Genetic Interactions Between SNP Variants in C3 Receptor Subunits in Patients with SLE

Jeffrey C. Edberg¹, Christine W. Duarte², Amit Patki², Elizabeth E. Brown MPH³, Kenneth M. Kaufman⁴, Jennifer A. Kelly⁵, Mary E. Comeau⁶, Marta E. Alarcon-Riquelme on behalf of BIOLUPUS and GENLES⁷, Sang-Cheol Bae⁸, Lindsey A. Criswell⁹, Barry I. Freedman¹⁰, Patrick M. Gaffney¹¹, Gary S. Gilkeson¹², Chaim O. Jacob¹³, Judith A. James⁵, Diane L. Kamen¹⁴, Kathy Moser Sivils⁵, Timothy B. Niewold¹⁵, Robert H. Scofield¹⁶, Betty P. Tsao¹⁷, Timothy J. Vyse¹⁸, John B. Harley¹⁹, Carl D. Langefeld²⁰, Hemant Tiwari² and Robert P. Kimberly²¹, ¹Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, ²Biostatistics, University of Alabama at Birmingham, Birmingham, AL, ³University of Alabama at Birmingham, Birmingham, AL, ⁴1Center for Autoimmune Genomics and Etiology and Rheumatology Division, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati, Cincinnati, OH, ⁵Oklahoma Medical Research Foundation, Oklahoma City, OK, ⁶Wake Forest University Health Sciences, Winston-Salem, NC, ⁷Arthritis & Clinical Immunology, Oklahoma Medical Research Foundation, Center for Genomics and Oncological Research Pfizer-University of Granada-Junta de Andalucia, Oklahoma City, OK, ⁸Hanyang University Hospital for Rheumatic Disease, Clinical Research Center for Rheumatoid Arthritis (CRCRA), Seoul, ⁹Department of Medicine, University of California, San Francisco, Rosalind Russell Medical Research Center for Arthritis, San Francisco, CA, ¹⁰Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, ¹¹Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, ¹²Department of Medicine, Division of Rheumatology, Medical University of South Carolina, Charleston, SC, ¹³Division of Rheumatology, University of Southern California Keck School of Medicine, Los Angeles, CA, ¹⁴Department of Medicine, Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Charleston, SC, ¹⁵Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL, ¹⁶Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation; Department of Medicine, University of Oklahoma Health Sciences Center; US Department of Veterans Affairs Medical Center, Oklahoma City, OK, ¹⁷Medicine/Rheumatology, UCLA School of Medicine, Los Angeles, CA, ¹⁸Medical & Molecular Genetics, King's College London, London, United Kingdom, ¹⁹Division 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, ²⁰Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, ²¹Department of Medicine, University of Alabama at Birmingham, Birmingham, AL

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: genomics and systemic lupus erythematosus (SLE)

Session Information

Title: Genetics and Genomics of Rheumatic Diseases

Session Type: Abstract Submissions (ACR)

Background/Purpose: Genome-wide and candidate gene studies have supported a role for genes involved in immune complex processing as being important contributors to development of SLE. The association of ITGAMvariants and SLE highlights the importance of complement and complement receptors in the SLE diathesis. We hypothesized that there may also be statistical interactions between variants in genes that encode proteins in the complement system. We have developed a gene-based analysis strategy and present data that support a role for genetic interactions between variants in genes involved in the complement system.

Methods: A newly developed variation of the Rank Truncated Product (RTP) statistic was used to assess the combined genetic contribution of loci involved in complement component 3 (C3), C3 activation (C2, C3, C4, CFH, CRP, MBL2), and C3 recognition (CR1, CR2, CR3 (ITGAM/ITGB2), CR4 (ITGAX/ITGB2)). The significance of the RTP statistic for each gene pair was assessed using a parametric bootstrap procedure. The study population included 16,105 unrelated SLE affecteds and controls from four different ancestry backgrounds (European (EA), African (AA), Hispanic (Hisp), Asian). All participants were of self-reported sex and race/ethnicity. Affecteds met 1997 American College of Rheumatology revised criteria for the classification of SLE. 347 SNPs in these loci were genotyped on an Illumina iSelect custom array as part of the Large Lupus Association Study 2 (LLAS2).

Results: We identify new SNP associations across multiple race/ethnicities in the C2 locus with SLE (p<10^-11/ <10^‑7, OR=1.8/1.7 in EA/AA) and confirm trans-racial associations of ITGAM and SLE (P<10^-27/10^-11/10^-12OR=1.7/1.6/2.1 in EA/AA/Hisp respectively).

We hypothesized that there are genetic interactions between variants in genes encoding proteins in the C3 pathway that are known to functionally and/or physically interact. Indeed, significant gene-by-gene genetic interactions were identified between receptor-ligand, between C3 and complement regulators and between C3 receptor loci. Specific interactions included C3-ITGAM (p<0.001 in AA), C3-ITGB2 (p=0.002 in Hisp), C3-CRP (p=0.003 in AA), C3-CFH (p=0.009 in AA), ITGAM-ITGB2 ( p<0.001 in Hisp) and ITGAX-ITGB2(with trans-racial association in both Hisp and EA, p=0.02/0.045).

Conclusion: We demonstrate significant and replicated genetic association of genes in the C3 pathway with SLE. These associations extend beyond the ITGAM locus to include other C3 receptor genes and regulators of C3 activation. The elucidation of genetic interactions between genes in this pathway demonstrates that the contribution of variants in the C3 pathway act both independently and jointly.

Disclosure:

J. C. Edberg,
None;

C. W. Duarte,
None;

A. Patki,
None;

E. E. Brown MPH,
None;

K. M. Kaufman,
None;

J. A. Kelly,
None;

M. E. Comeau,
None;

M. E. Alarcon-Riquelme on behalf of BIOLUPUS and GENLES,
None;

S. C. Bae,
None;

L. A. Criswell,
None;

B. I. Freedman,
None;

P. M. Gaffney,
None;

G. S. Gilkeson,
None;

C. O. Jacob,
None;

J. A. James,
None;

D. L. Kamen,
None;

K. Moser Sivils,
None;

T. B. Niewold,
None;

R. H. Scofield,
None;

B. P. Tsao,
None;

T. J. Vyse,
None;

J. B. Harley,

ERBA Diagnostics,

ERBA Diagnostics ,

ERBA DIagnostics,

C. D. Langefeld,
None;

H. Tiwari,
None;

R. P. Kimberly,
None.

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