TY - JOUR
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
N1 - Publisher Copyright:
© 2016 The Japan Society of Human Genetics.
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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U2 - 10.1038/jhg.2015.171
DO - 10.1038/jhg.2015.171
M3 - Article
C2 - 26791355
AN - SCOPUS:84971317679
SN - 1434-5161
VL - 61
SP - 435
EP - 441
JO - Journal of Human Genetics
JF - Journal of Human Genetics
IS - 5
ER -
