Identification Of a Novel Systemic Lupus Erythematosus Risk Locus Between FCHSD2 and P2RY2 In Koreans

Christopher J. Lessard^1,2, Satria Sajuthi³, So-Young Bang⁴, Hye-Soon Lee⁵, Young Mo Kang⁶, Chang-Hee Suh⁷, Won Tae Chung⁸, Soo-Kon Lee⁹, Jung-Yoon Choe¹⁰, Seung-Cheol Shim¹¹, Shin-Seok Lee¹², Ji Hee Oh¹³, Young Jin Kim¹⁴, Jong-Young Lee¹⁴, Bok-Ghee Han¹⁴, Patrick M. Gaffney¹⁵, Timothy J. Vyse for SLEGEN¹⁶, John B. Harley^17,18, Carl D. Langefeld³, Sang-Cheol Bae¹⁹, Kathy L. Sivils^1,2 and Betty P. Tsao²⁰, ¹Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, ²Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, ³Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, ⁴Hanyang University Guri Hospital, Guri, South Korea, ⁵Department of Rheumatology, Hanyang University Guri Hospital, Guri, South Korea, ⁶Department of Internal Medicine (Rheumatology), Kyungpook National University School of Medicine, Daegu, South Korea, ⁷Department of Rheumatology, Ajou University Hospital, Suwon, South Korea, ⁸Division of Rheumatology, Department of Internal Medicine, Dong-A University Hospital, Busan, South Korea, ⁹Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea, ¹⁰Catholic University of Daegu School of Medicine, Daegu, South Korea, ¹¹Division of Rheumatology, Daejeon Rheumatoid & Degenerative Arthritis Center, Chungnam National University Hospital, Daejeon, South Korea, ¹²Rheumatology, Chonnam National University Medical School and Hospital, Gwangju, South Korea, ¹³Division of Structural and Functional Genomics, Center for Genome Science, Korea National Institute of Health, Osong, South Korea, ¹⁴Korea National Institute of Health, Osong, South Korea, ¹⁵Oklahoma Medical Research Foundation, Oklahoma City, OK, ¹⁶King's College London, Guy's Hospital, London, United Kingdom, ¹⁷Division of Rheumatology and The Center for Autoimmune Genomics & Etiology, University of Cincinnati, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, ¹⁸US Department of Veterans Affairs Medical Center, Cincinnati, OH, ¹⁹Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea, ²⁰Division of Rheumatology, Department of Medicine, David Geffen School of Medicine University of California Los Angeles, Los Angeles, CA

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Genetic architecture, genetics, GWAS, pathogenesis and systemic lupus erythematosus (SLE)

Session Information

Title: Systemic Lupus Erythematosus-Human Etiology and Pathogenesis: Genetics and Genomics

Session Type: Abstract Submissions (ACR)

Background/Purpose: Systemic lupus erythematosus (SLE) is a chronic, heterogeneous autoimmune disorder characterized by inflammation, loss of tolerance to self-antigens, and dysregulated interferon responses. Although >40 loci have been associated with SLE, a substantial portion of the genetic risk has not been explained. Previous work has shown that the genetic architecture and associated loci differ among ancestral populations. In this study, we performed a genome-wide association scan to identify genes associated with SLE in Korean subjects.

Methods: Genotyping was performed using Illumina OMNI-express arrays with ~700,000 variants. Standard best practice quality control measures were applied for Hardy-Weinberg proportions, missing and differential missing genotypes data, genetic outliers determined by principal component (PC) analysis. Only SNPs with minor allele frequencies >1% are reported. After quality control filtering, a total of 1174 Korean SLE cases and 4248 population controls were available for analysis. SNP-SLE association was tested using logistic regression model adjusting for PC. Inference is the additive genetic model unless there was significant (P<0.05) departure from additivity, then dominant additive and recessive examined. Bioinformatic analysis was done using HaploReg ver. 2.0.

Results: Ten regions outside the HLA exceeded the genome-wide significance threshold of P<5x10E-8. Of these, 9 regions replicated previously identified SLE risk loci: TNFSF4, STAT1-STAT4, TNFAIP3, IKZF1, HIP1, IRF5, BLK, WDFY4, and ETS1. The novel associated locus was between FCHSD2 and P2RY2on 11q14. (rs11235667, P=1x10E-8, odds ratio = 0.59, 95% CI= 0.50-0.71). No additional SNP was significant after adjusting for rs11235667 via logistic regression. Bioinformatics analysis reported that rs11235667 is a strong enhancer in B lymphoblastoid cell lines. Chromatin immunoprecipitation followed by sequencing experiments done by the ENCODE project found POL2 and YY1 proteins cross-linked to this region. Moreover, sequence prediction methods indicate that rs11235667 can alter the binding motif for the FOXa family of transcription factors.

Conclusion: We have identified a novel association in the region of FCHSD2–P2RY2 and confirmed associations with 9 previously-associated SLE regions outside the HLA in Korean subjects. Although FCHSD2 (FCH and double SH3 domains 2) has no known function, variants in this region are associated with Crohn’s disease in Japanese subjects. P2RY2 (purinergic receptor P2Y, G-protein coupled, 2) is known to be involved in cell proliferation, apoptosis, and inflammation. In rheumatoid synoviocytes, IL-6 has been shown to increase the expression of P2RY2. Ongoing studies are seeking to replicate the FCHSD2-P2RY2 association in additional samples.

Disclosure:

C. J. Lessard,
None;

S. Sajuthi,
None;

S. Y. Bang,
None;

H. S. Lee,
None;

Y. M. Kang,
None;

C. H. Suh,
None;

W. T. Chung,
None;

S. K. Lee,
None;

J. Y. Choe,
None;

S. C. Shim,
None;

S. S. Lee,
None;

J. H. Oh,
None;

Y. J. Kim,
None;

J. Y. Lee,
None;

B. G. Han,
None;

P. M. Gaffney,
None;

T. J. Vyse for SLEGEN,
None;

J. B. Harley,
None;

C. D. Langefeld,
None;

S. C. Bae,

Regublic of Korea,

Abbott Immunology Pharmaceuticals,

Bristol-Myers Squibb,

Eisai,

GlaxoSmithKline,

MSD,

Pfizer Inc,

K. L. Sivils,
None;

B. P. Tsao,
None.

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