22. Watanabe Y, Yamagata K, Nishi S et al. Japanese society for dialysis therapy clinical guideline for "hemodialysis initiation for maintenance hemodialysis". Ther Apher Dial 2015; 19(Suppl 1): 93–107 23. Zaoui PM, Stone WJ, Hakim RM. Effects of dialysis membranes on beta 2-microglobulin production and cellular expression. Kidney Int 1990; 38: 962–968 24. Naiki H, Hashimoto N, Suzuki S et al. Establishment of a kinetic model of dialysis-related amyloid fibril extension in vitro. Amyloid 1997; 4: 223–232 25. Niwa T, Katsuzaki T, Momoi T et al. Modification of beta 2 m with advanced glycation end products as observed in dialysis-related amyloidosis by 3-DG accumulating in uremic serum. Kidney Int 1996; 49: 861–867 26. Miyata T, Inagi R, Iida Y et al. Involvement of beta 2-microglobulin modified with advanced glycation end products in the pathogenesis of hemodialysis-associated amyloidosis. Induction of human monocyte chemotaxis and macrophage secretion of tumor necrosis factor-alpha and interleukin-1. J Clin Invest 1994; 93: 521–528 27. Matsuo K, Ikizler TA, Hoover RL et al. Transforming growth factor-beta is involved in the pathogenesis of dialysis-related amyloidosis. Kidney Int 2000; 57: 697–708 28. Garbar C, Jadoul M, Noel H et al. Histological characteristics of sternoclavicular beta 2-microglobulin amyloidosis and clues for its histogenesis. Kidney Int 1999; 55: 1983–1990 Received for publication: 16.4.2015; Accepted in revised form: 15.6.2015

Nephrol Dial Transplant (2016) 31: 602–608 doi: 10.1093/ndt/gfv229 Advance Access publication 6 July 2015

APOL1 nephropathy risk variants are associated with altered high-density lipoprotein profiles in African Americans Orlando M. Gutiérrez1,2, Suzanne E. Judd3, Marguerite R. Irvin2, Degui Zhi3, Nita Limdi4, Nicholette D. Palmer5,6, Stephen S. Rich7,8,9, Michèle M. Sale7,8,9 and Barry I. Freedman10 1

Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA, 2Department of Epidemiology, University of Alabama at

Birmingham, Birmingham, AL, USA, 3Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA, 4Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA, 5Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA, 6Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA, 7Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA, 8Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA, 9Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA and 10Department of Internal Medicine-Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, USA

Correspondence and offprint requests to: Orlando M. Gutiérrez; E-mail: [email protected]


binds plasma high-density lipoproteins (HDLs), data on APOL1 risk variant associations with HDL subfractions are sparse. Methods. Two APOL1 G1 single nucleotide polymorphisms and the G2 insertion/deletion polymorphism were genotyped in 2010 Reasons for Geographic and Racial Differences in

Background. Two independent coding variants in the apolipoprotein L1 gene (APOL1), G1 and G2, strongly associate with nephropathy in African Americans; associations with cardiovascular disease are more controversial. Although APOL1 © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.


Downloaded from http://ndt.oxfordjournals.org/ at La Trobe University on September 30, 2016

13. Iseki K, Nakai S, Yamagata K et al. Tachycardia as a predictor of poor survival in chronic haemodialysis patients. Nephrol Dial Transplant 2011; 26: 963–969 14. Shoji T, Masakane I, Watanabe Y et al. Elevated non-high-density lipoprotein cholesterol (non-HDL-C) predicts atherosclerotic cardiovascular events in hemodialysis patients. Clin J Am Soc Nephrol 2011; 6: 1112–1120 15. Hoshino J, Yamagata K, Nishi S et al. Carpal tunnel surgery as proxy for dialysis-related amyloidosis: results from the Japanese society for dialysis therapy. Am J Nephrol 2014; 39: 449–458 16. Nakai S, Sinzato T, Sanaka T et al. An overview of dialysis treatment in Japan (as of Dec. 31, 1999). Ther Apher Dial 2001; 34: 1–13 17. Baz M, Durand C, Ragon A et al. Using ultrapure water in hemodialysis delays carpal tunnel syndrome. Int J Artif Organs 1991; 14: 681–685 18. Koda Y, Nishi S, Miyazaki S et al. Switch from conventional to high-flux membrane reduces the risk of carpal tunnel syndrome and mortality of hemodialysis patients. Kidney Int 1997; 52: 1096–1101 19. Kleophas W, Haastert B, Backus G et al. Long-term experience with an ultrapure individual dialysis fluid with a batch type machine. Nephrol Dial Transplant 1998; 13: 3118–3125 20. Kuchle C, Fricke H, Held E et al. High-flux hemodialysis postpones clinical manifestation of dialysis-related amyloidosis. Am J Nephrol 1996; 16: 484–488 21. Schiffl H, Lang SM, Fischer R. Ultrapure dialysis fluid slows loss of residual renal function in new dialysis patients. Nephrol Dial Transplant 2002; 17: 1814–1818

