ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 729

Apolipoprotein L1 Risk Variants Underlie Racial Disparities in Lupus Nephritis-Induced End-Stage Renal Disease

Robert P. Kimberly1, Barry I. Freedman2, Carl D. Langfeld3, Devin Absher4, Kelly K. Andringa1, Daniel Birmingham5, Elizabeth E. Brown6, Mary E. Comeau7, Karen H. Costenbader8, Lindsey A. Criswell9, Jeffrey C. Edberg10, John B. Harley11, Judith A. James12, Diane L. Kamen13, Joan T. Merrill14, Timothy B. Niewold15, Neha Patel16, Michelle Petri17, Rosalind Ramsey-Goldman18, Jane E. Salmon19, Mark Segal20, Kathy Moser Sivils12, Betty P. Tsao21, Bruce A. Julian1 and Lupus Nephritis-ESRD Consortium22, 1Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 2Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 3Department of Biostatistics, Wake Forest University Health Sciences, Winston-Salem, NC, 4HudsonAlpha Institute for Biotechnology, Huntsville, AL, 5Medicine, Ohio State University Medical Center, Columbus, OH, 6University of Alabama at Birmingham, Birmingham, AL, 7Wake Forest University Health Sciences, Winston-Salem, NC, 8Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 9Department of Medicine, University of California, San Francisco, Rosalind Russell Medical Research Center for Arthritis, San Francisco, CA, 10Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 11Division of Rheumatology and The Center for Autoimmune Genomics & Etiology, University of Cincinnati, Cincinnati Children's Hospital Medical Center; US Department of Veterans Affairs Medical Center, Cincinnati, OH, 12Oklahoma Medical Research Foundation, Oklahoma City, OK, 13Department of Medicine, Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Charleston, SC, 14Clinical Pharmacology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 15Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL, 16Rheumatology, SUNY Downstate Medical Center, Brooklyn, NY, 17Johns Hopkins University School of Medicine, Baltimore, MD, 18Medicine/Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL, 19Rheumatology, Hospital for Special Surgery, New York, NY, 20Medicine/Nephrology, University of Florida, Gainesville, FL, 21Medicine/Rheumatology, UCLA School of Medicine, Los Angeles, CA, 22Medicine, Birmingham, AL

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: , , ,

Session Information

Title: Plenary Session I: Discovery 2012

Session Type: Plenary Sessions

Background/Purpose: The G1 and G2 coding variants in the apolipoprotein L1 gene (APOL1;  G1: a compound missense allele (glycine-342/methionine-384) and G2: an in-frame deletion (deletion of asparagine-388 and tyrosine-389)),  are strongly and reproducibly associated with focal segmental glomerulosclerosis (FSGS), HIV-associated collapsing glomerulopathy, and hypertension-attributed end-stage renal disease (ESRD) in African Americans (AAs) [Genovese G et al. Science 329:841,2010; Tzur S et al. Hum Genet 128:345,2010]. The role of APOL1 in lupus nephritis (LN) related ESRD is unexplored. We tested for association between APOL1risk variants and LN-ESRD in a national sample of unrelated AAs with systemic lupus erythematosus (SLE).

Methods: The study sample included 668 AA cases with LN-ESRD (456 with kidney biopsy documentation; 212 physician-reported) and 697 AA patients with longstanding SLE lacking LN (mean duration of disease: 10.1 years).  Genotyping was performed on a Sequenom platform.  Allele frequency differences between LN-ESRD cases and SLE non-nephropathy cases were analyzed using multivariable logistic regression models, adjusting for non-muscle myosin heavy chain 9 gene single nucleotide polymorphism rs4821480 using a recessive genetic model.

Results: In cases with LN-ESRD, 87.1% were female, 89% received cytotoxic therapy, mean + SD age at SLE onset was 26.6 + 0.4 years, and duration of SLE to ESRD was 7.2 + 0.3 years with median at 5 years. In non-nephritis SLE patients, 93.5% were female with age at SLE onset 35.2 + 0.8 years. Contrasting all cases with and without ESRD, APOL1 risk variants were significantly associated with LN-ESRD (odds ratio 2.35 (1.77-3.3 95% CI); p=4.25E-9); significant differences in association were not observed when comparing cases with or without kidney biopsy documentation to SLE patients without LN.  The duration of SLE onset to ESRD for those with the G1/G2 variants was 5.49+/-0.54 (median=4) years, while that for those without the variants was 7.78+/-0.37 (median=6) years, p<0.05.

Conclusion: This study demonstrates strong association between both APOL1 G1 and G2 variants and LN-associated ESRD in AAs.  It appears likely that APOL1 G1 and G2 coding variants, which are rare in European populations, contribute to nephropathy progression in LN-ESRD, as well as in FSGS and other non-diabetic etiologies of ESRD.   These variants, and their higher prevalence in individuals with African ancestry, may explain, in part, disparities in clinical outcomes in LN with there being a higher prevalence of severe LN in AA.

Disclosure:

R. P. Kimberly,
None;

B. I. Freedman,
None;

C. D. Langfeld,
None;

D. Absher,
None;

K. K. Andringa,
None;

D. Birmingham,
None;

E. E. Brown,
None;

M. E. Comeau,
None;

K. H. Costenbader,
None;

L. A. Criswell,
None;

J. C. Edberg,
None;

J. B. Harley,
None;

J. A. James,
None;

D. L. Kamen,
None;

J. T. Merrill,
None;

T. B. Niewold,
None;

N. Patel,
None;

M. Petri,
None;

R. Ramsey-Goldman,
None;

J. E. Salmon,
None;

M. Segal,
None;

K. Moser Sivils,
None;

B. P. Tsao,
None;

B. A. Julian,
None;

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