Genome-wide association studies identify<i>PRKCB</i>as a novel genetic susceptibility locus for primary biliary cholangitis in the Japanese population

Kawashima, M.; Hitomi, Yuki; Aiba, Yoshihiro; Nishida, Nao; Kojima, Kazuyuki; Kawai, Yosuke; Nakamura, Hitomi; Tanaka, Atsushi; Zeniya, Mikio; Hashimoto, Etsuko; Ohira, Hiromasa; Yamamoto, Kazuhide; Abe, Masanori; Nakao, Kazuwa; Yamagiwa, Satoshi; Kaneko, Shuichi; Umemura, Takeji; Ichida, Takafumi; Seike, Masataka; Sakisaka, Shotaro; Harada, Masaru; Yokosuka, Osamu; Ueno, Yoshiyuki; Senju, Michio; Kanda, Tatsuo; Shibata, Hidetaka; Himoto, Takashi; Murata, Kazumoto; Miyake, Yasuhiro; Ebinuma, Hirotoshi; Taniai, Makiko; Joshita, Satoru; Nikami, Toshiki; Ota, Hajime; Kouno, Hiroshi; Kouno, Hirotaka; Nakamuta, Makoto; Fukushima, Nobuyoshi; Kohjima, Motoyuki; Komatsu, Tatsuji; Komeda, Toshiki; Ohara, Y.; Muro, Toyokichi; Yamashita, Tsutomu; Yoshizawa, Kaname; Nakamura, Yoko; Shimada, Muneaki; Hirashima, Noboru; Sugi, Kazuhiro; Ario, Keisuke; Takesaki, Eiichi; Naganuma, Atsushi; Mano, Hiroshi; Yamashita, Haruhiro; Matsushita, Kouki; Yamauchi, Kazuhiko; Makita, Fujio; Nishimura, Hideo; Furuta, Kiyoshi; Takahashi, Naohiro; Kikuchi, Masahiro; Masaki, Naohiko; Tanaka, Tomohiro; Tamura, Sumito; Mori, Akira; Yagi, Shintaro; Shirabe, Ken; Komori, Atsumasa; Migita, Kiyoshi; Ito, Masahiro; Nagaoka, Shinya; Abiru, Seigo; Yatsuhashi, Hiroshi; Yasunami, Michio; Shimoda, Shinji; Harada, Kenichi; Egawa, Hiroto; Maehara, Yoshihiko; Üemoto, Shinji; Kokudo, Norihiro; Takikawa, Hajime; Ishibashi, Hiromi; Chayama, Kazuaki; Mizokami, Masashi; Nagasaki, Masao; Tokunaga, Katsushi; Nakamura, Minoru

doi:10.1093/hmg/ddw406

Cited by 35 publications

(67 citation statements)

References 37 publications

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“…Chan Wang , 1 * Xiaodong Zheng, 2 * Peng Jiang, 1 * Ruqi Tang, 3 * Yuhua Gong, 4 * Yaping Dai, 5 * Lan Wang, 6 * Ping Xu, 7 * Wenjuan Sun, 1 Lu Wang, 1 Chongxu Han, 8 Yuzhang Jiang, 9 Yiran Wei, 3 Kui Zhang, 10 Jian Wu, 11 Youlin Shao, 12 Yueqiu Gao, 13 Jianjiang Yu, 14 Zhigang Hu, 15 Zhidong Zang, 16 Yi Zhao, 17 Xudong Wu, 18 Na Dai, 19 Lei Liu, 20 Jinshan Nie, 21 Bo Jiang, 22 Maosong Lin, 23 Li Li, 24 You Li, 3 Sufang Chen, 7 Lixin Shu, 1 Fang Qiu, 1 Qiuyuan Wu, 1 Mingming Zhang, 1 Ru Chen, 1 Rohil Jawed, 1 Yu Zhang, 1 Xingjuan Shi, 1 Zhen Zhu, 12 Hao Pei, 5 Lihua Huang, 5 Weifeng Zhao, 25 Ye Tian, 26 Xiang Zhu, 7 Hong Qiu, 6 M. Eric Gershwin, 27 Weichang Chen, 25 Michael F. Seldin, 28 Xiangdong Liu, 1 Liangdan Sun, 2…”

Section: Genome-wide Association Studies Of Specific Antinuclear Automentioning

confidence: 99%

“…(2) Several large-scale genome-wide association (GWA) studies in European, Japanese, and Han Chinese PBC cohorts have pointed to a strong genetic predisposition to PBC. (3)(4)(5)(6)(7) Specific human leukocyte antigen (HLA) alleles and common polymorphisms in interleukin 12 (IL12), IL12 receptor (IL12R), tumor necrosis factor superfamily member 15 (TNFSF15), IL21, IL21R, and other immune-associated genes have been implicated in PBC pathogenesis. (3,5,6) Although these studies provided many insights in our understanding of PBC pathogenesis, no further studies have examined the genetics of subphenotypes in PBC.…”

