predictive value of 95% for CKD cases and 97% for healthy controls. Independent case-control validation using 2350 patient records demonstrated diagnostic specificity of 97% and sensitivity of 87%. Application of the phenotype to 1.3 million patients demonstrated that over 80% of CKD cases are undetected using ICD codes alone. We also demonstrated several large-scale applications of the phenotype, including identifying stage-specific kidney disease comorbidities, in silico estimation of kidney trait heritability in thousands of pedigrees reconstructed from medical records, and biobank-based multicenter genome-wide and phenome-wide association studies.

Association of B-type natriuretic Peptide levels with estimated glomerular filtration rate and congestive heart failure.

BACKGROUND: The causes of elevated B-Type natriuretic peptide (BNP) levels are multifactorial. Renal dysfunction has been shown to affect BNP levels in some studies and the diagnostic value of BNP levels in the presence of chronic kidney disease has been questioned. Prior studies have involved small patient populations with variable outcomes noted. This study evaluated the association of BNP levels with an estimated glomerular filtration rate (eGFR) and presence or absence of congestive heart failure (CHF). METHODS: A retrospective, cross-sectional study in which medical records were electronically screened, identified patients with a BNP level and serum creatinine measurement on the same day between December 2002 and March 2006. RESULTS: Of 1739 eligible patients, 537 were positive for CHF and 1202 were negative for CHF by our criteria. There was a clear trend for BNP to be higher with the advancement of CHF, as determined by New York Heart Association (NYHA) classification (P<0.001). Median BNP levels increased from 65 pg/mL in patients without CHF to 496 pg/mL in patients with NYHA class IV CHF (P <0.001), and there was a strong inverse association with eGFR (P <0.001). CONCLUSION: BNP levels show a strong inverse association with eGFR in both CHF and non-CHF patients. Currently best practice at most institutions involves use of BNP cutoff diagnostic levels not adjusted for eGFR. The data presented underlines that eGFR is a significant confounder of BNP measurement especially when renal status is compromised and interpretation of clinical significance in the presence of elevated BNP measures should take renal status into consideration.

Evaluating the impact of motion artifact on noninvasive blood pressure devices.

Most automated sphygmomanometers use oscillometric algorithms. Motion, either patient-based or environmental, will affect the ability of a device to record an accurate blood pressure (BP). Members of the Association for the Advancement of Medical Instrumentation (AAMI) Sphygmomanometer Committee have been studying this problem for more than a decade. The AAMI TIR44 was the first publication to address the challenges of motion tolerance. The concepts described in TIR44 have led to the development of a draft of ISO 81060-4, a new standard for testing devices for which the manufacturer wishes to claim motion tolerance. The current ISO 81060-2 addresses both stress testing and 24-hour ambulatory BP monitoring. Recent publications have reported on testing of devices in response to voluntary and involuntary patient motion. The ISO 81060-4 will address testing in the presence of patient transport by ground, fixed-wing, and rotary (helicopter) ambulances. The protocol will utilize noise profiles recorded under those three conditions. The profiles will be digitally stored on a library with free access. The proposed testing will be performed using patient simulators introducing the noise library files into known BP oscillometric envelopes. The specifications of the data capture and playback devices are specified, as is the evaluation statistical testing. The authors expect that the final draft will be published in 2020.

NPHS2 variation in sporadic focal segmental glomerulosclerosis.

Mutations in NPHS2, the gene that encodes podocin, are well-established causes of both familial and sporadic steroid-resistant focal segmental glomerulosclerosis (FSGS) in the pediatric population, but have not been well-characterized in late-onset disease. To investigate the role of NPHS2 polymorphisms in sporadic cases of late-onset FSGS, we studied 377 biopsy-confirmed FSGS cases and 919 controls. We identified 18 single nucleotide polymorphisms (SNPs) by resequencing a subgroup of cases and controls, and subsequently genotyped African-American and European-American cases and controls for five missense SNPs, three SNPs within introns, and four SNPs in the 3' untranslated region. No homozygotes or compound heterozygotes were observed for any missense mutation. R138Q carriers were more frequent among FSGS cases relative to controls (OR = 4.9, P = 0.06), but heterozygosity for the other four missense mutations was equally distributed among FSGS cases and controls. Finally, a common haplotype of noncoding SNPs carried by 20% of African-Americans, but not observed in European-Americans, was strongly associated with a 50% reduction in risk for sporadic FSGS (OR = 0.5, P = 0.001). These results indicate that genetic variation or mutation of NPHS2 may play a role in late-onset sporadic FSGS.

