X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis

UK-PBC Consortium; Japan PBC-GWAS Consortium; Canadian-US PBC Consortium; Italian PBC Genetics Study Group

doi:10.1053/j.gastro.2021.02.061

X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis

UK-PBC Consortium, Japan PBC-GWAS Consortium, Canadian-US PBC Consortium, Italian PBC Genetics Study Group

Medicine

Résultat de recherche: Article › examen par les pairs

41 Citations (Scopus)

Résumé

Background & Aims: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. Methods: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). Results: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10^–4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10^–6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028–1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09–1.26; P = 9.93 × 10^–8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10^–9; OR, 1.33; 95% CI, 1.21–1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). Conclusions: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.

Langue d'origine	English
Pages (de-à)	2483-2495.e26
Journal	Gastroenterology
Volume	160
Numéro de publication	7
DOI	https://doi.org/10.1053/j.gastro.2021.02.061
Statut de publication	Published - juin 2021

Note bibliographique

Funding Information:
Funding This study was partly supported by Italian Ministry of Health grants (PE-2016-02363915 and GR-2018-12367794), National Institutes of Health grant R01DK091823, and National Natural Science Foundation of China grants (81830016 and 81620108002 to XM). The authors thank Associazione Malattie Autoimmuni del Fegato (AMAF) Monza Organizzazione non lucrativa di utilità sociale (ONLUS) and Associazione Italiana Ricerca Colangite Sclerosante (AIRCS) for the unrestricted research funding. This work was also supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (15K19314 to 17K15924 to Yuki Hitomi; 15K06908 to Minae Kawashima; 15K19357 and 17K09449 to Yoshihiro Aiba; and 23591006, 26293181, and 17H04169 to Minoru Nakamura), a Grant-in-Aid for Clinical Research from the National Hospital Organization (to Minoru Nakamura), a grant from the Research Program of Intractable Disease provided by the Ministry of Health, Labor, and Welfare of Japan to Minoru Nakamura, a grant from the Takeda Foundation (to Yuki Hitomi), and grants from the Japan Agency for Medical Research and Development (JP19km0405205 and JP19km0405501h0001 to Katsushi Tokunaga and Masao Nagasaki). Marco Carbone, Alessio Gerussi, and Pietro Invernizzi are members of the European Reference Network on Hepatological Diseases.

Funding Information:
Funding This study was partly supported by Italian Ministry of Health grants (PE-2016-02363915 and GR-2018-12367794), National Institutes of Health grant R01DK091823, and National Natural Science Foundation of China grants (81830016 and 81620108002 to XM). The authors thank Associazione Malattie Autoimmuni del Fegato (AMAF) Monza Organizzazione non lucrativa di utilità sociale (ONLUS) and Associazione Italiana Ricerca Colangite Sclerosante (AIRCS) for the unrestricted research funding. This work was also supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (15K19314 to 17K15924 to Yuki Hitomi; 15K06908 to Minae Kawashima; 15K19357 and 17K09449 to Yoshihiro Aiba; and 23591006, 26293181, and 17H04169 to Minoru Nakamura), a Grant-in-Aid for Clinical Research from the National Hospital Organization (to Minoru Nakamura), a grant from the Research Program of Intractable Disease provided by the Ministry of Health, Labor, and Welfare of Japan to Minoru Nakamura, a grant from the Takeda Foundation (to Yuki Hitomi), and grants from the Japan Agency for Medical Research and Development (JP19km0405205 and JP19km0405501h0001 to Katsushi Tokunaga and Masao Nagasaki). Marco Carbone, Alessio Gerussi, and Pietro Invernizzi are members of the European Reference Network on Hepatological Diseases.

Publisher Copyright:
© 2021 AGA Institute

ASJC Scopus Subject Areas

Hepatology
Gastroenterology

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Accès au document

10.1053/j.gastro.2021.02.061

Autres fichiers et liens

Citer

@article{2609486e3a35497bad533112b7b72399,

title = "X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis",

abstract = "Background & Aims: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. Methods: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). Results: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10–4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10–6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028–1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09–1.26; P = 9.93 × 10–8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10–9; OR, 1.33; 95% CI, 1.21–1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). Conclusions: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.",