INTRODUCTION Two independent coding variants (G1 and G2) in the gene encoding apolipoprotein L1 (APOL1) are strongly associated with the development of non-diabetic chronic kidney disease (CKD) and the progression of CKD to end-stage renal disease (ESRD) among African Americans [1–5]. The association of APOL1 risk alleles with cardiovascular disease is less clear. In a recent report from the Jackson Heart Study (JHS), greater numbers of APOL1 G1/G2 risk alleles were independently associated with higher cardiovascular disease event rates independently of traditional risk factors and baseline kidney function [6]. In contrast, the Systolic Blood Pressure Intervention Trial (SPRINT) failed to detect an association between APOL1 G1/G2 risk alleles and prevalent cardiovascular disease [7]. Furthermore, the African American-Diabetes Heart Study (AA-DHS) demonstrated an inverse association between numbers of APOL1 G1/G2 risk alleles and calcified atherosclerotic plaque [8]—similar to findings in the JHS [6]—as well as an association of greater numbers of APOL1 G1/G2 risk alleles with improved survival. The mechanisms by which APOL1 G1/G2 risk alleles impact kidney and cardiovascular outcomes remain unclear. The protein product of APOL1 (APOL1) is a member of a family of proteins originally discovered as component elements of high-density lipoprotein (HDL) particles [9]. Subsequent studies identified APOL1 as a key element of HDL molecule complexes known as trypanolytic factors because of their role in clearing trypanosomes from the bloodstream [10]. Given the physiologic relationship between APOL1 and HDL particles, one prior study examined the association of APOL1 G1/G2

APOL1 risk variants and lipoproteins

M AT E R I A L S A N D M E T H O D S The REGARDS Study is a population-based investigation of stroke incidence in African American and European American adults ≥45 years of age. The study design has been reported elsewhere [15]. In brief, participants were recruited from the 48 contiguous US states and the District of Columbia. The study was designed to provide approximately equal representation of men and women, and oversampled African Americans and persons residing in the stroke belt/buckle regions of the USA. Overall, 30 239 individuals were enrolled between January 2003 and October 2007 (42% African American, 55% women). The REGARDS Study protocol was approved by the Institutional Review Boards governing research in human subjects at the participating centers and all participants provided informed consent. For the current study, we utilized a case-control sample assembled as part of the Sea Islands Genetics Network (SIGNET), a study of genetic contributors to diabetes and dyslipidemia among African Americans. The SIGNET sample consisted of all African American participants of REGARDS with type 2 diabetes living in South Carolina, Georgia, North Carolina and Alabama (cases), and an equivalent number of race-, sex- and age-strata-matched diabetes-free controls, as well as all African American participants not already selected who were current residents of the 15-county ‘Low Country’ region of South Carolina and Georgia (South Carolina counties Beaufort, Berkeley, Charleston, Colleton, Dorchester, Georgetown, Hampton, Horry, Jasper; Georgia counties Bryan, Camden, Chatham, Glynn, Liberty, McIntosh). Diabetes status was determined at the baseline visit. A total of 2398 African American participants were selected, of whom 1149 had type 2 diabetes and 1249 did not. Of these, 2080 participants had lipoprotein subfraction measurements. Genotyping Two single nucleotide polymorphisms (SNPs) in APOL1 (rs73885319 and rs60910145) and a six base-pair insertion/ deletion polymorphism (rs71785313) were genotyped in



