title: Three missense variants of metabolic syndrome-related genes are associated with alpha-1 antitrypsin levels.
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.
authors.affiliation: Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Shogoinkawaramachi 53, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Setoh
authors.affiliation: Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Shogoinkawaramachi 53, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Chikashi
authors.initials: C
authors.lastname: Terao
authors.affiliation: Department of Respiratory Medicine, Kyoto University Graduate School of Medicine, Shogoinkawaramachi 54, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Muro
authors.affiliation: Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Shogoinkawaramachi 53, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kawaguchi
authors.affiliation: Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Shogoinkawaramachi 53, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Tabara
authors.affiliation: Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Shogoinkawaramachi 53, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Meiko
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Health Informatics, Kyoto University School of Public Health, Yoshidakonoemachi, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Nakayama
authors.affiliation: Department of Medical Ethics and Medical Genetics, Kyoto University School of Public Health, Yoshidakonoemachi, Sakyo-ku Kyoto, 606-8501, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kosugi
authors.affiliation: EBM Research Center, Kyoto University Graduate School of Medicine, Shogoinkawaramachi 54, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sekine
authors.affiliation: Statistical Genetics, Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Shogoinkawaramachi 53, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamada
authors.affiliation: Department of Respiratory Medicine, Kyoto University Graduate School of Medicine, Shogoinkawaramachi 54, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Mishima
authors.affiliation: 1] Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Shogoinkawaramachi 53, Sakyo-ku, Kyoto 606-8507, Japan. [2] Statistical Genetics, Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Shogoinkawaramachi 53, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D000428:Alcohol Drinking / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D044466:Asian People; D005260:Female; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D005838:Genotype; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics*; D006801:Humans; D007564:Japan; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics*; D008875:Middle Aged; D020125:Mutation, Missense; D000515:alpha 1-Antitrypsin / Q000097:blood / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C485100:GCKR protein, human; C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial