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Meta-analysis of two Chinese populations identifies an autoimmune disease risk allele in 22q11.21 as associated with systemic lupus erythematosus.

ABSTRACT: Systemic lupus erythematosus (SLE) is a heterogeneous disease with a diverse spectrum of clinical symptoms, ranging from skin rash to end-organ damage. 22q11.21 has been identified as a susceptibility region for several autoimmune diseases, including SLE. However, detailed information for SLE association and the underlying functional mechanism(s) is still lacking.Through meta-analysis of two genome-wide association studies (GWAS) on Han Chinese populations, comprising a total of 1,659 cases and 3,398 controls matched geographically, we closely examined the 22q11.21 region, especially on the reported single-nucleotide polymorphisms (SNPs) associated with different autoimmune diseases and their relationships. We further replicated the most significant associations of SNPs with SLE using 2,612 cases and 2,323 controls of Asian ancestry.All reported SNPs in the 22q11.21 region with different autoimmune diseases were examined using the two GWAS data and meta-analysis results, and supportive evidence of association with SLE was found (meta-analysis: P_meta???7.27E-05), which might require further investigation. SNP rs2298428 was identified as the most significant SNP associated with SLE in this region (P_meta =2.70E-09). It showed independent effects through both stepwise and conditional logistic regression, and there is no evidence of other independent association signals for SLE in this region. The association of rs2298428 was further replicated in three cohorts from Hong Kong, Anhui and Thailand comprising a total of 2,612 cases and 2,323 controls (joint analysis of GWAS and replication result: P_all =1.31E-11, odds ratio =1.23). SNP rs2298428 was shown to be an expression quantitative locus for UBE2L3 gene in different cell types, with the risk allele (T) being correlated with higher expression of UBE2L3. This is consistent with earlier reports on higher expression of UBE2L3 in patients with SLE.Association with distinct autoimmune diseases highlights the significance of this region in autoreactive responses and potentially shared functional mechanisms in these diseases.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC4404227 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Meta-analysis of two Chinese populations identifies an autoimmune disease risk allele in 22q11.21 as associated with systemic lupus erythematosus.

Zhang Yan Y Wang Yong-Fei YF Yang Jing J Zhang Jing J Sun Liangdan L Hirankarn Nattiya N Pan Hai-Feng HF Lau Chak Sing CS Chan Tak Mao TM Lee Tsz Leung TL Leung Alexander Moon Ho AM Mok Chi Chiu CC Zhang Lu L Shen Jiangshan Jane JJ Wong Sik Nin SN Lee Ka Wing KW Ho Marco Hok Kung MH Lee Pamela Pui Wah PP Chung Brian Hon-Yin BH Chong Chun Yin CY Wong Raymond Woon Sing RW Mok Mo Yin MY Wong Wilfred Hing Sang WH Tong Kwok Lung KL Tse Niko Kei Chiu NK Li Xiang-Pei XP Avihingsanon Yingyos Y Rianthavorn Pornpimol P Deekajorndej Thavatchai T Suphapeetiporn Kanya K Shotelersuk Vorasuk V Ying Shirley King Yee SK Fung Samuel Ka Shun SK Lai Wai Ming WM Wong Chun-Ming CM Ng Irene Oi Lin IO Garcia-Barcelo Maria-Merce MM Cherny Stacey S SS Tam Paul Kwong-Hang PK Sham Pak Chung PC Yang Sen S Ye Dong Qing DQ Cui Yong Y Zhang Xue-Jun XJ Yang Wanling W Lau Yu Lung YL

Arthritis research & therapy 20150320

<h4>Introduction</h4>Systemic lupus erythematosus (SLE) is a heterogeneous disease with a diverse spectrum of clinical symptoms, ranging from skin rash to end-organ damage. 22q11.21 has been identified as a susceptibility region for several autoimmune diseases, including SLE. However, detailed information for SLE association and the underlying functional mechanism(s) is still lacking.<h4>Methods</h4>Through meta-analysis of two genome-wide association studies (GWAS) on Han Chinese populations, c ...[more]

PMID: 25880549

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Project description:Systemic lupus erythematosus is a chronic autoimmune disease of complex clinical presentation and etiology and is likely influenced by numerous genetic and environmental factors. While a large number of susceptibility genes have been identified, the production of antibodies against a distinct subset of nuclear proteins remains a primary distinguishing characteristic in disease diagnosis. However, the utility of autoantibody biomarkers for disease sub-classification and grouping remains elusive, in part, because of the difficulty in large scale profiling using a uniform, quantitative platform. In the present study serological profiles of several known SLE antigens, including Sm-D3, RNP-A, RNP-70k, Ro52, Ro60, and La, as well as other cytokine and neuronal antigens were obtained using the luciferase immunoprecipitation systems (LIPS) approach. The resulting autoantibody profiles revealed that 88% of a pilot cohort and 98% of a second independent cohort segregated into one of two distinct clusters defined by autoantibodies against Sm/anti-RNP or Ro/La autoantigens, proteins often involved in RNA binding activities. The Sm/RNP cluster was associated with a higher prevalence of serositis in comparison to the Ro/La cluster (P?=?0.0022). However, from the available clinical information, no other clinical characteristics were associated with either cluster. In contrast, evaluation of autoantibodies on an individual basis revealed an association between anti-Sm (P?=?0.006), RNP-A (P?=?0.018) and RNP-70k (P?=?0.010) autoantibodies and mucocutaneous symptoms and between anti-RNP-70k and musculoskeletal manifestations (P?=?0.059). Serologically active, but clinically quiescent disease also had a higher prevalence of anti-IFN-? autoantibodies. Based on our findings that most SLE patients belong to either a Sm/RNP or Ro/La autoantigen cluster, these results suggest the possibility that alterations in RNA-RNA-binding protein interactions may play a critical role in triggering and/or the pathogenesis of SLE.

Dataset Information

Meta-analysis of two Chinese populations identifies an autoimmune disease risk allele in 22q11.21 as associated with systemic lupus erythematosus.

Publications

Meta-analysis of two Chinese populations identifies an autoimmune disease risk allele in 22q11.21 as associated with systemic lupus erythematosus.

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