※一部利用できない機能があります
| 1.
論文 |
論文
|
Tada, Hayato ; Kawashiri, Masa-aki ; Yamagishi, Masakazu ; 多田, 隼人 ; 川尻, 剛照 ; 山岸, 正和
概要:
金沢大学附属病院循環器内科<br />We have learned that low-density lipoprotein (LDL) cholesterol is the cause of atherosclerosis from v
…
arious aspects, including a single case with familial hypercholesterolemia, other cases with different types of Mendelian dyslipidemias, large-scale randomized controlled trials using LDL cholesterol lowering therapies, and Mendelian randomization studies using common as well as rare variants associated with LDL cholesterol levels. There is no doubt that determinations of genotypes in lipid-associated genes have contributed not only to the genetic diagnosis for Mendelian dyslipidemias but also to the discoveries of novel therapeutic targets. Furthermore, recent studies have shown that such genetic information could provide useful clues for the risk prediction as well as risk stratification in general and in particular population. We provide the current understanding of genetic analyses relating to plasma lipids and coronary artery disease.<br />This article distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.
続きを見る
|
||||
| 2.
論文 |
論文
|
Noguchi, Tohru ; Kobayashi, Junji ; Yagi, Kunimasa ; Nohara, Atsushi ; Yamaaki, Naoto ; Sugihara, Masako ; Ito, Naoko ; Oka, Rie ; Kawashiri, Masaaki ; Tada, Hayato ; Takata, Mutsuko ; Inazu, Akihiro ; Yamagishi, Masakazu ; Mabuchi, Hiroshi
概要:
金沢大学医学系研究科<br />Background: Bezafibrate and fenofibrate show different binding properties against peroxisome proliferato
…
r-activated receptor subtypes, which could cause different clinical effects on circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and on various metabolic markers. Methods: An open, randomized, four-phased crossover study using 400 mg of bezafibrate or 200 mg of fenofibrate was performed. Study subjects were 14 dyslipidemia with impaired glucose tolerance or type 2 diabetes mellitus (61 ± 16 years, body mass index (BMI) 26 ± 3 kg/m2, total cholesterol (TC) 219 ± 53 mg/dL, triglyceride (TG) 183 ± 83 mg/dL, high-density lipoprotein-cholesterol (HDL-C) 46 ± 8 mg/dL, fasting plasma glucose 133 ± 31 mg/dL and HbA1c 6.2 ± 0.8%). Subjects were given either bezafibrate or fenofibrate for 8 weeks, discontinued for 4 weeks and then switched to the other fibrate for 8 weeks. Circulating PCSK9 levels and other metabolic parameters, including adiponectin, leptin and urine 8-hydroxy-2′-deoxyguanosine (8-OHdG) were measured at 0, 8, 12 and 20 weeks. Results: Plasma PCSK9 concentrations were significantly increased (+39.7% for bezafibrate and +66.8% for fenofibrate, p < 0.001) in all patients except for one subject when treated with bezafibrate. Both bezafibrate and fenofibrate caused reductions in TG (-38.3%, p < 0.001 vs. -32.9%, p < 0.01) and increases in HDL-C (+18.0%, p < 0.001 vs. +11.7%, p < 0.001). Fenofibrate significantly reduced serum cholesterol levels (TC, -11.2%, p < 0.01; non-HDL-C, -17.3%, p < 0.01; apolipoprotein B, -15.1%, p < 0.01), whereas bezafibrate significantly improved glucose tolerance (insulin, -17.0%, p < 0.05) and metabolic markers (γ-GTP, -38.9%, p < 0.01; adiponectin, +15.4%, p < 0.05; urine 8-OHdG/Cre, -9.5%, p < 0.05). Conclusion: Both bezafibrate and fenofibrate increased plasma PCSK9 concentrations. The addition of a PCSK9 inhibitor to each fibrate therapy may achieve beneficial cholesterol lowering along with desirable effects of respective fibrates. © 2011 Elsevier Ireland Ltd. All rights reserved.
続きを見る
|
||||
| 3.
