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Title: Three missense variants of metabolic syndrome-related genes are associated with alpha-1 antitrypsin levels
Authors: Setoh, Kazuya
Terao, Chikashi
Muro, Shigeo
Kawaguchi, Takahisa
Tabara, Yasuharu  kyouindb  KAKEN_id
Takahashi, Meiko
Nakayama, Takeo  kyouindb  KAKEN_id
Kosugi, Shinji
Sekine, Akihiro
Yamada, Ryo
Mishima, Michiaki
Matsuda, Fumihiko
Author's alias: 寺尾, 知可史
室, 繁郎
田原, 康玄
高橋, めい子
中山, 健夫
小杉, 眞司
山田, 亮
松田, 文彦
Keywords: Biological sciences
Issue Date: 15-Jul-2015
Publisher: Nature Publishing Group
Journal title: Nature Communications
Volume: 6
Thesis number: 7754
Abstract: 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.
Rights: 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
DOI(Published Version): 10.1038/ncomms8754
Appears in Collections:Journal Articles

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