Treatment-Related Cardiovascular Outcomes in Patients with Symptomatic Subclavian Artery Stenosis.

BACKGROUND: Subclavian artery stenosis (SAS) is narrowing of the subclavian artery most commonly caused by atherosclerosis. It serves as a marker for cerebrovascular and myocardial ischemic events. METHODS: A retrospective cohort study was conducted to determine the association of treatment via combination therapy (antiplatelet drug plus either by-pass surgery or percutaneous transluminal angioplasty (PTA) with or without stent implantation) versus antiplatelet drug therapy alone on cardiovascular events and all-cause mortality in Marshfield Clinic patients diagnosed with symptomatic SAS from January 1, 1995 to December 31, 2009. RESULTS: Of the total 2153 cases, 100 patients were identified as eligible to be included in the study. Of these 100 patients that met inclusion criteria, 30 underwent combination therapy while 70 were managed only with drug treatment. A median length of follow-up was 8.45 years. Adverse cardiovascular events occurred in 5/30 (17%) of combination therapy patients compared to 28/70 (40%) of antiplatelet drug therapy only patients (p = 0.0355). Accordingly, all-cause mortality was higher (47%) in the antiplatelet drug therapy only group than the combination therapy group (13%) [hazard ratio = 3.45, p = 0.0218]. CONCLUSIONS: Preliminary findings in this pilot data set suggest that combination therapy (medications plus either surgical or interventional repair) of subclavian artery stenosis is associated with less cardiovascular adverse events and higher survival rates. However, prospective randomized studies with larger number of patients are needed to validate these findings.

Evaluating electronic health record data sources and algorithmic approaches to identify hypertensive individuals.

OBJECTIVE: Phenotyping algorithms applied to electronic health record (EHR) data enable investigators to identify large cohorts for clinical and genomic research. Algorithm development is often iterative, depends on fallible investigator intuition, and is time- and labor-intensive. We developed and evaluated 4 types of phenotyping algorithms and categories of EHR information to identify hypertensive individuals and controls and provide a portable module for implementation at other sites. MATERIALS AND METHODS: We reviewed the EHRs of 631 individuals followed at Vanderbilt for hypertension status. We developed features and phenotyping algorithms of increasing complexity. Input categories included International Classification of Diseases, Ninth Revision (ICD9) codes, medications, vital signs, narrative-text search results, and Unified Medical Language System (UMLS) concepts extracted using natural language processing (NLP). We developed a module and tested portability by replicating 10 of the best-performing algorithms at the Marshfield Clinic. RESULTS: Random forests using billing codes, medications, vitals, and concepts had the best performance with a median area under the receiver operator characteristic curve (AUC) of 0.976. Normalized sums of all 4 categories also performed well (0.959 AUC). The best non-NLP algorithm combined normalized ICD9 codes, medications, and blood pressure readings with a median AUC of 0.948. Blood pressure cutoffs or ICD9 code counts alone had AUCs of 0.854 and 0.908, respectively. Marshfield Clinic results were similar. CONCLUSION: This work shows that billing codes or blood pressure readings alone yield good hypertension classification performance. However, even simple combinations of input categories improve performance. The most complex algorithms classified hypertension with excellent recall and precision.

Specific receptor for angiotensinogen on human renal cells.

