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Variation in the ATP-binding cassette transporter 2 gene is a separate risk factor for systemic lupus erythematosus within the MHC

Genes & Immunity volume 10, pages 350–355 (2009)Cite this article

Abstract

The ATP-binding cassette transporter (TAP) proteins are functionally relevant candidates for predisposition to systemic lupus erythematosus (SLE) by virtue of their role in autoantigen presentation and location in the major histocompatibility complex (MHC). We tested if variation in the TAP genes (TAP1 and TAP2) is associated with SLE. We genotyped tag single nucleotide polymorphisms (SNPs) and performed family-based association analysis on 390 Caucasian pedigrees. We found significant evidence of association between TAP2 and SLE (rs241453, P=1.33 × 10−6). Conditional logistic regression analysis suggests that this TAP2 effect is separate from the HLA-DRB1 alleles. Our analyses show that both rs241453 (P=1.6 × 10−4) and HLA-DRB1*03xx (P=2.3 × 10−4) have significant autonomous effects not due to linkage disequilibrium. Moreover, these loci exhibit a significant statistical interaction (P<1.0 × 10−6), demonstrated by an increase in the odds ratio for the TAP2 association from OR=2.00 (95% confidence interval (CI)=1.17–3.42) in HLA-DRB1*03xx-negative subjects to OR=4.29 (CI=1.88–9.76) in the subjects with at least one HLA-DRB1*03xx allele group. We report the largest association study of the TAP genes with SLE to date, and the first to test for its separate effect and interaction with the HLA alleles consistently associated with SLE.

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Acknowledgements

We thank the families and their referring physicians for their participation in this study. We are grateful for the support of Lindsey A Criswell and Lisa F Barcellos. We acknowledge Julie A Lane for generating the HLA-DRB1 genotyping results, and Lingyi Lu and Miranda Marion for assistance with programming. This research was supported by NIH/NIAMS R01 AR043274 (KLM), R01 AR052300 (LAC, LFB), Lupus Foundation of Minnesota (KLM) and the Center for Public Health Genomics at Wake Forest University Health Sciences (CDL).

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Authors and Affiliations

  1. Division of Public Health Sciences, Department of Biostatistical Sciences and Center for Public Health Genomics, Section on Statistical Genetics and Bioinformatics, Wake Forest University Health Sciences, Winston-Salem, NC, USA

    P S Ramos & C D Langefeld

  2. Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA

    L A Bera

  3. Oklahoma Medical Research Foundation, Arthritis and Immunology Program, Oklahoma City, OK, USA

    P M Gaffney & K L Moser

  4. Children's Hospital Oakland Research Institute, Oakland, CA, USA

    J A Noble

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  1. P S Ramos
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  2. C D Langefeld
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  4. P M Gaffney
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  6. K L Moser
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Correspondence to K L Moser.

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Ramos, P., Langefeld, C., Bera, L. et al. Variation in the ATP-binding cassette transporter 2 gene is a separate risk factor for systemic lupus erythematosus within the MHC. Genes Immun 10, 350–355 (2009). https://doi.org/10.1038/gene.2009.21

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