Blood lipid-related low-frequency variants in LDLR and PCSK9 are associated with onset age and risk of myocardial infarction in Japanese.
Blood lipid-related low-frequency variants in LDLR and PCSK9 are associated with onset age and risk of myocardial infarction in Japanese.
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DOI：
10.1038/s41598-018-26453-x
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发表时间：
2018-05-25
影响因子：
4.6
通讯作者：
Momozawa Y
中科院分区：
文献类型：
--
作者：
Tajima T;Morita H;Ito K;Yamazaki T;Kubo M;Komuro I;Momozawa Y
最近的研究揭示了欧洲人群中心肌梗死（MI）易感性的罕见变异的重要性。由于不同人群的遗传结构不同，我们研究了它们如何影响日本受试者的MI易感性。我们在9,956例病例和8,373例对照中对36个冠状动脉疾病风险基因进行了靶向测序，这些基因是通过全基因组关联研究确定的。基于基因的关联检验发现MI病例中LDLR和PCSK 9的罕见变异显著富集。我们确定了52个（新的22个）LDLR变异预测是有害的。这些变异的携带者显示出更高的MI风险（病例中携带者/非携带者为89/9867，对照组为17/8356，OR = 4.4，P = 7.2 × 10−10），更高的LDL胆固醇水平和更年轻的MI发病年龄。关于PCSK 9，E32 K携带者显示出更高的LDL-胆固醇水平和更年轻的MI发病年龄，而R93 C携带者具有更低的LDL-胆固醇水平。在这些变异携带者中观察到LDL-胆固醇水平与MI发病年龄之间存在显著相关性。与既往在家族性高胆固醇血症患者中进行的研究一致，我们在日本普通人群中进行的研究表明，LDLR和PCSK 9的罕见变异通过改变LDL-胆固醇水平与MI的发病年龄相关。
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.