When the number of receptors increases, the rate of LDL degradation will also initially increase. or the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene will be found at a combined frequency of 0.005, which corresponds to 1/199 people in the general population in Japan. Statins and anti-PCSK9 monoclonal antibodies are highly specific and efficient drugs for treating hetero- or homo-FH patients. Most clinical studies have reported an amelioration of ASCVD using long-term statin therapy. Clinical results using anti-PCSK9 monoclonal antibodies will emerge in a few years. In homo-FH patients, mipomersen and lomitapide are expected to yield good results. It is important to sequentially unravel the unrecognized pathogenetic mechanisms of FH to reduce its under-recognition and develop new management strategies for it. gene, (gene and gene, (gene and gene In previously obscure cases, the elucidation of the mechanism of LDL metabolism at the cellular level facilitated the diagnosis of FH by DNA analysis of FH-related genes. Consequently, the number of FH cases increased rapidly. The total number of cases in which we performed genotypic diagnosis is presented in Table 117, 18). Clinical Severity of FH Diagnosed due to Abnormalities in the FH-related Genes Hetero-FH cases diagnosed due to abnormalities in the FH-related genes are highly diverse, and it is GI 181771 clear that the serum cholesterol level varies depending on the particular mutation. The genotypic heterogeneity of LDL-R produces the clinical phenotypic variation (Fig. 12)12, 16). Similar variations with respect to other FH-related genes have also been identified. An apparent difference was found GI 181771 by the genetic investigation of homo-FH while comparing the plasma cholesterol levels in homo-FH patients in whom LDL-R mutations, PCSK9 mutations, and the classical gene mutations are unknown (Fig. 13). In terms of clinical severity, the order of FH is as follows: LDL-R Rabbit polyclonal to SEPT4 mutation Apo-B-100 mutation PCSK9 mutation ARH mutation. Furthermore, gene mutations should be identified and the associated clinical severity should be investigated. Even in cases with same gene mutation, the diagnosis may be hypolipidemic FH, normolipidemic FH, or hyperlipidemic GI 181771 FH. In this context, although the search for FH-related genes is a desirable endeavor, the precise genotypic diagnosis is unlikely to alter the treatment paradigm (achievement of target LDL-C level) or the choice of pharmacotherapeutic agents. Open in a separate window Fig. 12. Plasma cholesterol distributions in each genotypic hetero-FH patient. Genotypic variations show phenotypic heterogeneity. Size of each boxes show mean SD. Open in a separate window Fig. 13. Plasma cholesterol levels in different genotypes of homo-FH patients. Plasma cholesterol levels in the homo-FH due to LDL-R mutants are higher than those in the homo-FH due to PCSK9 E32K homo-FH or autosomal recessive homo-FH. Data were obtained from our previous studies by Mabuchi = 31) GI 181771 due to LDL-R mutations were found to range widely from 362 to 1021 mg/dL, and the average cholesterol concentration was 612 145 mg/dL (mean SD) (Fig. 13). Serum cholesterol concentrations in homo-FH due to PCSK9 E32K mutation ranged from 269 to 630 mg/dL, and the mean serum TC concentration (401 117 mg/dL) in homozygotes caused by PCSK9 E32K was significantly lower than their counterparts with LDL-R mutation ( 0.001). As a result, the frequency of LDL-R mutant heterozygotes is estimated to be 0.0034, which corresponds to 1/293 people in the general population12). The frequency of PCSK9 mutant heterozygotes is estimated to be 0.0016, which corresponds to 1/622 people in the general population12). Thus, it is estimated that heterozygous mutations in the LDL-R or the PCSK9 gene will occur at a combined frequency of 0.005, corresponding to 1/199 people in the general population of the Hokuriku district of Japan12). Of the investigated 149 myocardial infarction (MI) patients younger than 65 years, 18 patients (12%) were FH, and in the 43 MI patients younger than 40 years, 17 patients (41%) were FH22). Our assumption from this data states that coronary artery stenosis detectable by angiography GI 181771 occurs after 17 and 25 years of age in male and female heterozygotes, respectively, and the treatment of heterozygotes using lipid-lowering drugs can be delayed until late.