期刊
ATHEROSCLEROSIS
卷 289, 期 -, 页码 101-108出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.atherosclerosis.2019.08.004
关键词
Familial hypercholesterolemia; Pathogenic variant; LDLR; PCSK9; Annotation
资金
- Ministry of Health, Labour and Welfare of Japan [H26-nanji-ippan-056, H30-nanji-ippan-003]
- JSPS KAKENHI [JP17K08681]
- Japan Agency for Medical Research and Development [16ek0210075h0001]
- Intramural Research Fund for Cardiovascular Diseases of the National Cerebral and Cardiovascular Center [28-2-2, 29-6-11]
- Japan Heart Foundation
- Astellas Grant for Research on Atherosclerosis Update
- Takeda Science Foundation
- Kanae Foundation for the Promotion of Medical Science
- Novartis Research Grants
- Japanese Circulation Society
Background and aims: More than 4970 variants in the low-density lipoprotein receptor (LDLR) gene and 350 variants in the proprotein convertase subtilisin/kexin 9 (PCSK9) gene have been reported in familial hyperch-olesterolemia (FH) patients. However, the effects of these variants on FH pathophysiology have not been fully clarified. We aimed to update the LDLR and PCSK9 variants in Japanese heterozygous FH (HeFH) patients and annotate their clinical significance for the genetic diagnosis of HeFH. Methods: A genetic analysis of the LDLR and PCSK9 genes was performed in 801 clinically diagnosed HeFH patients. The association of the pathogenic variants with the clinical FH phenotype was examined. Results: Pathogenic variants in the LDLR and PCSK9 genes were found in 46% (n= 296) and 7.8% (n= 51) of unrelated FH patients (n= 650), respectively. The prevalence of Achilles tendon thickness was low (44%) in patients harbouring PCSK9 pathogenic variants. Furthermore, 17% of unrelated FH patients harboured one of five frequent LDLR pathogenic variants: c.1845+2T > C, c.1012T > A: p.(Cys338Ser), c.1297G > C: p. (Asp433His), c.1702C > G: p.(Leu568Val), and c.2431A > T: p.(Lys811*). Patients harbouring the c.1845+2T > C and c.1702C > G: p.(Leu568Val) variants had significantly lower serum LDL-cholesterol levels and higher serum HDL-cholesterol levels, respectively, compared with those harbouring the other LDLR pathogenic variants. The proportion of LDLR pathogenic variants was higher in patients with a younger age of coronary artery disease (CAD) onset and significantly decreased as the age of CAD onset increased. Conclusions: This study annotated the clinical significance and characteristics of LDLR and PCSK9 pathogenic variants in Japanese HeFH patients.
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