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Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus.

ABSTRACT: Systemic lupus erythematosus is a complex and potentially fatal autoimmune disease, characterized by autoantibody production and multi-organ damage. By a genome-wide association study (320 patients and 1,500 controls) and subsequent replication altogether involving a total of 3,300 Asian SLE patients from Hong Kong, Mainland China, and Thailand, as well as 4,200 ethnically and geographically matched controls, genetic variants in ETS1 and WDFY4 were found to be associated with SLE (ETS1: rs1128334, P = 2.33x10(-11), OR = 1.29; WDFY4: rs7097397, P = 8.15x10(-12), OR = 1.30). ETS1 encodes for a transcription factor known to be involved in a wide range of immune functions, including Th17 cell development and terminal differentiation of B lymphocytes. SNP rs1128334 is located in the 3'-UTR of ETS1, and allelic expression analysis from peripheral blood mononuclear cells showed significantly lower expression level from the risk allele. WDFY4 is a conserved protein with unknown function, but is predominantly expressed in primary and secondary immune tissues, and rs7097397 in WDFY4 changes an arginine residue to glutamine (R1816Q) in this protein. Our study also confirmed association of the HLA locus, STAT4, TNFSF4, BLK, BANK1, IRF5, and TNFAIP3 with SLE in Asians. These new genetic findings may help us to gain a better understanding of the disease and the functions of the genes involved.

SUBMITTER: Yang W

PROVIDER: S-EPMC2820522 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus.

Yang Wanling W Shen Nan N Ye Dong-Qing DQ Liu Qiji Q Zhang Yan Y Qian Xiao-Xia XX Hirankarn Nattiya N Ying Dingge D Pan Hai-Feng HF Pan Hai-Feng HF Mok Chi Chiu CC Chan Tak Mao TM Wong Raymond Woon Sing RW Lee Ka Wing KW Mok Mo Yin MY Wong Sik Nin SN Leung Alexander Moon Ho AM Li Xiang-Pei XP Avihingsanon Yingyos Y Wong Chun-Ming CM Lee Tsz Leung TL Ho Marco Hok Kung MH Lee Pamela Pui Wah PP Chang Yuk Kwan YK Li Philip H PH Li Ruo-Jie RJ Zhang Lu L Wong Wilfred Hing Sang WH Ng Irene Oi Lin IO Lau Chak Sing CS Sham Pak Chung PC Lau Yu Lung YL

PLoS genetics 20100212 2

Systemic lupus erythematosus is a complex and potentially fatal autoimmune disease, characterized by autoantibody production and multi-organ damage. By a genome-wide association study (320 patients and 1,500 controls) and subsequent replication altogether involving a total of 3,300 Asian SLE patients from Hong Kong, Mainland China, and Thailand, as well as 4,200 ethnically and geographically matched controls, genetic variants in ETS1 and WDFY4 were found to be associated with SLE (ETS1: rs112833 ...[more]

PMID: 20169177

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Project description:BackgroundSystemic lupus erythematosus (SLE) is a genetically complex rheumatic disease characterized by heterogeneous clinical manifestations of unknown etiology. Recent studies have suggested the existence of a genetic basis for SLE heterogeneity. The objective of the present study was to identify new genetic variation associated with the clinically relevant phenotypes in SLE.MethodsA two-stage pathway-based approach was used to identify the genetic variation associated with the main clinical phenotypes in SLE. In the discovery stage, 482 SLE patients were genotyped using Illumina Human Quad610 microarrays. Association between 798 reference genetic pathways from the Molecular Signatures Database and 11 SLE phenotypes was tested using the set-based method implemented in PLINK software. Pathways significantly associated after multiple test correction were subsequently tested for replication in an independent cohort of 425 SLE patients. Using an in silico approach, we analyzed the functional effects of common SLE therapies on the replicated genetic pathways. The association of known SLE risk variants with the development of the clinical phenotypes was also analyzed.ResultsIn the discovery stage, we found a significant association between the vascular endothelial growth factor (VEGF) pathway and oral ulceration (P value for false discovery rate (P FDR) < 0.05), and between the negative regulation signaling pathway of retinoic acid inducible gene-I/melanoma differentiation associated gene 5 and the production of antinuclear antibodies (P FDR < 0.05). In the replication stage, we validated the association between the VEGF pathway and oral ulceration. Therapies commonly used to treat mucocutaneous phenotypes in SLE were found to strongly influence VEGF pathway gene expression (P = 4.60e-4 to 5.38e-14). Analysis of known SLE risk loci identified a strong association between PTPN22 and the risk of hematologic disorder and with the development of antinuclear antibodies.ConclusionsThe present study has identified VEGF genetic pathway association with the risk of oral ulceration in SLE. New therapies targeting the VEGF pathway could be more effective in reducing the severity of this phenotype. These findings represent a first step towards the understanding of the genetic basis of phenotype heterogeneity in SLE.

Project description:BACKGROUND:African Americans with systemic lupus erythematosus (SLE) have increased renal disease compared to Caucasians, but differences in other comorbidities have not been well-described. We used an electronic health record (EHR) technique to test for differences in comorbidities in African Americans compared to Caucasians with SLE. METHODS:We used a de-identified EHR with 2.8 million subjects to identify SLE cases using a validated algorithm. We performed phenome-wide association studies (PheWAS) comparing African American to Caucasian SLE cases and African American SLE cases to matched non-SLE controls. Controls were age, sex, and race matched to SLE cases. For multiple testing, a false discovery rate (FDR) p value of 0.05 was used. RESULTS:We identified 270 African Americans and 715 Caucasians with SLE and 1425 matched African American controls. Compared to Caucasians with SLE adjusting for age and sex, African Americans with SLE had more comorbidities in every organ system. The most striking included hypertension odds ratio (OR) = 4.25, FDR p = 5.49 × 10- 15; renal dialysis OR = 10.90, FDR p = 8.75 × 10- 14; and pneumonia OR = 3.57, FDR p = 2.32 × 10- 8. Compared to the African American matched controls without SLE, African Americans with SLE were more likely to have comorbidities in every organ system. The most significant codes were renal and cardiac, and included renal failure (OR = 9.55, FDR p = 2.26 × 10- 40) and hypertensive heart and renal disease (OR = 8.08, FDR p = 1.78 × 10- 22). Adjusting for race, age, and sex in a model including both African American and Caucasian SLE cases and controls, SLE was independently associated with renal, cardiovascular, and infectious diseases (all p <?0.01). CONCLUSIONS:African Americans with SLE have an increased comorbidity burden compared to Caucasians with SLE and matched controls. This increase in comorbidities in African Americans with SLE highlights the need to monitor for cardiovascular and infectious complications.

Dataset Information

Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus.

Publications

Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus.

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