A functional SNP in FLT1 increases risk of coronary artery disease in a Japanese population

Atsuko Konta, Kouichi Ozaki, Yasuhiko Sakata, Atsushi Takahashi, Takashi Morizono, Shinichiro Suna, Yoshihiro Onouchi, Tatsuhiko Tsunoda, Michiaki Kubo, Issei Komuro, Yoshinobu Eishi, Toshihiro Tanaka

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Abstract

Coronary artery disease (CAD) including myocardial infarction is one of the leading causes of death in many countries. Similar to other common diseases, its pathogenesis is thought to result from complex interactions among multiple genetic and environmental factors. Recent large-scale genetic association analysis for CAD identified 15 new loci. We examined the reproducibility of these previous association findings with 7990 cases and 6582 controls in a Japanese population. We found a convincing association of rs9319428 in FLT1, encoding fms-related tyrosine kinase 1 (P=5.98 × 10 -8). Fine mapping using tag single-nucleotide polymorphisms (SNPs) at FLT1 locus revealed that another SNP (rs74412485) showed more profound genetic effect for CAD (P=2.85 × 10 -12). The SNP, located in intron 1 in FLT1, enhanced the transcriptional level of FLT1. RNA interference experiment against FLT1 showed that the suppression of FLT1 resulted in decreased expression of inflammatory adhesion molecules. Expression of FLT1 was observed in endothelial cells of human coronary artery. Our results indicate that the genetically coded increased expression of FLT1 by a functional SNP implicates activation in an inflammatory cascade that might eventually lead to CAD.

Original languageEnglish
Pages (from-to)435-441
Number of pages7
JournalJournal of Human Genetics
Volume61
Issue number5
DOIs
Publication statusPublished - 01-05-2016

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Single Nucleotide Polymorphism
Coronary Artery Disease
Population
RNA Interference
Protein-Tyrosine Kinases
Introns
Cause of Death
Coronary Vessels
Endothelial Cells
Myocardial Infarction

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Konta, A., Ozaki, K., Sakata, Y., Takahashi, A., Morizono, T., Suna, S., ... Tanaka, T. (2016). A functional SNP in FLT1 increases risk of coronary artery disease in a Japanese population. Journal of Human Genetics, 61(5), 435-441. https://doi.org/10.1038/jhg.2015.171
Konta, Atsuko ; Ozaki, Kouichi ; Sakata, Yasuhiko ; Takahashi, Atsushi ; Morizono, Takashi ; Suna, Shinichiro ; Onouchi, Yoshihiro ; Tsunoda, Tatsuhiko ; Kubo, Michiaki ; Komuro, Issei ; Eishi, Yoshinobu ; Tanaka, Toshihiro. / A functional SNP in FLT1 increases risk of coronary artery disease in a Japanese population. In: Journal of Human Genetics. 2016 ; Vol. 61, No. 5. pp. 435-441.
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abstract = "Coronary artery disease (CAD) including myocardial infarction is one of the leading causes of death in many countries. Similar to other common diseases, its pathogenesis is thought to result from complex interactions among multiple genetic and environmental factors. Recent large-scale genetic association analysis for CAD identified 15 new loci. We examined the reproducibility of these previous association findings with 7990 cases and 6582 controls in a Japanese population. We found a convincing association of rs9319428 in FLT1, encoding fms-related tyrosine kinase 1 (P=5.98 × 10 -8). Fine mapping using tag single-nucleotide polymorphisms (SNPs) at FLT1 locus revealed that another SNP (rs74412485) showed more profound genetic effect for CAD (P=2.85 × 10 -12). The SNP, located in intron 1 in FLT1, enhanced the transcriptional level of FLT1. RNA interference experiment against FLT1 showed that the suppression of FLT1 resulted in decreased expression of inflammatory adhesion molecules. Expression of FLT1 was observed in endothelial cells of human coronary artery. Our results indicate that the genetically coded increased expression of FLT1 by a functional SNP implicates activation in an inflammatory cascade that might eventually lead to CAD.",
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Konta, A, Ozaki, K, Sakata, Y, Takahashi, A, Morizono, T, Suna, S, Onouchi, Y, Tsunoda, T, Kubo, M, Komuro, I, Eishi, Y & Tanaka, T 2016, 'A functional SNP in FLT1 increases risk of coronary artery disease in a Japanese population', Journal of Human Genetics, vol. 61, no. 5, pp. 435-441. https://doi.org/10.1038/jhg.2015.171

