Explore the vast range of titles available.

[This corrects the article DOI: 10.1371/journal.pone.0294764.].

Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters in plasma from high density lipoprotein (HDL) to very low density lipoprotein and low density lipoprotein. Loss-of-function variants in the CETP gene cause elevated levels of HDL cholesterol. In this study, we have determined the functional consequences of 24 missense variants in the CETP gene. The 24 missense variants studied were the ones reported in the Human Gene Mutation Database and in the literature to affect HDL cholesterol levels, as well as two novel variants identified at the Unit for Cardiac and Cardiovascular Genetics, Oslo University Hospital in subjects with hyperalphalipoproteinemia. HEK293 cells were transiently transfected with mutant CETP plasmids. The amounts of CETP protein in lysates and media were determined by Western blot analysis, and the lipid transfer activities of the CETP variants were determined by a fluorescence-based assay. Four of the CETP variants were not secreted. Five of the variants were secreted less than 15% compared to the WT-CETP, while the other 15 variants were secreted in varying amounts. There was a linear relationship between the levels of secreted protein and the lipid transfer activities (r = 0.96, p<0.001). Thus, the secreted variants had similar specific lipid transfer activities. The effect of the 24 missense variants in the CETP gene on the lipid transfer activity was mediated predominantly by their impact on the secretion of the CETP protein. The four variants that prevented CETP secretion cause autosomal dominant hyperalphalipoproteinemia. The five variants that markedly reduced secretion of the respective variants cause mild hyperalphalipoproteinemia. The majority of the remaining 15 variants had minor effects on the secretion of CETP, and are considered neutral genetic variants.

To study whether subjects with a molecular genetic diagnosis of familial hypercholesterolemia (FH) or familial defective apoB-100 (FDB) are being adequately treated. A questionnaire regarding medical history was sent to 2611 subjects who had been provided with a molecular genetic diagnosis of FH or FDB, and a blood sample was obtained for lipid measurements. 956 (36.6%) of the 2611 subjects participated. The mean age for starting lipid-lowering therapy was 33.4 (±12.1) years. Among those below 18 years of age, only 20.4% were on lipid-lowering drugs, whereas 89.1% of those aged 18 and above were on lipid-lowering drugs. The mean levels of total serum cholesterol and LDL-cholesterol were 5.7 (±1.5) mmol/l and 3.9 (±1.3) mmol/l, respectively. Among those who were on lipid-lowering drugs, 29.0% and 12.2% had levels of LDL cholesterol below 3.0 mmol/l and 2.6 mmol/l, respectively. Only 47.3% of the 956 subjects were considered as being adequately treated largely due to a failure to titrate their drug regimens. From the use of cholesterol-years score, lipid-lowering therapy must start before the age of 20 in order to prevent the subjects from contracting premature coronary heart disease. The majority of FH/FDB subjects are being diagnosed late in life and are not being adequately treated. In order to prevent them from contracting premature coronary heart disease, it is key that levels of LDL cholesterol are normalized from a young age and that sufficient doses of lipid-lowering drugs are being used.

ObjectiveThe primary objective was to study the risk of acute myocardial infarction (AMI) and coronary heart disease (CHD) in patients with familial hypercholesterolaemia (FH) and compare with the risk in the general population.MethodsPatients with an FH mutation but without prior AMI (n=3071) and without prior CHD (n=2795) were included in the study sample during 2001–2009. We obtained data on all AMI and CHD hospitalisations in Norway. We defined incident cases as first time hospitalisation or out-of-hospital death due to AMI or CHD. We estimated standardised incidence ratios (SIRs) with 95% CIs with indirect standardisation using incidence rates for the total Norwegian population stratified by sex, calendar year and 1 year age groups as reference rates.ResultsSIRs for AMI (95% CIs) were highest in the age group 25–39 years; 7.5 (3.7 to 14.9) in men and 13.6 (5.1 to 36.2) in women and decreased with age to 0.9 (0.4 to 2.1) in men and 1.8 (0.9 to 3.7) in women aged 70–79 years. Similarly, SIRs for CHD were highest among patients 25–39 years old; 11.1 (7.1–17.5) in men and 17.3 (9.6–31.2) in women and decreased 2.4 (1.4–4.2) in men and 3.2 (1.5–7.2) in women at age 70–79. For all age groups, combined SIRs for CHD were 4.2 (3.6–5.0) in men and 4.7 (3.9–5.7) in women.ConclusionPatients with FH are at severely increased risk of AMI and CHD compared with the general population. The highest excess risk was in the youngest group aged 25–39 years, in both sexes.

