995 - Association of Functional Fcgammariic (FCGR2C) Polymorphisms with Rheumatoid Arthritis in African Americans

Monday, November 7, 2011: 9:00 AM-6:00 PM
Hall F2 - Poster Hall (McCormick Place West)
Jianming Wu1, Xinrui Li2, Rui Lin3, Howard Wiener4, Hemant Tiwari4, Cunren Liu4, Travis Ptacek2, Jeffrey C. Edberg5, S. Louis Bridges Jr.6 and Robert P. Kimberly4, 1University of minnesota, St. Paul, MN, 2University of Alabama at Birmingham, Brimingham, AL, 3University of Minnesota, St. Paul, MN, 4University of Alabama at Birmingham, Birmingham, AL, 5Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 6Marguerite Jones Harbert-Gene V. Ball, MD Professor of Medicine, and Director, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL
Presentation Number: 995

Background/Purpose: Functional polymorphisms in human Fcg receptor (FcgR) genes play important roles in the pathogenesis of various autoimmune diseases. FcgRIIC (FCGR2C or CD32C), an activating Fcg receptor gene, contains a stop codon/open-reading frame polymorphism (SNP 202T>C, rs10917661) and two novel SNPs at the intron 6 splicing junctions. The current study was intended to investigate whether FcgRIIC polymorphisms (SNPs) are associated with rheumatoid arthritis (RA) and to examine biological functions of the FcgRIIC SNPs.

Method: FcgRIIC SNP 202T>C and the intron 6 SNPs (SNP6L-A>G and SNP6R-C>G) were genotyped in 833 African American (AA) healthy controls and 764 AA RA patients using Pyrosequecing methodology. SNP allele, genotype, and haplotype distributions were compared between RA and healthy controls. The functions of the FcgRIIC SNP were investigated in mini-gene and transfected cell systems.

Result: Our genotyping data demonstrated that the SNP 202C (open-reading frame allele) is significantly associated with RA susceptibility (P = 0.0002, Odds Ratio 1.584; 95% CI: 1.238–2.027) in AA. In addition, the frequency of the SNP-6L G allele (which forms a canonical splicing donor motif) is significantly increased in AA RA patients compared to controls (P = 0.0007, OR = 1.923, 95% CI 1.312-2.819). No association of SNP-6R alleles with RA susceptibility was observed in AA (P = 0.9400, OR = 1.005, CI = 0.874–1.156). The haplotype 202C/6L-G/6R-G is a major risk factor for RA in African Americans (P = 0.015, OR 3.533; 95% CI: 1.278-9.772). Functionally, the expression of SNP 202T allele enhanced the inhibitory FcgRIIB expression in human B cells. Furthermore, the intron 6 SNPs are the main origin of the various FcgRIIC mRNA species and the 202C/6L-G/6R-G is the sole FcgRIIC SNP haplotype capable of producing an activating receptor.

Conclusion: The functional FcgRIIC SNP haplotype 202C/6L-G/6R-G is a genetic marker for RA in AA and may have important biological consequences.


Keywords: CD32C, Polymorphism and rheumatoid arthritis

Disclosure: J. Wu, None; X. Li, None; R. Lin, None; H. Wiener, None; H. Tiwari, None; C. Liu, None; T. Ptacek, None; J. C. Edberg, None; S. L. Bridges Jr., None; R. P. Kimberly, None.