author = "{UK-PBC Consortium} and {Japan PBC-GWAS Consortium} and {Canadian-US PBC Consortium} and {Italian PBC Genetics Study Group} and Rosanna Asselta and Paraboschi, {Elvezia M.} and Alessio Gerussi and Cordell, {Heather J.} and Mells, {George F.} and Sandford, {Richard N.} and Jones, {David E.} and Minoru Nakamura and Kazuko Ueno and Yuki Hitomi and Minae Kawashima and Nao Nishida and Katsushi Tokunaga and Masao Nagasaki and Atsushi Tanaka and Ruqi Tang and Zhiqiang Li and Yongyong Shi and Xiangdong Liu and Ma Xiong and Gideon Hirschfield and Siminovitch, {Katherine A.} and Erin Walker and Gang Xie and Andy Mason and Robert Myers and Kevork Peltekian and Cameron Ghent and Elizabeth Atkinson and Bruce Juran and Kostas Lazaridis and Yue Lu and Xiangjun Gu and Kaiyan Jing and Chris Amos and Andrea Affronti and Maurizia Brunetto and Barbara Coco and Giancarlo Spinzi and Gianfranco Elia and Carlo Ferrari and Ana Lleo and Luigi Muratori and Paolo Muratori and Piero Portincasa and Agostino Colli and Savino Bruno and Guido Colloredo and Francesco Azzaroli and Pietro Andreone",

note = "Funding Information: Funding This study was partly supported by Italian Ministry of Health grants (PE-2016-02363915 and GR-2018-12367794), National Institutes of Health grant R01DK091823, and National Natural Science Foundation of China grants (81830016 and 81620108002 to XM). The authors thank Associazione Malattie Autoimmuni del Fegato (AMAF) Monza Organizzazione non lucrativa di utilit{\`a} sociale (ONLUS) and Associazione Italiana Ricerca Colangite Sclerosante (AIRCS) for the unrestricted research funding. This work was also supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (15K19314 to 17K15924 to Yuki Hitomi; 15K06908 to Minae Kawashima; 15K19357 and 17K09449 to Yoshihiro Aiba; and 23591006, 26293181, and 17H04169 to Minoru Nakamura), a Grant-in-Aid for Clinical Research from the National Hospital Organization (to Minoru Nakamura), a grant from the Research Program of Intractable Disease provided by the Ministry of Health, Labor, and Welfare of Japan to Minoru Nakamura, a grant from the Takeda Foundation (to Yuki Hitomi), and grants from the Japan Agency for Medical Research and Development (JP19km0405205 and JP19km0405501h0001 to Katsushi Tokunaga and Masao Nagasaki). Marco Carbone, Alessio Gerussi, and Pietro Invernizzi are members of the European Reference Network on Hepatological Diseases. Funding Information: Funding This study was partly supported by Italian Ministry of Health grants (PE-2016-02363915 and GR-2018-12367794), National Institutes of Health grant R01DK091823, and National Natural Science Foundation of China grants (81830016 and 81620108002 to XM). The authors thank Associazione Malattie Autoimmuni del Fegato (AMAF) Monza Organizzazione non lucrativa di utilit{\`a} sociale (ONLUS) and Associazione Italiana Ricerca Colangite Sclerosante (AIRCS) for the unrestricted research funding. This work was also supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (15K19314 to 17K15924 to Yuki Hitomi; 15K06908 to Minae Kawashima; 15K19357 and 17K09449 to Yoshihiro Aiba; and 23591006, 26293181, and 17H04169 to Minoru Nakamura), a Grant-in-Aid for Clinical Research from the National Hospital Organization (to Minoru Nakamura), a grant from the Research Program of Intractable Disease provided by the Ministry of Health, Labor, and Welfare of Japan to Minoru Nakamura, a grant from the Takeda Foundation (to Yuki Hitomi), and grants from the Japan Agency for Medical Research and Development (JP19km0405205 and JP19km0405501h0001 to Katsushi Tokunaga and Masao Nagasaki). Marco Carbone, Alessio Gerussi, and Pietro Invernizzi are members of the European Reference Network on Hepatological Diseases. Publisher Copyright: {\textcopyright} 2021 AGA Institute",

year = "2021",

month = jun,

doi = "10.1053/j.gastro.2021.02.061",

language = "English",

volume = "160",

pages = "2483--2495.e26",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders Ltd",

number = "7",

}

TY - JOUR

T1 - X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis

AU - UK-PBC Consortium

AU - Japan PBC-GWAS Consortium

AU - Canadian-US PBC Consortium

AU - Italian PBC Genetics Study Group

AU - Asselta, Rosanna

AU - Paraboschi, Elvezia M.

AU - Gerussi, Alessio

AU - Cordell, Heather J.

AU - Mells, George F.

AU - Sandford, Richard N.

AU - Jones, David E.

AU - Nakamura, Minoru

AU - Ueno, Kazuko

AU - Hitomi, Yuki

AU - Kawashima, Minae

AU - Nishida, Nao

AU - Tokunaga, Katsushi

AU - Nagasaki, Masao

AU - Tanaka, Atsushi

AU - Tang, Ruqi

AU - Li, Zhiqiang

AU - Shi, Yongyong

AU - Liu, Xiangdong

AU - Xiong, Ma

AU - Hirschfield, Gideon

AU - Siminovitch, Katherine A.