•Mutation G805R is in the transmembrane domain of the LDLR.•A polar residue in the transmembrane domain induced metalloproteinase cleavage.•Mutation G805R caused reduced amounts of the precursor LDLR.•Reduced amounts of precursor LDLR led to reduced amounts of the mature LDLR.•Mutation G805R prevented γ-secretase cleavage within the transmembrane domain. More than 1700 mutations in the low density lipoprotein receptor (LDLR) gene have been found to cause familial hypercholesterolemia (FH). These are commonly divided into five classes based upon their effects on the structure and function of the LDLR. However, little is known about the mechanism by which mutations in the transmembrane domain of the LDLR gene cause FH. We have studied how the transmembrane mutation G805R affects the function of the LDLR. Based upon Western blot analyses of transfected HepG2 cells, mutation G805R reduced the amounts of the 120kDa precursor LDLR in the endoplasmic reticulum. This led to reduced amounts of the mature 160kDa LDLR at the cell surface. However, significant amounts of a secreted 140kDa G805R-LDLR ectodomain fragment was observed in the culture media. Treatment of the cells with the metalloproteinase inhibitor batimastat largely restored the amounts of the 120 and 160kDa forms in cell lysates, and prevented secretion of the 140kDa ectodomain fragment. Together, these data indicate that a metalloproteinase cleaved the ectodomain of the 120kDa precursor G805R-LDLR in the endoplasmic reticulum. It was the presence of the polar Arg805 and not the lack of Gly805 which led to ectodomain cleavage. Arg805 also prevented γ-secretase cleavage within the transmembrane domain. It is conceivable that introducing a charged residue within the hydrophobic membrane lipid bilayer, results in less efficient incorporation of the 120kDa G805R-LDLR in the endoplasmic reticulum membrane and makes it a substrate for metalloproteinase cleavage.

According to guidelines, individuals with familial hypercholesterolemia (FH) shall receive lifestyle intervention and intensive lipid-lowering treatment from early in life to reduce the risk of coronary heart disease. Our aim was to study if treatment of FH also could affect risk of lifestyle-related cancer. We presented cumulative incidence of total cancer and lifestyle-related cancer sites in individuals with genetically verified FH (n = 5531) compared with age and sex matched controls (n = 108354). Individuals with FH had 20% lower risk of smoking-related cancer compared with the control population [HR 0.80 (95% CI, 0.65–0.98)], in particular men with FH at 40–69 years at age of diagnosis with HR 0.69 (95% CI, 0.49–0.97). The FH population and controls had similar rates of total cancer [HR 0.97 (95% CI, 0.86–1.09)], cancer related to poor diet [HR 0.82 (95% CI, 0.59–1.15)], cancer related to physical inactivity [HR 0.93 (95% CI, 0.73–1.18)], alcohol-related cancer [HR 0.98 (95% CI, 0.80–1.22)] and cancer related to obesity [HR 1.03 (95% CI, 0.89–1.21)]. In summary, we found reduced risk of smoking-related cancer in individuals with FH, most likely due to a lower prevalence of smoking. Implications of these findings can be increased motivation and thus compliance to treatment of hypercholesterolemia.

Familial hypercholesterolemia (FH) is caused by a defective low-density lipoprotein receptor (LDLR), and >1000 mutations in LDLR have been identified. However, in some patients with clinically defined FH, no mutation can be detected within the exons and adjacent intronic segments of the LDLR . We have analyzed RNA extracted from blood samples of patients with clinically defined FH and identified an aberrantly spliced mRNA containing an 81-bp insert from intron 14. The aberrant splicing was caused by a novel intronic mutation, c.2140+86C>G, which activated a cryptic splice site. Although the cryptic splice site does not completely surpass the normal splice site, the mutation was found to cosegregate with high cholesterol levels in a family, which supports the notion that c.2140+86C>G causes FH. The insertion of 81 bp in LDLR mRNA encodes an in-frame insertion of 27 amino acids in the LDLR. However, the insertion was found to hamper LDLR activity by preventing the receptor from leaving the endoplasmic reticulum, probably because of misfolding of the protein. In patients with clinically defined hypercholesterolemia, despite normal results from sequencing of exonic regions of the LDLR gene, characterization of the LDLR mRNA might identify the underlying genetic defect.

