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

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          Abstract

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

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          APOL1 risk variants, race, and progression of chronic kidney disease.

          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. 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. 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). 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.).
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            Estimation of individual admixture: analytical and study design considerations.

            The genome of an admixed individual represents a mixture of alleles from different ancestries. In the United States, the two largest minority groups, African-Americans and Hispanics, are both admixed. An understanding of the admixture proportion at an individual level (individual admixture, or IA) is valuable for both population geneticists and epidemiologists who conduct case-control association studies in these groups. Here we present an extension of a previously described frequentist (maximum likelihood or ML) approach to estimate individual admixture that allows for uncertainty in ancestral allele frequencies. We compare this approach both to prior partial likelihood based methods as well as more recently described Bayesian MCMC methods. Our full ML method demonstrates increased robustness when compared to an existing partial ML approach. Simulations also suggest that this frequentist estimator achieves similar efficiency, measured by the mean squared error criterion, as Bayesian methods but requires just a fraction of the computational time to produce point estimates, allowing for extensive analysis (e.g., simulations) not possible by Bayesian methods. Our simulation results demonstrate that inclusion of ancestral populations or their surrogates in the analysis is required by any method of IA estimation to obtain reasonable results. (c) 2005 Wiley-Liss, Inc.
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              Apolipoprotein L1 risk variants associate with systemic lupus erythematosus-associated collapsing glomerulopathy.

              Collapsing glomerulopathy is a devastating renal disease that primarily affects African Americans and associates with numerous etiologies, such as HIV and autoimmune disease. The presence of APOL1 risk alleles associates with HIV-associated collapsing glomerulopathy, but it is unknown whether these risk alleles also associate with systemic lupus erythematosus (SLE) -associated collapsing glomerulopathy. Here, re-examination of 546 renal biopsies from African-American patients with SLE identified 26 cases of collapsing glomerulopathy, which we genotyped for APOL1 risk alleles using DNA extracted from archived biopsy tissue. APOL1 strongly associated with SLE-associated collapsing glomerulopathy (P<0.001). In a recessive model, two APOL1 risk alleles conferred 5.4-fold (95% CI=2.4 to 12.1) higher odds of developing SLE-associated collapsing glomerulopathy (P<0.001). In conclusion, APOL1 genotyping of African-American patients with SLE might help identify patients at risk for collapsing glomerulopathy, an entity with a poor prognosis that is often resistant to treatment.
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                Author and article information

                Journal
                0323470
                5428
                Kidney Int
                Kidney Int.
                Kidney international
                0085-2538
                1523-1755
                25 June 2014
                16 July 2014
                January 2015
                01 July 2015
                : 87
                : 1
                : 169-175
                Affiliations
                [1 ]Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC
                [2 ]Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC
                [3 ]Internal Medicine–Nephrology, Wake Forest School of Medicine, Winston-Salem, NC
                [4 ]Patient-Centered Outcomes Research Institute (PCORI), Washington, DC
                [5 ]University of California Davis Healthcare System, Sacramento, CA
                [6 ]National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD
                [7 ]Medicine-Nephrology, George Washington University School of Medicine, Washington, DC
                [8 ]Medicine-Nephrology, University of Illinois College of Medicine at Chicago, Chicago, IL
                [9 ]Medicine-Hypertension, University Hospitals, Case Medical Center, Cleveland, OH
                [10 ]Medicine, Physiology & Biophysics, Case Western Reserve University, Cleveland, OH
                Author notes
                Correspondence: Barry I. Freedman, M.D., Section on Nephrology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1053, U.S.A. Phone: 336-716-6192, Fax: 336-716-4318, bfreedma@ 123456wakehealth.edu
                Article
                NIHMS607977
                10.1038/ki.2014.254
                4281289
                25029429
                8272cf7f-e7e4-483e-9b0d-5851b6cfdb35
                History
                Categories
                Article

                Nephrology
                african americans,albuminuria,apol1,cardiovascular disease,chronic kidney disease,sprint
                Nephrology
                african americans, albuminuria, apol1, cardiovascular disease, chronic kidney disease, sprint

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