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Abstract: FR-PO844

CTLA4-ICOS Intergenic Variants Associated with Lupus Nephritis in Chinese Populations

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Qi, Yuan-yuan, Institute of Nephrology ,Nephrology Hospital, the First Affiliated Hospital of Zhengzhou University, Henan,China, Zhengzhou, Henan, China
  • Liu, Xinran, Institute of Nephrology ,Nephrology Hospital, the First Affiliated Hospital of Zhengzhou University, Henan,China, Zhengzhou, Henan, China
  • Zhang, Xiao-xue, Institute of Nephrology ,Nephrology Hospital, the First Affiliated Hospital of Zhengzhou University, Henan,China, Zhengzhou, Henan, China
  • Zhai, Yaling, Institute of Nephrology ,Nephrology Hospital, the First Affiliated Hospital of Zhengzhou University, Henan,China, Zhengzhou, Henan, China
  • Xinyu, Pu, Institute of Nephrology ,Nephrology Hospital, the First Affiliated Hospital of Zhengzhou University, Henan,China, Zhengzhou, Henan, China
  • Wang, Xiao-yang, Institute of Nephrology ,Nephrology Hospital, the First Affiliated Hospital of Zhengzhou University, Henan,China, Zhengzhou, Henan, China
  • Dou, Yanna, Institute of Nephrology ,Nephrology Hospital, the First Affiliated Hospital of Zhengzhou University, Henan,China, Zhengzhou, Henan, China
  • Xiao, Jing, Institute of Nephrology ,Nephrology Hospital, the First Affiliated Hospital of Zhengzhou University, Henan,China, Zhengzhou, Henan, China
  • Zhao, Zhan-zheng, Institute of Nephrology ,Nephrology Hospital, the First Affiliated Hospital of Zhengzhou University, Henan,China, Zhengzhou, Henan, China
Background

Lupus nephritis (LN) is one of the most prevalent and serious complications of systemic lupus erythematosus (SLE). CTLA4 (cytotoxic T lymphocyte-associated protein 4) and ICOS (inducible T cell co-stimulator) are good candidate genes for SLE because of their role in regulating T cell activation. And the combination of CTLA-4Ig and cyclophosphamide therapy very effectively arrested the progression of murine lupus nephritis. Therefore, the aim of the present study was to identify susceptibility variants in CTLA4-ICOS intergenic region along with its functional significance.

Methods

In genetic association analysis, the discovery Beijing cohort (500 LN patients and 500 healthy controls) was adopted from previous reported GWAS data with the use of ImmunoChip arrays. The replication cohort was recruited from Henan population (508 LN patients and 812 healthy controls) and the genotyping was conducted by Sequenom Massarray. To identify functional significance, we analyzed publicly available Encyclopedia of DNA Elements data on transcription factor binding sites, blood expression quantitative trait locus data. The effect of SNP on expression was referred to GTEx2015_v6 and Westra2013 eQTL studies.

Results

In the discovery stage, a total of 136 single-nucleotide polymorphisms in a region spanning 113 kb encompassing CTLA4-ICOS were analyzed in 1000 individuals from Beijing cohort. Twenty four of them were significantly associated the susceptibility to LN (p<0.05). rs17268364 and rs13029135 were the top signals (p = 1.41 × 10-2, OR = 0.77, 95% CI 0.62 - 0.95) and were in high linkage disequilibrium (r-square = 0.99, D’ = 1). This genetic association of rs17268364 was successfully replicated in an independent cohort with 508 LN patients and 812 healthy controls in Henan cohort (p = 3.08 × 10-4, OR 0.71, 95%CI 0.58 - 0.85). After combined analysis of Beijing cohort and Henan cohort, the association was further reinforced (p = 1.31 × 10-5, OR 0.73, 95%CI 0.64 - 0.84). Functional analysis predicted conservative and regulatory features of rs17268364. In eQTL analysis, rs17268364 was associated with the expression of CTLA4 (p = 2.62×10-6) and ICOS (p = 3×10-3).

Conclusion

Our results suggested genetic association between variants in the intergenic region of CTLA4-ICOS and LN risk in Chinese population.

Funding

  • Government Support - Non-U.S.