BACKGROUND: We recently demonstrated the existence of an angiotensinogen (AGT) receptor on placental cells. It has been established that there is a tissue-specific renin-angiotensin system (RAS) in the human kidney. This study focused on whether human renal proximal tubule epithelial cells possessed an AGT receptor. METHODS: Human renal proximal tubule epithelial cells were cultured in plastic wells. Binding assays were carried out by adding iodinated angiotensinogen ((125)I-AGT) to each culture well, with or without unlabeled AGT. The cells were washed, lysed, and the radioactivity was measured. RESULTS: Human renal proximal tubule epithelial cells bound (125)I-AGT in a time-dependent manner. This binding was competitively and specifically inhibited by unlabeled AGT. Bound (125)I-AGT was competitively displaced by AGT. Acid washing removed 30% at 8 h, indicating that 70% bound AGT had been internalized. Scatchard plot binding analysis showed that the identified AGT receptor possessed a single class of high-affinity binding sites (K(d)=1.73 nmol, B(max)=23.39 pmol/10(6) cells). CONCLUSION: The results of this study provide evidence for the presence of an AGT receptor on human renal proximal tubule epithelial cells. Our finding suggests that the AGT receptor may be an integral component of the renal RAS.

Small molecule antagonists of the TGF-beta1/TGF-beta receptor binding interaction.

Excessive and inappropriate action of transforming growth factor (TGF)-beta has been implicated in the pathogenesis of several disease processes, especially cancer and fibrosis. To identify antagonists of the TGF- beta ligand-binding domain that may have therapeutic potential, we screened the National Cancer Institute open access chemical repository for molecules that inhibited binding of TGF-beta to the type II receptor (TbetaRII). About 30,000 molecules were screened resulting in the identification of five structurally related molecules that reduced binding of TGF-beta1 to soluble TbetaRII with an ED50 of approx 10 microM. The chemicals blocked inhibition of Mv1Lu cell growth by TGF-beta, TGF-beta - induced expression of luciferase driven by the TGF-beta response element, and induction of plasminogen inhibitor mRNA detected by Northern blot. In contrast, the chemicals did not block activin-induced inhibition of cell growth. Our results identify a novel chemical group that blocks binding of TGF-beta to its receptor and may result in novel treatment for disease.

Variants in the Wilms' tumor gene are associated with focal segmental glomerulosclerosis in the African American population.

Wilms' tumor gene (WT1) is important for nephrogenesis and gonadal growth. WT1 mutations cause Denys-Drash and Frasier syndromes, which are characterized by glomerular scarring. To test whether genetic variations in WT1 and WIT1 (gene immediately 5' to WT1) associate with focal segmental glomerulosclerosis (FSGS), patients with biopsy-proven idiopathic and HIV-1-associated FSGS were enrolled in a multicenter study. We genotyped SNP rs6508 located in WIT1 exon 1, three SNPs (rs2301250, rs2301252, rs2301254) in the promoter shared by WT1 and WIT1, rs2234590 in exon 6, rs2234591 in intron 6, rs16754 in exon 7, and rs1799937 in intron 9 of WT1. Cases (n = 218) and controls (n = 281) were compared in the African American population. Stratification by HIV-1 infection status showed that SNPs rs6508, rs2301254, and rs1799937 were significantly associated with FSGS [rs6508 odds ratio (OR) 1.82, P = 0.006; rs2301254 OR 1.65, P = 0.049; rs1799937 OR 1.91, P = 0.005] in the non-HIV-1 group and rs2234591 (OR 0.234, P = 0.011) in the HIV-1 group. Haplotype analyses in the population revealed that seven SNPs were associated with FSGS; five SNPs had the highest contingency score [-log10(P value) = 13.57] in the HIV-1 group. This association could not be explained by population substructure. We conclude that SNPs in WT1 and WIT1 genes are significantly associated with FSGS, suggesting that variants in these genes may mediate pathogenesis by altering WT1 function. Furthermore, HIV-1 infection status interacts with genetic variations in both genes to influence this phenotype. We speculate that nephropathy liability alleles in WT1 pathway genes cause podocyte dysfunction and glomerular scarring.