title: Confirmation of five novel susceptibility loci for systemic lupus erythematosus (SLE) and integrated network analysis of 82 SLE susceptibility loci.
abstract: We recently identified ten novel SLE susceptibility loci in Asians and uncovered several additional suggestive loci requiring further validation. This study aimed to replicate five of these suggestive loci in a Han Chinese cohort from Hong Kong, followed by meta-analysis (11,656 cases and 23,968 controls) on previously reported Asian and European populations, and to perform bioinformatic analyses on all 82 reported SLE loci to identify shared regulatory signatures. We performed a battery of analyses for these five loci, as well as joint analyses on all 82 SLE loci. All five loci passed genome-wide significance: MYNN (rs10936599, Pmeta = 1.92 × 10-13, OR = 1.14), ATG16L2 (rs11235604, Pmeta = 8.87 × 10 -12, OR = 0.78), CCL22 (rs223881, Pmeta = 5.87 × 10-16, OR = 0.87), ANKS1A (rs2762340, Pmeta = 4.93 × 10-15, OR = 0.87) and RNASEH2C (rs1308020, Pmeta = 2.96 × 10-19, OR = 0.84) and co-located with annotated gene regulatory elements. The novel loci share genetic signatures with other reported SLE loci, including effects on gene expression, transcription factor binding, and epigenetic characteristics. Most (56%) of the correlated (r2 > 0.8) SNPs from the 82 SLE loci were implicated in differential expression (9.81 × 10-198 < P < 5 × 10-3) of cis-genes. Transcription factor binding sites for p53, MEF2A and E2F1 were significantly (P < 0.05) over-represented in SLE loci, consistent with apoptosis playing a critical role in SLE. Enrichment analysis revealed common pathways, gene ontology, protein domains, and cell type-specific expression. In summary, we provide evidence of five novel SLE susceptibility loci. Integrated bioinformatics using all 82 loci revealed that SLE susceptibility loci share many gene regulatory features, suggestive of conserved mechanisms of SLE etiopathogenesis.
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: Julio E
authors.initials: JE
authors.lastname: Molineros
authors.affiliation: Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Wanling
authors.initials: W
authors.lastname: Yang
authors.affiliation: Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, and Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People's Republic of China.
authors.forename: Xu-Jie
authors.initials: XJ
authors.lastname: Zhou
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: Celi
authors.initials: C
authors.lastname: Sun
authors.affiliation: Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan.|Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Huoru
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Kek
authors.initials: K
authors.lastname: Heng Chua
authors.affiliation: Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Yu-Lung
authors.initials: YL
authors.lastname: Lau
authors.affiliation: Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Kochi
authors.affiliation: Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
authors.forename: Akari
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.|Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Joint Molecular Rheumatology Laboratory of the Institute of Health Sciences and Shanghai Renji Hospital, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai Jiaotong University School of Medicine, Shanghai 200025, People's Republic of China.
authors.forename: Jianyang
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea.
authors.forename: So-Young
authors.initials: SY
authors.lastname: Bang
authors.affiliation: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea.
authors.forename: Hye-Soon
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Department of Biology, Kyung Hee University, Seoul 02447, Korea.
authors.forename: Kwangwoo
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea.
authors.forename: Sang-Cheol
authors.initials: SC
authors.lastname: Bae
authors.affiliation: Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, and Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People's Republic of China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Joint Molecular Rheumatology Laboratory of the Institute of Health Sciences and Shanghai Renji Hospital, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai Jiaotong University School of Medicine, Shanghai 200025, People's Republic of China.
authors.forename: Nan
authors.initials: N
authors.lastname: Shen
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA.
authors.forename: Loren L
authors.initials: LL
authors.lastname: Looger
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: Swapan K
authors.initials: SK
authors.lastname: Nath
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D044466:Asian People; D000071183:Autophagy-Related Proteins / Q000235:genetics; D054422:Chemokine CCL22 / Q000235:genetics; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D016914:Ribonuclease H / Q000235:genetics; D014157:Transcription Factors
chemical_list: C557872:ANKS1A protein, human; C518959:ATG16L1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; C515482:CCL22 protein, human; D054422:Chemokine CCL22; D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; C410903:MYNN protein, human; D014157:Transcription Factors; C091139:ribonuclease HII; D016914:Ribonuclease H