論文 |
論文
|
Tada, Hayato ; Kawashiri, Masa-aki ; Yamagishi, Masakazu ; 多田, 隼人 ; 川尻, 剛照 ; 山岸, 正和
概要:
We have learned that low-density lipoprotein (LDL) cholesterol is the cause of atherosclerosis from various aspects, inc
…
luding a single case with familial hypercholesterolemia, other cases with different types of Mendelian dyslipidemias, large-scale randomized controlled trials using LDL cholesterol lowering therapies, and Mendelian randomization studies using common as well as rare variants associated with LDL cholesterol levels. There is no doubt that determinations of genotypes in lipid-associated genes have contributed not only to the genetic diagnosis for Mendelian dyslipidemias but also to the discoveries of novel therapeutic targets. Furthermore, recent studies have shown that such genetic information could provide useful clues for the risk prediction as well as risk stratification in general and in particular population. We provide the current understanding of genetic analyses relating to plasma lipids and coronary artery disease.<br />出版者照会後に全文公開
続きを見る
|
||||
| 4.
論文 |
論文
|
Tada, Hayato ; Kawashiri, Masa-aki ; Ohtani, Rumiko ; Noguchi, Tohru ; Nakanishi, Chiaki ; Konno, Tetsuo ; Hayashia, Kenshi ; Nohara, Atsushi ; Inazu, Akihiro ; Kobayashi, Junji ; Mabuchi, Hiroshi ; Yamagishi, Masakazu
概要:
Background: Autosomal recessive hypercholesterolemia (ARH) is an extremely rare inherited hypercholesterolemia, the caus
…
e of which is mutations in low-density lipoprotein (LDL) receptor adaptor protein 1 (LDLRAP1) gene. Methods: A total of 146 heterozygous familial hypercholesterolemic (FH) patients with a mutation in LDLR gene were screened for genes encoding proprotein convertase subtilisin/kexin type 9 (PCSK9) and LDLRAP1. Results: Among the 146 subjects, we identified a 79-year-old Japanese female with double mutations in LDLR gene (c.2431A > T) and LDLRAP1 gene (c.606dup). Two other relatives with double mutations in those genes in her family were also identified. Although the proband exhibited massive Achilles tendon xanthoma and coronary and aortic valvular disease, serum LDL-C level of subjects with double mutations was similar with that of subjects with single LDLR mutation (284.0 ± 43.5 versus 265.1 ± 57.4 mg/dl). Conclusion: Additional mutation in LDLRAP1 may account for severer phenotype in terms of xanthoma and atherosclerotic cardiovascular disease in FH patients. © 2011 Elsevier Ireland Ltd. All rights reserved.
続きを見る
|
||||
| 5.
論文 |
論文
|
Tada, Hayato ; Kawashiri, Masa-aki ; Ohtani, Rumiko ; Noguchi, Tohru ; Nakanishi, Chiaki ; Konno, Tetsuo ; Hayashi, Kenshi ; Nohara, Atsushi ; Inazu, Akihiro ; Kobayashi, Junji ; Mabuchi, Hiroshi ; Yamagishi, Masakazu
概要:
Background: Autosomal recessive hypercholesterolemia (ARH) is an extremely rare inherited hypercholesterolemia, the caus
…
e of which is mutations in low-density lipoprotein (LDL) receptor adaptor protein 1 (LDLRAP1) gene. Methods: A total of 146 heterozygous familial hypercholesterolemic (FH) patients with a mutation in LDLR gene were screened for genes encoding proprotein convertase subtilisin/kexin type 9 (PCSK9) and LDLRAP1. Results: Among the 146 subjects, we identified a 79-year-old Japanese female with double mutations in LDLR gene (c.2431A > T) and LDLRAP1 gene (c.606dup). Two other relatives with double mutations in those genes in her family were also identified. Although the proband exhibited massive Achilles tendon xanthoma and coronary and aortic valvular disease, serum LDL-C level of subjects with double mutations was similar with that of subjects with single LDLR mutation (284.0 ± 43.5 versus 265.1 ± 57.4. mg/dl). Conclusion: Additional mutation in LDLRAP1 may account for severer phenotype in terms of xanthoma and atherosclerotic cardiovascular disease in FH patients. © 2011 Elsevier Ireland Ltd.
続きを見る
|
||||
| 6.
