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

Kazuya Setoh, Chikashi Terao (), Shigeo Muro, Takahisa Kawaguchi, Yasuharu Tabara, Meiko Takahashi, Takeo Nakayama, Shinji Kosugi, Akihiro Sekine, Ryo Yamada, Michiaki Mishima and Fumihiko Matsuda
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Kazuya Setoh: Center for Genomic Medicine, Kyoto University Graduate School of Medicine
Chikashi Terao: Center for Genomic Medicine, Kyoto University Graduate School of Medicine
Shigeo Muro: Kyoto University Graduate School of Medicine
Takahisa Kawaguchi: Center for Genomic Medicine, Kyoto University Graduate School of Medicine
Yasuharu Tabara: Center for Genomic Medicine, Kyoto University Graduate School of Medicine
Meiko Takahashi: Center for Genomic Medicine, Kyoto University Graduate School of Medicine
Takeo Nakayama: Kyoto University School of Public Health
Shinji Kosugi: Kyoto University School of Public Health
Akihiro Sekine: EBM Research Center, Kyoto University Graduate School of Medicine
Ryo Yamada: Statistical Genetics, Center for Genomic Medicine, Kyoto University Graduate School of Medicine
Michiaki Mishima: Kyoto University Graduate School of Medicine
Fumihiko Matsuda: Center for Genomic Medicine, Kyoto University Graduate School of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-9

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8754

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