Low-density lipoprotein (LDL) receptor and apolipoprotein B-100 (apoB) gene mutations cause increased levels of LDL cholesterol, and is frequently associated with premature coronary atherosclerosis. Molecular genetic study of FH showed extreme heterogeneity in their underlying LDL receptor gene mutations, and suggested that this heterogeneity appeared to be responsible for the variability of its clinical manifestations. Since 1988, we have identified 11 mutations (10 novel and 1 previously reported) in the LDL receptor gene among 201 unrelated FH families in Hokuriku district, Japan. However, they could only explain 38.8% of the whole study patients and this suggested that more efficient mutation screening method should be developed. Through mutation detection, genetically-determined mild type of FH (homozygotes with relative longevity and normocholesterolemic heterozygotes) was found in case that the exons 2 and 3 were eliminated by 10kb deletion (Tonami-2). In addition, cholesterol-lowering drug therapy was significanlty more effective in heterozygous patients with P664L mutation (Kanazawa-2) as compared to those with 6kb deletion including the exon 15 (Tonami-1). These observations raise the possibility that we can manage FH patients based on the results of their gene analyses.

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Serum paraoxonase (PON1) is an esterase associated with plasma HDL and protects LDL against oxidative change. The PON1 gene has two polymorphisms of 191Q/R and 54L/M which affect the enzymatic activities. It was reported that the 191Q/R polymorphism of PON1 gene may be involved in the pathogenesis of coronary heart disease (CHD), but our case-control study in Japanese subjects did not show that the polymorphism associated with a risk for CHD.
The enzymatic activity of PON1 in patients with noninsulin dependent diabetes mellitus (NIDDM) or in patients with renal failure was significantly lower than that in controls. The distribution of each genotype of 191Q/R and 54L/M polymorphisms did not show any differences between the patient and control groups. These results suggest that the PON1 function suffers from diabetes mellitus or renal failure independently of the polymorphisms, and PON1 in these diseases may not protect LDL against oxidative modification.
We found a novel polymorphism of cytosine/thymidine (C/T) at the -108 position from the ATG colon in the upstream region of the PON1 gene. The promoter activity (luciferase activity) was lower in the -108T allele than in the -108C allele. The serum PON1 concentrations in normal subjects were as follows, -108CC>-108CT and>-108TT genotypes. The novel polymorphism upstream from the PON1 gene is associated with transcription of the PON1 gene and the serum PUN1 concentration.

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By clarifying candidate genes of essential hypertension, the development of gene diagnosis based on the clarified molecular pathopysiology, becomes possible. Especially, the current gene diagnosis using the polymorphism of the reninangiotensin system gene, which seems to be deeply concerned in the origin of the hypertension, is a promissing method for the prediction of hypertension.

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粥状動脈硬化病変形成において, 内皮細胞の活性化に引き続く内皮下層へのマクロファージ浸潤には, 活性化内皮細胞から分泌されるMCP-1が重要な働きをしている. 活性化内皮細胞に付着した血小板や内皮下層に浸潤したマクロファージから分泌されるPDGFは, 内膜肥厚病変形成に中心的役割を演じている. 粥腫の不安定化には, 活性化Tリンパ球から分泌されるインターフェロンγが, マクロファージのプロテアーゼ産生を増加させるとともに平滑筋細胞のコラーゲン合成を抑制する結果, 線維性被膜が脆弱化することが深く関与している.

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