End-stage renal disease in African Americans with lupus nephritis is associated with APOL1.

• Type of Material: Article
• Authors: Barry I. Freedman, Wake Forest School of Medicine; Carl D. Langefeld, Wake Forest School of Medicine; Kelly K. Andringa, University of Alabama Birmingham; Jennifer A. Croker, University of Alabama Birmingham; Adrienne H. Williams, Wake Forest School of Medicine; Neva E. Garner, University of Alabama Birmingham; Daniel J. Birmingham, Ohio State University; Lee A. Hebert, Ohio State University; Pamela J. Hicks, Wake Forest School of Medicine; Mark S. Segal, University of Florida; Jeffrey C. Edberg, University of Alabama Birmingham; Elizabeth E. Brown, University of Alabama Birmingham; Graciela S. Alarcón, University of Alabama Birmingham; Karen H. Costenbader, Brigham and Women’s Hospital; Mary E. Comeau, Wake Forest School of Medicine; Lindsey A. Criswell, University of California, San Francisco; John B. Harley, Cincinnati Children’s Hospital Medical Center; Judith A. James, Oklahoma Medical Research Foundation; Diane L. Kamen, Medical University of South Carolina; S Sam Lim, Emory University
• Language: English
• Date: 2014-02
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Copyright © 2014 by the American College of Rheumatology
• Final Published Version (URL): http://dx.doi.org/10.1002/art.38220
• Title of Journal or Parent Work: Arthritis and Rheumatology
• ISSN: 2326-5191
• Volume: 66
• Issue: 2
• Start Page: 390
• End Page: 396
• Grant/Funding Information: The Hospital for Special Surgery Registry and Repository is supported by the Mary Kirkland Center for Lupus Research.; Additional support was provided by awards from the James D. Casto Research Fund (to Dr. Hebert); the Alliance for Lupus Research (to Drs. Criswell and Niewold); the US Department of Defense (PO094002 to Dr. Harley); the US Department of Veterans Affairs (to Dr. Harley); and the Lupus Research Institute (to Dr. Niewold).; Supported by NIH grants R01-DK-070941 and DK-084149 to Dr. Freedman; P01-DK-55546 and UL1-RR-025755 to Dr. Hebert; P60-AR-053308, K24-AR-02175, R01-AR-052300, and UL1-TR-000004 to Dr. Criswell; AI-024717, AI-083194, AR-049084, and AR-042460 to Dr. Harley; U191082714, P30-AR-053483, P30-GM-103510, and U01-AI-101934 to Dr. James and the Oklahoma Medical Research Foundation; P60-AR-062755 and UL1-RR-029882 to Dr. Kamen; R01-AR-060861, K08-AI-083790, P30-DK-42086, L30-AI-071651, and UL1-RR-024999 to Dr. Niewold; R01-AR-043727 to Dr. Petri; K24-AR-002138, P60-AR-30692, and UL1-RR-025741 to Dr. Ramsey-Goldman; R01-AR-043814 to Dr. Tsao; RC2-AR-058951 and UL1-TR-000165 to Dr. Kimberly; P01-AR-049084 to Dr. Kimberly and the PROFILE investigators (Drs. Edberg, Brown, Alarcón, Petri, Ramsey-Goldman, and Reveille); and P01-AI-083194 to the International Consortium on the Genetics of Systemic Lupus Erythematosus (SLEGEN).; Dr. Criswell is recipient of a Kirkland Scholar Award.
• Keywords: Genotype; Female; Disease Progression; Adult; Risk Factors; Middle Aged; Lupus Nephritis; Alleles; Lipoproteins, HDL; African Americans; Apolipoproteins; Apolipoprotein L1; Logistic Models; Genetic Predisposition to Disease; European Continental Ancestry Group; Kidney Failure, Chronic; Humans; Male
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Genetics

Abstract

OBJECTIVE: Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) that exhibits familial aggregation and may progress to end-stage renal disease (ESRD). LN is more prevalent among African Americans than among European Americans. This study was undertaken to investigate the hypothesis that the apolipoprotein L1 gene (APOL1) nephropathy risk alleles G1/G2, common in African Americans and rare in European Americans, contribute to the ethnic disparity in risk. METHODS: APOL1 G1 and G2 nephropathy alleles were genotyped in 855 African American SLE patients with LN-ESRD (cases) and 534 African American SLE patients without nephropathy (controls) and tested for association under a recessive genetic model, by logistic regression. RESULTS: Ninety percent of the SLE patients were female. The mean ± SD age at SLE diagnosis was significantly lower in LN-ESRD cases than in SLE non-nephropathy controls (27.3 ± 10.9 years versus 39.5 ± 12.2 years). The mean ± SD time from SLE diagnosis to development of LN-ESRD in cases was 7.3 ± 7.2 years. The G1/G2 risk alleles were strongly associated with SLE-ESRD, with 25% of cases and 12% of controls having 2 nephropathy alleles (odds ratio [OR] 2.57, recessive model P = 1.49 × 10(-9)), and after adjustment for age, sex, and ancestry admixture (OR 2.72, P = 6.23 × 10(-6)). The age-, sex-, and admixture-adjusted population attributable risk for ESRD among patients with G1/G2 polymorphisms was 0.26, compared to 0.003 among European American patients. The mean time from SLE diagnosis to ESRD development was ∼2 years earlier among individuals with APOL1 risk genotypes (P = 0.01). CONCLUSION: APOL1 G1/G2 alleles strongly impact the risk of LN-ESRD in African Americans, as well as the time to progression to ESRD. The high frequency of these alleles in African Americans with near absence in European Americans explains an important proportion of the increased risk of LN-ESRD in African Americans.