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Sci Rep. 2018 May 25;8(1):8107. doi: 10.1038/s41598-018-26453-x.

Blood lipid-related low-frequency variants in LDLR and PCSK9 are associated with onset age and risk of myocardial infarction in Japanese.

Author information

1
Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
2
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
3
Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. hmrt-tky@umin.net.
4
Laboratory for Cardiovascular Disease, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan. kaoru.ito@riken.jp.
5
Center for Epidemiology and Preventive Medicine, The University of Tokyo Hospital, Tokyo, Japan.
6
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan. momozawa@riken.jp.

Abstract

Recent studies have revealed the importance of rare variants in myocardial infarction (MI) susceptibility in European populations. Because genetic architectures vary in different populations, we investigated how they contribute to MI susceptibility in Japanese subjects. We performed targeted sequencing of 36 coronary artery disease risk genes, identified by genome-wide association studies, in 9,956 cases and 8,373 controls. Gene-based association tests identified significant enrichment of rare variants in LDLR and PCSK9 in MI cases. We identified 52 (novel 22) LDLR variants predicted to be damaging. Carriers of these variants showed a higher risk of MI (carriers/non-carriers 89/9867 in cases, 17/8356 controls, OR = 4.4, P = 7.2 × 10-10), higher LDL-cholesterol levels and younger age of onset for MI. With respect to PCSK9, E32K carriers showed higher LDL-cholesterol levels and younger age of onset for MI, whereas R93C carriers had lower LDL-cholesterol levels. A significant correlation between LDL-cholesterol levels and onset age of MI was observed in these variant carriers. In good agreement with previous studies in patients with familial hypercholesterolaemia, our study in the Japanese general population showed that rare variants in LDLR and PCSK9 were associated with the onset age of MI by altering LDL-cholesterol levels.

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