論文 - 詳細
| RRC ID | 78520 |
|---|---|
| 著者 | Hori M, Takahashi A, Hosoda K, Ogura M, Harada-Shiba M. |
| タイトル | A Low-Frequency APOB p.(Pro955Ser) Variant Contributes to the Severity of/Variability in Familial Hypercholesterolemia. |
| ジャーナル | J Clin Endocrinol Metab |
| Abstract |
CONTEXT:Heterozygous familial hypercholesterolemia (HeFH) is caused by a rare pathogenic variant in the LDLR, APOB, and PCSK9 genes. However, the causative variants in these genes have not been identified in approximately 40% of HeFH patients. OBJECTIVE:Our aim was to identify novel (or additional) genes/variants that contribute to HeFH. METHODS:Whole-exome sequencing was performed for 215 family members from 122 families with HeFH without pathogenic variants in the LDLR or PCSK9 genes. RESULTS:We could not find novel causative familial hypercholesterolemia (FH) genes/variants by family analysis. Next, we examined all APOB variants. Twenty-four nonsynonymous APOB variants were identified. The allele frequencies of the c.2863C > T:p.(Pro955Ser) variant in the HeFH probands and the general Japanese population were 0.15 and 0.034, respectively [odds ratio 4.9 (95% CI 3.4-7.1); P = 6.9 × 10-13]. The patients harboring the c.2863C > T:p.(Pro955Ser) variant accounted for 9.8% (n = 63) of unrelated patients with HeFH (n = 645). The penetrance of the c.2863C > T:p.(Pro955Ser) variant was low in the pedigree-based genetic analysis. In an in vitro assay, low-density lipoprotein (LDL) uptake from patients with the homozygous c.2863C > T:p.(Pro955Ser) variant was 44% of the LDL uptake from control subjects, and it was similar to that of the LDL uptake from patients with the known pathogenic heterozygous p.(Arg3527Gln) variant. CONCLUSIONS:The low-frequency APOB c.2863C > T:p.(Pro955Ser) variant is not an FH-causative variant, but it has a moderate effect size in HeFH. These findings suggest that the combination of the APOB c.2863C > T:p.(Pro955Ser) variant and age, environmental factors, or other genetic factors contributes to the severity of or variability in the HeFH phenotype. |
| 巻・号 | 108(2) |
| ページ | 422-432 |
| 公開日 | 2023-1-17 |
| DOI | 10.1210/clinem/dgac572 |
| PII | 6747529 |
| PMID | 36190978 |
| MeSH | Apolipoproteins B / genetics Humans Hypercholesterolemia* Hyperlipoproteinemia Type II* / genetics Mutation Phenotype Proprotein Convertase 9 / genetics Receptors, LDL / genetics |
| リソース情報 | |
| ヒト・動物細胞 | Hep G2(RCB1886) |