Setoh Kazuya, Terao Chikashi, Muro Shigeo, Kawaguchi Takahisa, Tabara Yasuharu, Takahashi Meiko, Nakayama Takeo, Kosugi Shinji, Sekine Akihiro, Yamada Ryo, Mishima Michiaki, Matsuda Fumihiko
Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Shogoinkawaramachi 53, Sakyo-ku, Kyoto 606-8507, Japan.
Department of Respiratory Medicine, Kyoto University Graduate School of Medicine, Shogoinkawaramachi 54, Sakyo-ku, Kyoto 606-8507, Japan.
Nat Commun. 2015 Jul 15;6:7754. doi: 10.1038/ncomms8754.
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.
由SERPINA1编码的α-1抗胰蛋白酶（AAT）是一种急性期炎症标志物，AAT缺乏症（AATD）是欧洲人群中常见的遗传性疾病之一。然而，迄今为止，除了SERPINA基因簇外，尚未发现影响AAT水平的遗传决定因素。在此，我们对血清AAT水平进行了全基因组关联研究，随后进行了两阶段复制研究，共招募了9359名日本社区居住人群。代谢综合征相关基因的三个错义变体，即ALDH2中的rs671、HNF1A中的rs1169288和GCKR中的rs1260326，与AAT水平显著相关（P≤1.5×10^(-12)）。先前的报道显示了ALDH2和HNF1A与AAT的功能相关性。我们观察到rs671与饮酒对AAT水平有显著的相互作用。我们证实了AAT与SERPINA1中的rs2896268之间的关联，这与已知的AATD致病变体无关。这些发现将支持包括代谢过程在内的各种AAT功能。
