Three missense variants of metabolic syndrome-related genes are associated with alpha-1 antitrypsin levels

Alpha-1 antitrypsin (AAT) encoded by SERPINA1 is an acute-phase inflammation marker, and AAT deficiency (AATD) is known as one of the common genetic disorders in European populations. However, no genetic determinants to AAT levels apart from the SERPINA gene clusters have been identified to date. He...

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Main Authors:	Setoh, Kazuya, Terao, Chikashi, Muro, Shigeo, Kawaguchi, Takahisa, Tabara, Yasuharu, Takahashi, Meiko, Nakayama, Takeo, Kosugi, Shinji, Sekine, Akihiro, Yamada, Ryo, Mishima, Michiaki, Matsuda, Fumihiko
Format:	Online
Language:	English
Published:	Nature Pub. Group 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4518310/

id	pubmed-4518310
recordtype	oai_dc
spelling	pubmed-45183102015-08-07 Three missense variants of metabolic syndrome-related genes are associated with alpha-1 antitrypsin levels Setoh, Kazuya Terao, Chikashi Muro, Shigeo Kawaguchi, Takahisa Tabara, Yasuharu Takahashi, Meiko Nakayama, Takeo Kosugi, Shinji Sekine, Akihiro Yamada, Ryo Mishima, Michiaki Matsuda, Fumihiko Article Alpha-1 antitrypsin (AAT) encoded by SERPINA1 is an acute-phase inflammation marker, and AAT deficiency (AATD) is known as one of the common genetic disorders in European populations. However, no genetic determinants to AAT levels apart from the SERPINA gene clusters have been identified to date. Here we perform a genome-wide association study of serum AAT levels followed by a two-staged replication study recruiting a total of 9,359 Japanese community-dwelling population. Three missense variants of metabolic syndrome-related genes, namely, rs671 in ALDH2, rs1169288 in HNF1A and rs1260326 in GCKR, significantly associate with AAT levels (P≤1.5 × 10−12). Previous reports have shown the functional relevance of ALDH2 and HNF1A to AAT. We observe a significant interaction of rs671 and alcohol consumption on AAT levels. We confirm the association between AAT and rs2896268 in SERPINA1, which is independent of known causative variants of AATD. These findings would support various AAT functions including metabolic processes. Nature Pub. Group 2015-07-15 /pmc/articles/PMC4518310/ /pubmed/26174136 http://dx.doi.org/10.1038/ncomms8754 Text en Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Setoh, Kazuya Terao, Chikashi Muro, Shigeo Kawaguchi, Takahisa Tabara, Yasuharu Takahashi, Meiko Nakayama, Takeo Kosugi, Shinji Sekine, Akihiro Yamada, Ryo Mishima, Michiaki Matsuda, Fumihiko
spellingShingle	Setoh, Kazuya Terao, Chikashi Muro, Shigeo Kawaguchi, Takahisa Tabara, Yasuharu Takahashi, Meiko Nakayama, Takeo Kosugi, Shinji Sekine, Akihiro Yamada, Ryo Mishima, Michiaki Matsuda, Fumihiko Three missense variants of metabolic syndrome-related genes are associated with alpha-1 antitrypsin levels
author_facet	Setoh, Kazuya Terao, Chikashi Muro, Shigeo Kawaguchi, Takahisa Tabara, Yasuharu Takahashi, Meiko Nakayama, Takeo Kosugi, Shinji Sekine, Akihiro Yamada, Ryo Mishima, Michiaki Matsuda, Fumihiko
author_sort	Setoh, Kazuya
title	Three missense variants of metabolic syndrome-related genes are associated with alpha-1 antitrypsin levels
title_short	Three missense variants of metabolic syndrome-related genes are associated with alpha-1 antitrypsin levels
title_full	Three missense variants of metabolic syndrome-related genes are associated with alpha-1 antitrypsin levels
title_fullStr	Three missense variants of metabolic syndrome-related genes are associated with alpha-1 antitrypsin levels
title_full_unstemmed	Three missense variants of metabolic syndrome-related genes are associated with alpha-1 antitrypsin levels
title_sort	three missense variants of metabolic syndrome-related genes are associated with alpha-1 antitrypsin levels
description	Alpha-1 antitrypsin (AAT) encoded by SERPINA1 is an acute-phase inflammation marker, and AAT deficiency (AATD) is known as one of the common genetic disorders in European populations. However, no genetic determinants to AAT levels apart from the SERPINA gene clusters have been identified to date. Here we perform a genome-wide association study of serum AAT levels followed by a two-staged replication study recruiting a total of 9,359 Japanese community-dwelling population. Three missense variants of metabolic syndrome-related genes, namely, rs671 in ALDH2, rs1169288 in HNF1A and rs1260326 in GCKR, significantly associate with AAT levels (P≤1.5 × 10−12). Previous reports have shown the functional relevance of ALDH2 and HNF1A to AAT. We observe a significant interaction of rs671 and alcohol consumption on AAT levels. We confirm the association between AAT and rs2896268 in SERPINA1, which is independent of known causative variants of AATD. These findings would support various AAT functions including metabolic processes.
publisher	Nature Pub. Group
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4518310/
_version_	1613253375533514752

Three missense variants of metabolic syndrome-related genes are associated with alpha-1 antitrypsin levels

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