Establishment of personal protection method for life-style diseases : type IV hyperlipoproteinemia as a model case

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The aim of this study is to establish individual methods of prevention for life-style-related diseases, especially hypertriglyceridemia as a model case, because we think it is practical to focus on an individual genetical weakness for prevention against life-style-related diseases. We have elucidated etiology of primary type IV hyperlipidemia is a genetic background of heterozygous lipoprotein lipase (LPL) deficiency and superimposing triglyceride synthesis-stimulating factor on its genetic background. It means a LPL heterozygous deficient person without triglyceride synthesis-stimulating factor doesn't manifest hypertriglyceridemia. Individuals with heterozygous LPL deficiency have to be more carefully of superimposition of triglyceride synthesis-stimulating factor, alcohol drinking for example, than persons with two alleles of a normal LPL gene. The reliable and accurate genetic diagnosis of heterozygous LPL aberration is needed for development of individual methods of prevention for … More hypertiglyceridemia. We developed and improved LPL and hepatic triglyceride lipase mass measurement methods, direct sequencing of LPL gene, PCR method which didn't overlook mutations, and hypertriglyceride-induced atherogenic small dense LDL detection method. On the basis of these developments, we accumulated LPL gene mutations in Japanese. From the subjects with low LPL mass values, Y61X, G188E, D204E, Int3-3' c(-6)t, G154V, G105R, Int8-5' t(2)c mutations were detected. These missense mutations were confirmed to lead non-functional LPL production with COS-1 in vitro-expression system. As the Int3-3' c(-6)t mutation didn't have an aberrant splicing product in vivo and in vitro, this mutation seemed to link to another mutation which led to LPL deficiency. The Int8-5' t(2)c mutation led to the utilization of a cryptic 5' donor splice site in exon8 as an alternative splice site, skipping of a 134-bp fragment of exon8. These technical developments and improvements, and an accumulation of LPL mutations would contribute to LPL gene diagnosis that makes individual methods of prevention for hypertriglyceridemia possible. Less