Keywords: APOL1, chronic kidney disease, ethnic disparities, genetics

risk alleles with HDL subfractions among African Americans and found that greater numbers of risk alleles were associated with lower concentrations of medium-sized HDL particles [11]. Since lower medium HDL concentrations have been linked with excess cardiovascular risk [12–14], these prior findings showing an association of APOL1 G1/G2 risk alleles with HDL subfractions suggest that APOL1 genotypes may impact renal and cardiovascular health, potentially by altering the distribution of HDL subfractions with varying atherogenic potential. However, the prior study was limited by a small sample size and inability to adjust for key confounders. Accordingly, the primary focus of this report was to examine the association of the number of APOL1 G1/G2 risk alleles with HDL subfractions in a large sample of African American participants of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study, a cohort of European Americans and African Americans living throughout the USA. Downloaded from http://ndt.oxfordjournals.org/ at La Trobe University on September 30, 2016

Stroke (REGARDS) Study participants with nuclear magnetic resonance spectroscopy-based lipoprotein subfraction measurements. Linear regression was used to model associations between numbers of APOL1 G1/G2 risk variants and HDL subfractions, adjusting for demographic, clinical and ancestral covariates. Results. Female sex and higher percentage of African ancestry were positively associated with the number of APOL1 G1/G2 risk alleles. In the unadjusted analysis, mean (standard error) small HDL concentrations (μmol/L) for participants with zero, one and two G1/G2 risk alleles were 19.0 (0.2), 19.7 (0.2) and 19.9 (0.4), respectively (P = 0.02). Adjustment for age, sex, diabetes and African ancestry did not change the results but strengthened the statistical significance (P = 0.004). No significant differences in large or medium HDL, very lowdensity lipoprotein or low-density lipoprotein particle concentrations were observed by APOL1 genotype. Conclusions. Greater numbers of APOL1 G1/G2 risk alleles were associated with higher small HDL particle concentrations in African Americans. These results may suggest novel areas of investigation to uncover reasons for the association between APOL1 risk variants with adverse outcomes in African Americans.

mg/dL or the use of anti-diabetes medications; coronary heart disease (CHD) defined as having any of the following: evidence of myocardial infarction on the baseline ECG, self-report of a prior history of a cardiac procedure (coronary artery bypass surgery or percutaneous angioplasty) or self-reported history of myocardial infarction; stroke ascertained by self-report; estimated glomerular filtration rate (eGFR), urine albumin to creatinine ratio (UACR) and high-sensitivity C-reactive protein. Serum creatinine was calibrated to an international isotope dilution mass spectroscopic (IDMS)-traceable standard, measured by colorimetric reflectance spectrophotometry. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation [20]. Albumin and creatinine were measured in a random spot urine specimen by nephelometry (BN ProSpec Nephelometer, Dade Behring, Marburg, Germany) and Modular-P chemistry analyzer (Roche/Hitachi, Indianapolis, IN), respectively. Spot UACR was calculated in mg/g. Prevalent CKD was defined as an eGFR < 60 mL/min/1.73 m2 or a UACR ≥30 mg/g. Serum highsensitivity C-reactive protein was measured using a highsensitivity particle-enhanced immunonephelometric assay.

Data collection Lipoprotein subfractions were measured by LipoScience, Inc. (Raleigh, NC, USA) using nuclear magnetic resonance (NMR) spectroscopy as reported [17, 18]. In brief, lipoprotein subpopulation particle concentrations (VLDL, LDL and HDL) were obtained from the measured amplitudes of their spectroscopically distinct lipid methyl group NMR signals using the LipoProfile-3 spectral deconvolution algorithm. Lipoprotein subclasses were grouped into small, medium and large categories based upon size classifications used in previous studies [13, 19]. Covariates of interest included the following sociodemographic, clinical and laboratory factors: age, sex, annual family income and educational attainment, all determined via selfreport; body mass index; waist circumference; systolic and diastolic blood pressure defined as the average of two seated measures taken after a 5 min rest; diabetes defined as fasting serum glucose ≥126 mg/dL, non-fasting serum glucose ≥200

Statistical analyses The primary independent variable of interest was the number of APOL1 G1/G2 alleles (risk status). The two SNPs comprising the G1 locus are reported to be in near perfect linkage disequilibrium in African American populations [3], thus either can be used to assess risk status. G1/G2 risk was defined according to the number of copies of the high-risk haplotypes— zero, comprising individuals lacking either the high-risk G1or

Table 1. Baseline characteristics by category of APOL1 risk allele status

n Age Male (%) African ancestry (%) Geographic region (%) Buckle Belt Income (%)

APOL1 nephropathy risk variants are associated with altered high-density lipoprotein profiles in African Americans.

Two independent coding variants in the apolipoprotein L1 gene (APOL1), G1 and G2, strongly associate with nephropathy in African Americans; associatio...
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