Hypercholesterolemia, which is a cardiovascular risk factor, may also be associated with dementia risk. The benefit of statin treatment on dementia risk is controversial. To determine whether individuals with familial hypercholesterolemia (FH), who have been exposed to lifelong hypercholesterolemia, have an excess risk of dementia and whether statin use is associated with dementia risk. This was a prospective cohort study performed from 2008 to 2018 in Norway. Statistical analysis was performed from January 2021 to February 2022. This study included individuals with genetically verified FH and age-matched and sex-matched controls obtained from the general Norwegian population. Dementia was defined according to International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes F00-03 and G30. Incident cases of total dementia, vascular dementia, Alzheimer disease-dementia in Alzheimer disease, and data on lipid-lowering medication were obtained from the Norwegian Patient Registry, Cause of Death Registry, and the Norwegian Prescription Database. Hazard ratios (HRs) for risk of dementia for individuals with FH vs matched controls were calculated using Cox regression. The cumulative sum of defined daily doses (DDDs) of statins prescribed during study follow-up was calculated for individuals with FH and was analyzed as a time-varying covariate with 3 levels: 1 to 4999 DDDs, 5000 to 10 000 DDDs, and more than 10 000 DDDs. Among the 3520 individuals with FH (1863 women [52.9%]; mean [SD] age at the start of follow-up, 51.8 [11.5] years) and the 69 713 controls (36 958 women [53.0%]; mean [SD] age at the start of follow-up, 51.7 [11.5] years), 62 patients with FH (39 women [62.9%]) and 1294 controls (801 women [61.9%]) had developed dementia over the course of 10 years of follow-up. Most dementia cases occurred among individuals aged 70 years and older (39 patients with FH [62.9%] and 870 patients [67.2%] in the control group). We found no excess risk of dementia in patients with FH vs matched controls (HR for total dementia, 0.9; 95% CI, 0.7-1.2). There was no association between cumulative DDDs of statins and total dementia in patients with FH with HRs of 1.2 (95% CI, 0.4-3.8) for cumulative DDDs of 5000 to 10 000 and 1.9 (95% CI, 0.7-5.0) for cumulative DDDs greater than 10 000. These findings suggest that individuals with FH have no excess risk of dementia compared with age-matched and sex-matched controls and that there is no association between use of statins and risk of dementia in patients with FH.

BackgroundMyosin binding protein C (MyBPC) is essential for the structure of the sarcomeres in striated muscle. There is one cardiac specific isoform and two skeletal muscle specific isoforms. Mutations in MYBPC3 encoding the cardiac isoform cause cardiomyopathy.Methods and resultsWe have identified an infant with fatal cardiomyopathy due to a homozygous mutation, p.R943X, in MYBPC3. The patient also had an unexpected skeletal myopathy. The patient expressed the cardiac specific MyBPC isoform in skeletal muscle at transcript and protein levels. Numerous muscle fibres expressing the mutant cardiac isoform showed structural abnormalities with disorganisation of sarcomeres and depletion of myosin thick filaments.ConclusionsThe surprising identification of a skeletal myopathy in this patient was due to aberrant expression of mutant cardiac MyBPC in skeletal muscle.

Background: Too few familial hypercholesterolemia (FH) patients are diagnosed. The most cost-effective strategy to diagnose FH is to examine first-degree relatives of already diagnosed patients. This is referred to as cascade genetic screening. Methods and Results: One thousand eight hundred and five first-degree relatives of index patients with molecularly defined FH consented to cascade genetic screening by the use of molecular genetic testing. Of these, 44.8% were mutation carriers and 55.2% were noncarriers. Only 44.2% of the mutation carriers were on lipid-lowering drugs at the time of genetic testing. Of these, only 9.4% had a value for total serum cholesterol below 5 mM. Among adult mutation carriers who were not on lipid-lowering treatment at the time of genetic testing, reductions in total serum cholesterol and low-density lipoprotein cholesterol of 18.4% (p < 0.0001) and 25.3% (p < 0.0001), respectively, were observed 6 months after genetic testing. It is assumed that this improvement in the lipid profile is due to a definite diagnosis obtained by molecular genetic testing. By using the results of genetic testing as the gold standard for diagnosis of FH, data from a questionnaire filled out by the relatives showed that the use of clinical criteria to diagnose FH in general practice had a sensitivity of 46.2% and a specificity of 88.0%. Conclusions: The use of clinical diagnostic criteria to diagnose FH in general practice identifies only approximately 50% of FH patients. Molecular genetic testing as part of cascade genetic screening is an efficient tool to diagnose patients, leading to significant improvement in the lipid profile. It should therefore be implemented in clinical medicine. Copyright © 2008 S. Karger AG, Basel [PUBLICATION ABSTRACT]