AU - Walker, Erin

AU - Xie, Gang

AU - Mason, Andy

AU - Myers, Robert

AU - Peltekian, Kevork

AU - Ghent, Cameron

AU - Atkinson, Elizabeth

AU - Juran, Bruce

AU - Lazaridis, Kostas

AU - Lu, Yue

AU - Gu, Xiangjun

AU - Jing, Kaiyan

AU - Amos, Chris

AU - Affronti, Andrea

AU - Brunetto, Maurizia

AU - Coco, Barbara

AU - Spinzi, Giancarlo

AU - Elia, Gianfranco

AU - Ferrari, Carlo

AU - Lleo, Ana

AU - Muratori, Luigi

AU - Muratori, Paolo

AU - Portincasa, Piero

AU - Colli, Agostino

AU - Bruno, Savino

AU - Colloredo, Guido

AU - Azzaroli, Francesco

AU - Andreone, Pietro

N1 - Funding Information: Funding This study was partly supported by Italian Ministry of Health grants (PE-2016-02363915 and GR-2018-12367794), National Institutes of Health grant R01DK091823, and National Natural Science Foundation of China grants (81830016 and 81620108002 to XM). The authors thank Associazione Malattie Autoimmuni del Fegato (AMAF) Monza Organizzazione non lucrativa di utilità sociale (ONLUS) and Associazione Italiana Ricerca Colangite Sclerosante (AIRCS) for the unrestricted research funding. This work was also supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (15K19314 to 17K15924 to Yuki Hitomi; 15K06908 to Minae Kawashima; 15K19357 and 17K09449 to Yoshihiro Aiba; and 23591006, 26293181, and 17H04169 to Minoru Nakamura), a Grant-in-Aid for Clinical Research from the National Hospital Organization (to Minoru Nakamura), a grant from the Research Program of Intractable Disease provided by the Ministry of Health, Labor, and Welfare of Japan to Minoru Nakamura, a grant from the Takeda Foundation (to Yuki Hitomi), and grants from the Japan Agency for Medical Research and Development (JP19km0405205 and JP19km0405501h0001 to Katsushi Tokunaga and Masao Nagasaki). Marco Carbone, Alessio Gerussi, and Pietro Invernizzi are members of the European Reference Network on Hepatological Diseases. Funding Information: Funding This study was partly supported by Italian Ministry of Health grants (PE-2016-02363915 and GR-2018-12367794), National Institutes of Health grant R01DK091823, and National Natural Science Foundation of China grants (81830016 and 81620108002 to XM). The authors thank Associazione Malattie Autoimmuni del Fegato (AMAF) Monza Organizzazione non lucrativa di utilità sociale (ONLUS) and Associazione Italiana Ricerca Colangite Sclerosante (AIRCS) for the unrestricted research funding. This work was also supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (15K19314 to 17K15924 to Yuki Hitomi; 15K06908 to Minae Kawashima; 15K19357 and 17K09449 to Yoshihiro Aiba; and 23591006, 26293181, and 17H04169 to Minoru Nakamura), a Grant-in-Aid for Clinical Research from the National Hospital Organization (to Minoru Nakamura), a grant from the Research Program of Intractable Disease provided by the Ministry of Health, Labor, and Welfare of Japan to Minoru Nakamura, a grant from the Takeda Foundation (to Yuki Hitomi), and grants from the Japan Agency for Medical Research and Development (JP19km0405205 and JP19km0405501h0001 to Katsushi Tokunaga and Masao Nagasaki). Marco Carbone, Alessio Gerussi, and Pietro Invernizzi are members of the European Reference Network on Hepatological Diseases. Publisher Copyright: © 2021 AGA Institute

PY - 2021/6

Y1 - 2021/6

N2 - Background & Aims: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. Methods: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). Results: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10–4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10–6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028–1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09–1.26; P = 9.93 × 10–8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10–9; OR, 1.33; 95% CI, 1.21–1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). Conclusions: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.

AB - Background & Aims: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. Methods: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). Results: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10–4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10–6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028–1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09–1.26; P = 9.93 × 10–8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10–9; OR, 1.33; 95% CI, 1.21–1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). Conclusions: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.

UR - http://www.scopus.com/inward/record.url?scp=85107319095&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85107319095&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2021.02.061

DO - 10.1053/j.gastro.2021.02.061

M3 - Article

C2 - 33675743

AN - SCOPUS:85107319095

SN - 0016-5085

VL - 160

SP - 2483-2495.e26

JO - Gastroenterology

JF - Gastroenterology

IS - 7

ER -

X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis

Résumé

Note bibliographique

ASJC Scopus Subject Areas

PubMed: MeSH publication types

Accès au document

Autres fichiers et liens

Empreinte numérique

Citer