Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Association of PPP2CA Polymorphisms with SLE Susceptibility in Multiple Ethnic Groups.

Tan15,  Wenfeng, Zhao15,  Jian, Deng15,  Yun, Kaufman2,  Kenneth M., Kelly1,  Jennifer A., Bae5,  Sang-Cheol, Chang9,  Deh-Ming

Arthritis and Immunology Program, Oklahoma Medical Research Foundation
Oklahoma Medical Research Foundation
On Behalf of PROFILE Investigators, University of Alabama
On Behalf of the BIOLUPUS and GENLES Networks, Uppsala University, Sweden, Center for Genomics and Oncological Research, Granada, Spain, Oklahoma Medical Research Foundation
Seoul National University, Seoul, Korea
The Ohio State University
University of California, Los Angeles, CA
University of Chicago
University of Southern California
Arthritis and Immunology Program, Oklahoma Medical Research Foundation and US Department of Veterans Affairs Medical Center
Beth Israel Deaconess Medical Center, Harvard Medical School
Cincinnati Children's Hospital Medical Center and US Department of Veterans Affairs Medical Center
Hanyang University, Korean
Imperial College London, Hammersmith Hospital, London, UK
Medical University of South Carolina
Medical University of South Carolina
National Defense Medical Center, Taipei, Taiwan

Purpose:

PPP2CA encodes the most highly expressed catalytic subunit a of protein phosphatase 2A (PP2A), which comprises a family of serine/threonine protein phosphatase with various important roles in regulation of NF-kB, MAPK and WNT signaling pathways, as well as cell growth and division. Abnormal expression of PP2A in T cells from SLE patients results in the decreased production of IL-2, suggesting the involvement of PP2A in the abnormal immune regulation in SLE patients (JCI, 115, 3193, 2005). Here we examined the association of PPP2CA variants with SLE.

Methods:

We genotyped a panel of 18 SNPs spanning a 32kb region from PPP2CA promoter to 3.2kb downstream (including 1 at promoter, 15 at intron and 2 at downstream) in six populations: African-Americans and Gullahs (AA&Gullah) (1,651 cases, 1,962 controls), Asians (1,272 cases, 1,270 controls), European Americans (EA) (3,980 cases, 3,546 controls), Hispanic and Native Americans (Hisp&NA) (1,508 cases, 812 controls) using Illumina iSelect system. Additionally, ~400 ancestry informative markers were used to control population admixture and to eliminate genetic outliers. Chi-square and Mantel-Haenszel test were performed to compare the allelic difference and conduct the trans-ethnic meta-analysis.

Results:

Multiple SNPs of PPP2CA showed significant association with SLE in Asians, EA and Hisp&NA but not in AA&Gullah. Two SNPs (rs7704116 at intron 2 and rs10491322 at the 3` downstream) showed consistently strong association with SLE across Asian, EA and Hisp&NA, which were in almost complete linkage disequilibrium (LD) (r2= 0.98–0.99) with each other in each population. Of note, rs7704116 showed the strongest association signal with SLE in Asians and Hisp&NA and the smallest P value after Meta-analysis of genotype data in Asian, EA, Hisp&NA and AA&Gullah populations (pMeta= 3.8 × 10-7, OR = 1.21[1.12–1.30]) (Table 1). One 32kb haplotype block spanning from promoter to 3`UTR downstream of PPP2CA was constructed based on the genotyping data of 18 SNPs in Asian, EA, Hisp&NA and AA&Gullah populations, which led to the identification of a common risk haplotype (GGCAAAACGAAAAAAAAG) strongly associated with SLE (pMeta= 2.3 × 10-7, OR= 1.28 [1.13–1.31]) (Table 1).

Table 1. Associations of rs7704116 and common risk haplotype with SLE in multiple ethnic groups

   Number of subjects MAF  Meta-analysis
SNP/HaplotypePositionPopulationCasesControlsMACasesControlsP valueOR (95% CI)P valueOR (95% CI)
  Asian12721270A0.070.048.1×10-51.64 [1.28–2.11]  
rs7704116Intron 2European39713536A0.080.075.8×10-41.24 [1.1–1.4]3.8×10-71.21 [1.12–1.30]
  Hisp&NA1507810A0.190.153.4×10-31.28 [1.08–1.5]  
  AA&Gullah16511962A0.130.130.681.03 [0.9–1.18]  
 Haplotype frequencies
  Asian12721270 0.060.042×10-41.59 [1.2–2.0]  
GGCAAAACGAAAAAAAAGEuropean397135360.090.080.0011.22 [1.1–1.4]2.3×10-71.28 [1.13–1.31]
  Hisp&NA1507810 0.230.180.021.29 [1.1–1.5]  
  AA&Gullah16511962 0.120.120.481.05 [0.9–1.2]  

Conclusions:

This study provides evidence that PPP2CA represents a novel locus predisposing to SLE susceptibility in Asian, European, Hispanic and Native American populations. The common risk haplotype shared in these populations is likely to carry one or more underlying causal variant(s) that increase risk for the development of SLE.

To cite this abstract, please use the following information:
Tan, Wenfeng, Zhao, Jian, Deng, Yun, Kaufman, Kenneth M., Kelly, Jennifer A., Bae, Sang-Cheol, et al; Association of PPP2CA Polymorphisms with SLE Susceptibility in Multiple Ethnic Groups. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1583
DOI: 10.1002/art.29349

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