Identification of a glutamic acid repeat polymorphism of ALMS1 as a novel genetic risk marker for early-onset myocardial infarction by genome-wide linkage analysis

Sahoko Ichihara, Ken Yamamoto, Hiroyuki Asano, Masahiro Nakatochi, Mayo Sukegawa, Gaku Ichihara, Hideo Izawa, Akihiro Hirashiki, Fumimaro Takatsu, Hisashi Umeda, Mitsunori Iwase, Haruo Inagaki, Haruo Hirayama, Takahito Sone, Kazuhiko Nishigaki, Shinya Minatoguchi, Myeong Chan Cho, Yangsoo Jang, Hyo Soo Kim, Jeong E. ParkSaeko Tada-Oikawa, Hidetoshi Kitajima, Tatsuaki Matsubara, Kenji Sunagawa, Hiroaki Shimokawa, Akinori Kimura, Jong Young Lee, Toyoaki Murohara, Ituro Inoue, Mitsuhiro Yokota

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13 Citations (Scopus)

Abstract

Background-Myocardial infarction (MI) is a leading cause of death worldwide. Given that a family history is an independent risk factor for coronary artery disease, genetic variants are thought to contribute directly to the development of this condition. The identification of susceptibility genes for coronary artery disease or MI may thus help to identify high-risk individuals and offer the opportunity for disease prevention. Methods and Results-We designed a 5-step protocol, consisting of a genome-wide linkage study followed by association analysis, to identify novel genetic variants that confer susceptibility to coronary artery disease or MI. A genome-wide affected sib-pair linkage study with 221 Japanese families with coronary artery disease yielded a statistically significant logarithm of the odds score of 3.44 for chromosome 2p13 and MI. Further association analysis implicated Alström syndrome 1 gene (ALMS1) as a candidate gene within the linkage region. Validation association analysis revealed that representative single-nucleotide polymorphisms of the ALMS1 promoter region were significantly associated with early-onset MI in both Japanese and Korean populations. Moreover, direct sequencing of the ALMS1 coding region identified a glutamic acid repeat polymorphism in exon 1, which was subsequently found to be associated with early-onset MI. Conclusions-The glutamic acid repeat polymorphism of ALMS1 identified in the present study may provide insight into the pathogenesis of early-onset MI.

Original languageEnglish
Pages (from-to)569-578
Number of pages10
JournalCirculation: Cardiovascular Genetics
Volume6
Issue number6
DOIs
Publication statusPublished - 12-2013

All Science Journal Classification (ASJC) codes

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)

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    Ichihara, S., Yamamoto, K., Asano, H., Nakatochi, M., Sukegawa, M., Ichihara, G., Izawa, H., Hirashiki, A., Takatsu, F., Umeda, H., Iwase, M., Inagaki, H., Hirayama, H., Sone, T., Nishigaki, K., Minatoguchi, S., Cho, M. C., Jang, Y., Kim, H. S., ... Yokota, M. (2013). Identification of a glutamic acid repeat polymorphism of ALMS1 as a novel genetic risk marker for early-onset myocardial infarction by genome-wide linkage analysis. Circulation: Cardiovascular Genetics, 6(6), 569-578. https://doi.org/10.1161/CIRCGENETICS.111.000027