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.
| Original language | English |
|---|---|
| Article number | 8107 |
| Journal | Scientific reports |
| Volume | 8 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 01-12-2018 |
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Blood lipid-related low-frequency variants in LDLR and PCSK9 are associated with onset age and risk of myocardial infarction in Japanese. / Tajima, Tomoyuki; Morita, Hiroyuki; Ito, Kaoru; Yamazaki, Tsutomu; Kubo, Michiaki; Komuro, Issei; Momozawa, Yukihide.
In: Scientific reports, Vol. 8, No. 1, 8107, 01.12.2018.Research output: Contribution to journal › Article
TY - JOUR
T1 - Blood lipid-related low-frequency variants in LDLR and PCSK9 are associated with onset age and risk of myocardial infarction in Japanese
AU - Tajima, Tomoyuki
AU - Morita, Hiroyuki
AU - Ito, Kaoru
AU - Yamazaki, Tsutomu
AU - Kubo, Michiaki
AU - Komuro, Issei
AU - Momozawa, Yukihide
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85047727426&partnerID=8YFLogxK
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U2 - 10.1038/s41598-018-26453-x
DO - 10.1038/s41598-018-26453-x
M3 - Article
VL - 8
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 8107
ER -