Genome-wide pathway analysis of genome-wide association studies on systemic lupus erythematosus and rheumatoid arthritis.
The aim of this study was to explore candidate single nucleotide polymorphisms (SNPs) and candidate mechanisms of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Two SLE genome-wide association studies (GWASs) datasets were included in this study. Meta-analysis was conducted using 737,984 SNPs in 1,527 SLE cases and 3,421 controls of European ancestry, and 4,429 SNPs that met a threshold of p < 0.01 in a Korean RA GWAS dataset was used. ICSNPathway (identify candidate causal SNPs and pathways) analysis was applied to the meta-analysis results of the SLE GWAS datasets, and a RA GWAS dataset. The most significant result of SLE GWAS meta-analysis concerned rs2051549 in the human leukocyte antigen (HLA) region (p = 3.36E-22). In the non-HLA region, meta-analysis identified 6 SNPs associated with SLE with genome-wide significance (STAT4, TNPO3, BLK, FAM167A, and IRF5). ICSNPathway identified five candidate causal SNPs and 13 candidate causal pathways. This pathway-based analysis provides three hypotheses of the biological mechanism involved. First, rs8084 and rs7192 → HLA-DRA → bystander B cell activation. Second, rs1800629 → TNF → cytokine network. Third, rs1150752 and rs185819 → TNXB → collagen metabolic process. ICSNPathway analysis identified three candidate causal non-HLA SNPs and four candidate causal pathways involving the PADI4, MTR, PADI2, and TPH2 genes of RA. We identified five candidate SNPs and thirteen pathways, involving bystander B cell activation, cytokine network, and collagen metabolic processing, which may contribute to SLE susceptibility, and we revealed candidate causal non-HLA SNPs, genes, and pathways of RA.
Division of Rheumatology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, 126-1, 5-ga, Anam-dong, Seongbuk-gu, Seoul, 136-705, Korea. lyhcgh@korea.ac.kr
Young Ho
YH
Lee
Sang-Cheol
SC
Bae
Sung Jae
SJ
Choi
Jong Dae
JD
Ji
Gwan Gyu
GG
Song
D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D030541:Databases, Genetic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*
D006680:HLA Antigens