論文 |
論文
|
Tada, Hayato ; Kawashiri, Masa-aki ; Ohtani, Rumiko ; Noguchi, Tohru ; Nakanishi, Chiaki ; Konno, Tetsuo ; Hayashi, Kenshi ; Nohara, Atsushi ; Inazu, Akihiro ; Kobayashi, Junji ; Mabuchi, Hiroshi ; Yamagishi, Masakazu
概要:
Background: Autosomal recessive hypercholesterolemia (ARH) is an extremely rare inherited hypercholesterolemia, the caus
…
e of which is mutations in low-density lipoprotein (LDL) receptor adaptor protein 1 (LDLRAP1) gene. Methods: A total of 146 heterozygous familial hypercholesterolemic (FH) patients with a mutation in LDLR gene were screened for genes encoding proprotein convertase subtilisin/kexin type 9 (PCSK9) and LDLRAP1. Results: Among the 146 subjects, we identified a 79-year-old Japanese female with double mutations in LDLR gene (c.2431A > T) and LDLRAP1 gene (c.606dup). Two other relatives with double mutations in those genes in her family were also identified. Although the proband exhibited massive Achilles tendon xanthoma and coronary and aortic valvular disease, serum LDL-C level of subjects with double mutations was similar with that of subjects with single LDLR mutation (284.0 ± 43.5 versus 265.1 ± 57.4. mg/dl). Conclusion: Additional mutation in LDLRAP1 may account for severer phenotype in terms of xanthoma and atherosclerotic cardiovascular disease in FH patients. © 2011 Elsevier Ireland Ltd.
続きを見る
|
||||
| 7.
論文 |
論文
|
野口, 徹 ; Noguchi, Tohru
概要:
金沢大学医薬保健研究域医学系<br />従来法では家族性高コレステロール(FH)症例の約4割で遺伝子変異が未検出である.そこで,大規模欠失・重複変異(CNV)を簡便に検出可能なMLPA法を新たに導入し,FHと臨床診断された518例の病因遺伝
…
子変異を検索した.MLPA法導入で新たに8種のCNVが検出され,本施設における未解決症例は27%に減少した.さらに,PCSK9遺伝子変異がFHの臨床像に及ぼす影響についても明らかにした.<br />In this study, we introduced the multiplex ligation-dependent probe amplification (MLPA) to detect copy number variations (CNVs) of the low-density lipoprotein receptor gene in 518 familial hypercholesterolemia (FH) subjects. As the result of this research, 8 CNVs were newly identified and the mutation detection rate was improved from 63.5% to 73.0%. Furthermore, we revealed the effects of the proprotein convertase subtilisin/kexin type 9 gene mutations on the clinical phenotype of FH.<br />研究課題/領域番号:20790642, 研究期間(年度):2008 – 2009
続きを見る
|
||||
| 8.
論文 |
論文
|
川尻, 剛照 ; Kawashiri, Masaaki
概要:
金沢大学医薬保健研究域医学系<br />PCSK9はLDL受容体分解を促進し、その機能亢進型変異は家族性高コレステロール血症（FH）の原因となる。われわれが見出したE32K変異を導入したHepG2細胞は野生型に比しPCSK9を39%過剰に分
…
泌し機能亢進変異と考えられた。LDL受容体変異にPCSK9E32K変異を合併した症例を9例見出したが、そのLDLコレステロール値は195から581mg/dLと広く分布し、重症例は著明な腱黄色腫を合併しホモFH類似の病態を呈していた。FHの臨床像の重症化には何らかの追加の遺伝的因子の存在が示唆された。<br />A gain-of-function mutation of proprotein convertase subtilisin/kexin type9 (PCSK9) gene results in familial hypercholesterolemia (FH) through degeneration of hepatic low-density lipoprotein (LDL) receptor. PCSK9 E32K is considered as gain-of-function mutation because HepG2 cells transient transfected PCSK9 E32K plasmid secretes 139% of PCSK9 protein compared with wild type. We found 9 patient with double heterozygous of LDL receptor gene mutation and PCSK9 E32K mutation, and their LDL-cholesterol levels ranged from 195 to 581 mg/dL. The most severe case was accompanied with large tendon xanthoma resembling homozygous FH as well as extreme hypercholesterolemia. These findings suggest that some additive hereditary factors are needed to exacerbate clinical features of PCSK9 E32K carriers.<br />研究課題/領域番号:24591041, 研究期間(年度):2012-04-01 - 2015-03-31
続きを見る
|