Section: And Xiong Mamentioning

confidence: 99%

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Genome‐wide Association Studies of Specific Antinuclear Autoantibody Subphenotypes in Primary Biliary Cholangitis

et al. 2019

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Anti‐nuclear antibodies to speckled 100 kDa (sp100) and glycoprotein 210 (gp210) are specific serologic markers of primary biliary cholangitis (PBC) of uncertain/controversial clinical or prognostic significance. To study the genetic determinants associated with sp100 and gp210 autoantibody subphenotypes, we performed a genome‐wide association analysis of 930 PBC cases based on their autoantibody status, followed by a replication study in 1,252 PBC cases. We confirmed single‐nucleotide polymorphisms rs492899 (P = 3.27 × 10−22; odds ratio [OR], 2.90; 95% confidence interval [CI], 2.34‐3.66) and rs1794280 (P = 5.78 × 10−28; OR, 3.89; 95% CI, 3.05‐4.96) in the human major histocompatibility complex (MHC) region associated with the sp100 autoantibody. However, no genetic variant was identified as being associated with the gp210 autoantibody. To further define specific classical human leukocyte antigen (HLA) alleles or amino acids associated with the sp100 autoantibody, we imputed 922 PBC cases (211 anti‐sp100‐positive versus 711 negative cases) using a Han Chinese MHC reference database. Conditional analysis identified that HLA‐DRβ1‐Asn77/Arg74, DRβ1‐Ser37, and DPβ1‐Lys65 were major determinants for sp100 production. For the classical HLA alleles, the strongest association was with DRB1*03:01 (P = 1.51 × 10−9; OR, 2.97; 95% CI, 2.06‐4.29). Regression analysis with classical HLA alleles identified DRB1*03:01, DRB1*15:01, DRB1*01, and DPB1*03:01 alleles can explain most of the HLA association with sp100 autoantibody. Conclusion: This study indicated significant genetic predisposition to the sp100 autoantibody, but not the gp210 autoantibody, subphenotype in PBC patients. Additional studies will be necessary to determine if these findings have clinical significance to PBC pathogenesis and/or therapeutics.

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Section: Genome-wide Association Studies Of Specific Antinuclear Automentioning

confidence: 99%

Section: And Xiong Mamentioning

confidence: 99%

Genome‐wide Association Studies of Specific Antinuclear Autoantibody Subphenotypes in Primary Biliary Cholangitis

et al. 2019

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“…Among the SNPs previously reported to be associated with susceptibility to PBC, only HLA has been consistently linked to the disease in distinct patient cohorts across ethnicities as depicted by many significant dots on genome-wide Manhattan plots of GWASs [34][35][36][37][38][39][40][41][42][43].…”

Section: Associations Between Hla and Pbc Susceptibilitymentioning

confidence: 99%

Genetics and epigenetics in the pathogenesis of primary biliary cholangitis

Joshita

Umemura

Tanaka

et al. 2017

Clin J Gastroenterol

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Primary biliary cholangitis (PBC) is a chronic, slowly progressive cholestatic autoimmune liver disease predominantly afflicting women. PBC is characterized by the presence of disease-specific antimitochondrial antibodies and the histological destruction of intrahepatic bile ducts, which eventually lead to cirrhosis and hepatic failure. Fortunately, ursodeoxycholic acid therapy has improved the outcome of the vast majority of PBC cases. Although the etiology of PBC has not yet been elucidated, human leukocyte antigen (HLA) class II alleles have been consistently associated with disease onset for decades. PBC patients may also have genetically determined risk factors in non-HLA regions. Meanwhile, exposure to environmental factors, such as infectious diseases and harmful chemicals, can produce epigenetic alterations in some individuals and subsequent PBC onset. In this review, we describe the influence of HLA alleles and other gene polymorphisms on PBC along with the results of genome-wide association studies on this disease and its future prospects in terms of epigenetics.

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“…PRKCB is involved in a diversity of cellular signaling pathway, including B cell activation during immune response (Lutzny et al 2013), apoptosis (Reyland 2009), and autophagy (Patergnani et al 2013). As a result, mutations in PRKCB are associated with numerous common diseases, including several cancers (Lutzny et al 2013;Wallace et al 2014;Antal et al 2015) and autoimmune diseases (Han et al 2009a;Sheng et al 2010;Kawashima et al 2017). The association with autoimmune diseases is particularly intriguing, as such genes are often identified as targets of recent positive selection (Barreiro and Quintana-Murci 2010;Ramos et al 2014).…”

Section: Relationships Of Population-specific Sequence and Expressionmentioning

confidence: 99%

Population-specific sequence and expression differentiation in Europeans

Jiang

Assis

2019

Preprint

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Much of the enormous phenotypic variation observed across human populations is thought to have arisen from events experienced as our ancestors peopled different regions of the world. However, little is known about the genes involved in these population-specific adaptations. Here we explore this problem by simultaneously examining populationspecific sequence and expression differentiation in four human populations. In particular, we design a branch-based statistic to estimate population-specific differentiation in four populations, and apply this statistic to single nucleotide polymorphism (SNP) and RNAseq data from Italian, British, Finish, and Yoruban populations. As expected, genome-wide estimates of sequence and expression differentiation each independently recapitulate the known demographic history of these four human populations, highlighting the utility of our statistic for identifying genic targets of population-specific adaptations. Application of our statistic reveals that genes containing large copy number variations (CNVs) have elevated levels of population-specific sequence and expression differentiation, consistent with the hypothesis that gene turnover is a key reservoir of adaptive variation. Further, European genes displaying population-specific sequence and expression differentiation are enriched for functions related to epigenetic regulation, immunity, and reproduction. Together, our findings illustrate that population-specific sequence and expression differentiation in humans may preferentially target genes with CNVs and play important roles in a diversity of adaptive and disease-related phenotypes.

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Genome-wide association studies identifyPRKCBas a novel genetic susceptibility locus for primary biliary cholangitis in the Japanese population

Cited by 35 publications

References 37 publications

Genome‐wide Association Studies of Specific Antinuclear Autoantibody Subphenotypes in Primary Biliary Cholangitis

Genome‐wide Association Studies of Specific Antinuclear Autoantibody Subphenotypes in Primary Biliary Cholangitis

Genetics and epigenetics in the pathogenesis of primary biliary cholangitis

Population-specific sequence and expression differentiation in Europeans

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