title: Fine-mapping analysis revealed complex pleiotropic effect and tissue-specific regulatory mechanism of TNFSF15 in primary biliary cholangitis, Crohn's disease and leprosy.
abstract: Genetic polymorphism within the 9q32 locus is linked with increased risk of several diseases, including Crohn's disease (CD), primary biliary cholangitis (PBC) and leprosy. The most likely disease-causing gene within 9q32 is TNFSF15, which encodes the pro-inflammatory cytokine TNF super-family member 15, but it was unknown whether these disparate diseases were associated with the same genetic variance in 9q32, and how variance within this locus might contribute to pathology. Using genetic data from published studies on CD, PBC and leprosy we revealed that bearing a T allele at rs6478108/rs6478109 (r(2) = 1) or rs4979462 was significantly associated with increased risk of CD and decreased risk of leprosy, while the T allele at rs4979462 was associated with significantly increased risk of PBC. In vitro analyses showed that the rs6478109 genotype significantly affected TNFSF15 expression in cells from whole blood of controls, while functional annotation using publicly-available data revealed the broad cell type/tissue-specific regulatory potential of variance at rs6478109 or rs4979462. In summary, we provide evidence that variance within TNFSF15 has the potential to affect cytokine expression across a range of tissues and thereby contribute to protection from infectious diseases such as leprosy, while increasing the risk of immune-mediated diseases including CD and PBC.
authors: Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong 250000, China.|Shandong Provincial Key Laboratory for Dermatovenereology, Jinan, Shandong 250000, China.|Shandong Provincial Hospital for Skin Diseases, Shandong University, Jinan, Shandong 250000, China.
authors: Yonghu
authors: Y
authors: Sun
authors: Human Genetics, Genome Institute of Singapore, Singapore 138672, Singapore.
authors: Astrid
authors: A
authors: Irwanto
authors: Human Genetics, University of Tokyo, Graduate School of Medicine, Tokyo 113-0033, Japan.
authors: Licht
authors: L
authors: Toyo-Oka
authors: Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul 138736, Korea.
authors: Myunghee
authors: M
authors: Hong
authors: Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong 250000, China.|Shandong Provincial Key Laboratory for Dermatovenereology, Jinan, Shandong 250000, China.|Shandong Provincial Hospital for Skin Diseases, Shandong University, Jinan, Shandong 250000, China.
authors: Hong
authors: H
authors: Liu
authors: Immune Regulation, Singapore Immunology Network, Singapore 138648, Singapore.
authors: Anand Kumar
authors: AK
authors: Andiappan
authors: Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul 138736, Korea.
authors: Hyunchul
authors: H
authors: Choi
authors: Human Genetics, University of Tokyo, Graduate School of Medicine, Tokyo 113-0033, Japan.
authors: Yuki
authors: Y
authors: Hitomi
authors: Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong 250000, China.|Shandong Provincial Key Laboratory for Dermatovenereology, Jinan, Shandong 250000, China.|Shandong Provincial Hospital for Skin Diseases, Shandong University, Jinan, Shandong 250000, China.
authors: Gongqi
authors: G
authors: Yu
authors: Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong 250000, China.|Shandong Provincial Key Laboratory for Dermatovenereology, Jinan, Shandong 250000, China.|Shandong Provincial Hospital for Skin Diseases, Shandong University, Jinan, Shandong 250000, China.
authors: Yongxiang
authors: Y
authors: Yu
authors: Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong 250000, China.|Shandong Provincial Key Laboratory for Dermatovenereology, Jinan, Shandong 250000, China.|Shandong Provincial Hospital for Skin Diseases, Shandong University, Jinan, Shandong 250000, China.
authors: Fangfang
authors: F
authors: Bao
authors: Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong 250000, China.|Shandong Provincial Key Laboratory for Dermatovenereology, Jinan, Shandong 250000, China.|Shandong Provincial Hospital for Skin Diseases, Shandong University, Jinan, Shandong 250000, China.
authors: Chuan
authors: C
authors: Wang
authors: Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong 250000, China.|Shandong Provincial Key Laboratory for Dermatovenereology, Jinan, Shandong 250000, China.|Shandong Provincial Hospital for Skin Diseases, Shandong University, Jinan, Shandong 250000, China.
authors: Xian
authors: X
authors: Fu
authors: Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong 250000, China.|Shandong Provincial Key Laboratory for Dermatovenereology, Jinan, Shandong 250000, China.|Shandong Provincial Hospital for Skin Diseases, Shandong University, Jinan, Shandong 250000, China.
authors: Zhenhua
authors: Z
authors: Yue
authors: Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong 250000, China.|Shandong Provincial Key Laboratory for Dermatovenereology, Jinan, Shandong 250000, China.|Shandong Provincial Hospital for Skin Diseases, Shandong University, Jinan, Shandong 250000, China.
authors: Honglei
authors: H
authors: Wang
authors: Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong 250000, China.|Shandong Provincial Key Laboratory for Dermatovenereology, Jinan, Shandong 250000, China.|Shandong Provincial Hospital for Skin Diseases, Shandong University, Jinan, Shandong 250000, China.
authors: Huimin
authors: H
authors: Zhang
authors: Human Genetics, University of Tokyo, Graduate School of Medicine, Tokyo 113-0033, Japan.
authors: Minae
authors: M
authors: Kawashima
authors: Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan.
authors: Kaname
authors: K
authors: Kojima
authors: Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan.
authors: Masao
authors: M
authors: Nagasaki
authors: Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Onuma, Nagasaki 856-8562, Japan.
authors: Minoru
authors: M
authors: Nakamura
authors: Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138736, Korea.
authors: Suk-Kyun
authors: SK
authors: Yang
authors: Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138736, Korea.
authors: Byong Duk
authors: BD
authors: Ye
authors: Human Genetics, Genome Institute of Singapore, Singapore 138672, Singapore.|Faculty of Biotechnology, Atma Jaya Catholic University of Indonesia, South Jakarta 12930, Indonesia.
authors: Yosua
authors: Y
authors: Denise
authors: Immune Regulation, Singapore Immunology Network, Singapore 138648, Singapore.
authors: Olaf
authors: O
authors: Rotzschke
authors: Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul 138736, Korea.
authors: Kyuyoung
authors: K
authors: Song
authors: Human Genetics, University of Tokyo, Graduate School of Medicine, Tokyo 113-0033, Japan.
authors: Katsushi
authors: K
authors: Tokunaga
authors: Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Sciences, Jinan, Shandong 250000, China.|Shandong Provincial Key Laboratory for Dermatovenereology, Jinan, Shandong 250000, China.|Shandong Provincial Hospital for Skin Diseases, Shandong University, Jinan, Shandong 250000, China.|School of Medicine, Shandong University, Jinan, Shandong 250000, China.|National Clinical Key Project of Dermatology and Venereology, Jinan, Shandong 250000, China.
authors: Furen
authors: F
authors: Zhang
authors: Human Genetics, Genome Institute of Singapore, Singapore 138672, Singapore.
authors: Jianjun
authors: J
authors: Liu
mesh_terms: D003424:Crohn Disease / Q000235:genetics* / Q000378:metabolism; D030541:Databases, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007918:Leprosy / Q000235:genetics* / Q000378:metabolism; D008105:Liver Cirrhosis, Biliary / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009928:Organ Specificity; D020641:Polymorphism, Single Nucleotide; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000235:genetics* / Q000378:metabolism
chemical_list: C117026:TNFSF15 protein, human; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15