A functional SNP in FLT1 increases risk of coronary artery disease in a Japanese population. / Konta, Atsuko; Ozaki, Kouichi; Sakata, Yasuhiko; Takahashi, Atsushi; Morizono, Takashi; Suna, Shinichiro; Onouchi, Yoshihiro; Tsunoda, Tatsuhiko; Kubo, Michiaki; Komuro, Issei; Eishi, Yoshinobu; Tanaka, Toshihiro.

In: Journal of Human Genetics, Vol. 61, No. 5, 01.05.2016, p. 435-441.

Research output: Contribution to journalArticle

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T1 - A functional SNP in FLT1 increases risk of coronary artery disease in a Japanese population

AU - Konta, Atsuko

AU - Ozaki, Kouichi

AU - Sakata, Yasuhiko

AU - Takahashi, Atsushi

AU - Morizono, Takashi

AU - Suna, Shinichiro

AU - Onouchi, Yoshihiro

AU - Tsunoda, Tatsuhiko

AU - Kubo, Michiaki

AU - Komuro, Issei

AU - Eishi, Yoshinobu

AU - Tanaka, Toshihiro

PY - 2016/5/1

Y1 - 2016/5/1

N2 - Coronary artery disease (CAD) including myocardial infarction is one of the leading causes of death in many countries. Similar to other common diseases, its pathogenesis is thought to result from complex interactions among multiple genetic and environmental factors. Recent large-scale genetic association analysis for CAD identified 15 new loci. We examined the reproducibility of these previous association findings with 7990 cases and 6582 controls in a Japanese population. We found a convincing association of rs9319428 in FLT1, encoding fms-related tyrosine kinase 1 (P=5.98 × 10 -8). Fine mapping using tag single-nucleotide polymorphisms (SNPs) at FLT1 locus revealed that another SNP (rs74412485) showed more profound genetic effect for CAD (P=2.85 × 10 -12). The SNP, located in intron 1 in FLT1, enhanced the transcriptional level of FLT1. RNA interference experiment against FLT1 showed that the suppression of FLT1 resulted in decreased expression of inflammatory adhesion molecules. Expression of FLT1 was observed in endothelial cells of human coronary artery. Our results indicate that the genetically coded increased expression of FLT1 by a functional SNP implicates activation in an inflammatory cascade that might eventually lead to CAD.

AB - Coronary artery disease (CAD) including myocardial infarction is one of the leading causes of death in many countries. Similar to other common diseases, its pathogenesis is thought to result from complex interactions among multiple genetic and environmental factors. Recent large-scale genetic association analysis for CAD identified 15 new loci. We examined the reproducibility of these previous association findings with 7990 cases and 6582 controls in a Japanese population. We found a convincing association of rs9319428 in FLT1, encoding fms-related tyrosine kinase 1 (P=5.98 × 10 -8). Fine mapping using tag single-nucleotide polymorphisms (SNPs) at FLT1 locus revealed that another SNP (rs74412485) showed more profound genetic effect for CAD (P=2.85 × 10 -12). The SNP, located in intron 1 in FLT1, enhanced the transcriptional level of FLT1. RNA interference experiment against FLT1 showed that the suppression of FLT1 resulted in decreased expression of inflammatory adhesion molecules. Expression of FLT1 was observed in endothelial cells of human coronary artery. Our results indicate that the genetically coded increased expression of FLT1 by a functional SNP implicates activation in an inflammatory cascade that might eventually lead to CAD.

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