The genetics and screening of familial hypercholesterolaemia

Henderson, Raymond; O’Kane, Maurice; McGilligan, Victoria; Watterson, Steven

doi:10.1186/s12929-016-0256-1

Cited by 132 publications

(107 citation statements)

References 89 publications

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“…PMI is a great life‐threatening disease, which is considered as one of the important clinical manifestations of FH. Therefore, screening for FH among PMI patients is significant . It has been shown that the prevalence of FH with common pathogenic gene mutations in PMI patients is about 1.3% to 7.0% .…”

Section: Discussionmentioning

confidence: 99%

Prevalence of familial hypercholesterolemia in patients with premature myocardial infarction

Cui

Zhang

et al. 2019

Clinical Cardiology

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Background Familial hypercholesterolemia (FH) is a genetic cause of premature myocardial infarction (PMI). Early diagnosis of FH is critical for prognosis. Hypothesis To investigate the prevalence of FH among a cohort of Chinese patients with PMI using genetic testing, and to evaluate different diagnostic criteria. Methods A total of 225 consecutive PMI patients were recruited. Low‐density lipoprotein receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin‐kexin type 9 (PCSK9) and low‐density lipoprotein receptor adaptor protein 1 (LDLRAP1) genes were detected by Sanger sequencing. FH was diagnosed using the Dutch Lipid Clinic Network (DLCN) criteria and modified DLCN criteria, respectively. The prevalence and clinical features of FH were analyzed. Results In all PMI patients, pathogenic mutations of LDLR, APOB, PCSK9 and LDLRAP1 genes were found in 10 of 225 patients. Among all mutations, four mutations (LDLR c.129G>C, LDLR c.1867A>T, LDLRAP1 c.65G>C, and LDLRAP1 c.274G>A) were newly discovered. The prevalence of FH diagnosed by genetic testing was 4.4%. The prevalence of definite/probable FH diagnosed by DLCN and modified DLCN criteria reached 8.0% and 23.6%, respectively, and the mutation rates were 33.3% and 12.2%, respectively. The low‐density lipo‐protein cholesterol (LDL‐C) levels in PMI patients with FH were far from goal attainment. Only one of the FH patients had LDL‐C <2.5 mmol/L, and none of them had LDL‐C <1.8 mmol/L. Conclusions The prevalence of FH among Chinese patients with PMI appeared relatively common. Underdiagnosis and undertreatment of FH are still a big problem, which should arouse a widespread concern.

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Section: Discussionmentioning

confidence: 99%

Prevalence of familial hypercholesterolemia in patients with premature myocardial infarction

Cui

Zhang

et al. 2019

Clinical Cardiology

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“…Generally, people with untreated FH are at a higher risk of coronary heart disease [57]. Genetic variants in three genes-low-density lipoprotein receptor (LDLR) [58], APOB, and proprotein convertase subtilisin/kexin type 9 (PCSK9) [59]-account for the majority of cases with autosomal dominant FH [60].…”

Section: Familial Hypercholesterolemiamentioning

confidence: 99%

Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals

et al. 2017

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Clarifying allele frequencies of disease-related genetic variants in a population is important in genomic medicine; however, such data is not yet available for the Japanese population. To estimate frequencies of actionable pathogenic variants in the Japanese population, we examined the reported pathological variants in genes recommended by the American College of Medical Genetics and Genomics (ACMG) in our reference panel of genomic variations, 2KJPN, which was created by whole-genome sequencing of 2049 individuals of the resident cohort of the Tohoku Medical Megabank Project. We searched for pathogenic variants in 2KJPN for 57 autosomal ACMG-recommended genes responsible for 26 diseases and then examined their frequencies. By referring to public databases of pathogenic variations, we identified 143 reported pathogenic variants in 2KJPN for the 57 ACMG recommended genes based on a classification system. At the individual level, 21% of the individuals were found to have at least one reported pathogenic allele. We then conducted a literature survey to review the variants and to check for evidence of pathogenicity. Our results suggest that a substantial number of people have reported pathogenic alleles for the ACMG genes, and reviewing variants is indispensable for constructing the information infrastructure of genomic medicine for the Japanese population.

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“…Although plenty of medications have been used by the aim of managing lipid profile and reducing the risk of cardiovascular diseases in FH patients, still it is not under control (37). Statins, which are the most efficient agents for alleviating LDL-C level, many of the patients treating with statins are incapable to tolerate them mainly because of muscle-related side effects or higher dose is required to attain the target LDL-C (38).…”

Section: Discussionmentioning

confidence: 99%

Does Evolocumab, as a PCSK9 Inhibitor, Ameliorate the Lipid Profile in Familial Hypercholesterolemia Patients? A Meta-Analysis of Randomized Controlled Trials

et al. 2017

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-Proprotein convertase subtilisin-kexin type 9 (PCSK9) is a member of regulatory serine proteases which is mostly expressed in liver. In the physiological condition, LDL-C binds to LDL receptors (LDLRs) and via endocytosis, LDLRs are degraded. PCSK9 binds to the epidermal growth factor-like repeat A (EGFA) domain of extracellular LDLRs, and then physiological recycling of LDLRs from surface of liver is cancelled, resulting in elevation of circulating LDL-C in plasma. To evaluate whether evolucomab, as PCSK9 inhibitor monoclonal antibody, ameliorates lipid profile in familial hypercholesterolemia (FH) patients, this meta-analysis has been conducted. PubMed, Web of Science (ISI) and Scopus databases were searched for studies which had investigated the efficacy of evolucomab. Types of outcome investigated were percentage changes from baseline of the lipid profile. Our meta-analysis shows that evolucomab at the dosage of 420 mg monthly could decrease LDL-C by 54.71%, TC by 35.08%, VLDL-C by 28.37 %, ratio of TC to HDL-C by 39.14 %, triglycerides by 12.11 %, and increased HDL-C by 6.06% from baseline compared to placebo at the end of study in FH patients. Our findings indicate that evolocumab could be a hopeful agent for challenging patients, such as statin intolerance or patients who fail to attain the target goal of LDL-C despite consumption of maximum doses of statins.

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The genetics and screening of familial hypercholesterolaemia

Cited by 132 publications

References 89 publications

Prevalence of familial hypercholesterolemia in patients with premature myocardial infarction

Prevalence of familial hypercholesterolemia in patients with premature myocardial infarction

Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals

Does Evolocumab, as a PCSK9 Inhibitor, Ameliorate the Lipid Profile in Familial Hypercholesterolemia Patients? A Meta-Analysis of Randomized Controlled Trials

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