Familial Hypercholesterolemia In China Research Articles

Familial hypercholesterolemia in China requires greater efforts

Familial hypercholesterolemia in China requires greater efforts

Homozygous familial hypercholesterolemia in China: Genetic and clinical characteristics from a real-world, multi-center, cohort study

BackgroundThere is a lack of large-scale data on the clinical and genotype characteristics of homozygous familial hypercholesterolemia (HoFH) patients in Asia. ObjectiveTo define the characteristics of phenotypic and genetic HoFH probands from mainland China. MethodsWe collected data from patients with suspected HoFH from ten clinical hospitals across mainland China from 2003 to 2019. Clinical data and DNA testing were obtained in all patients. The Kaplan-Meier method was used to generate survival curves, and the groups were compared with the log-rank test. ResultsA total of 108 unrelated probands with suspected HoFH (mean age 14.9 years) were included. The three most common variants were W483X (c.1448 G>A), A627T (c.1879 G>A), H583Y (c.1747 C>T). The majority (64.8%) were compound heterozygotes (n = 70), 23 (21.3%) were true HoFH patients. True HoFH showed higher LDL-C levels compared to compound HoFH (16.8±3.6 mmol/L vs. 15.0±3.1 mmol/L, P = 0.022). During follow-up, only 21.2% patients exhibited an LDL-C reduction of more than 50%. Kaplan-Meier analysis showed that the true HoFH probands had significantly worse survival rates compared to other genotype probands (13-year survival; 20.3% vs. 76.7%, respectively; P = 0.016). In addition, true HoFH shows that 2.8-fold (P = 0.022) increase any death and 3.0-fold (P = 0.023) increase cardiovascular death risk in relative to other FH. ConclusionsThis report shows that HoFH has devastating consequences, and that patients are often only diagnosed after they have been exposed to severely elevated LDL-C for years. Systematic screening and early intensive treatment are an absolute requirement for these young individuals with HoFH.

Familial Hypercholesterolemia in Asia Pacific: A Review of Epidemiology, Diagnosis, and Management in the Region.

Familial hypercholesterolemia (FH) is a common genetic disease that is estimated to affect at least 15 million people in the Asia Pacific region. Affected individuals are at significantly increased risk of premature atherosclerotic cardiovascular disease. A literature review was undertaken to provide an overview of the epidemiology, diagnosis, and management of FH across the region.Currently, epidemiological data relating to FH are lacking across the Asia Pacific. Of the 15 countries and regions considered, locally conducted studies to determine FH prevalence were only identified for Australia, China, India, and Japan. Although practically all national clinical guidelines for dyslipidemia include some commentary on FH, specific guidelines on the management of FH are available for only one third of the countries and regions evaluated. Estimates of current FH diagnosis rates suggest that most affected individuals remain undiagnosed and untreated. Although innovative medications such as proprotein convertase subtilisin/kexin type 9 inhibitors have been approved and are available in most countries and regions considered, they are currently reimbursed in only one quarter.Despite these shortcomings, there is cause for optimism. Early experience with cascade screening in Hong Kong, India, and Vietnam has proven an effective means of identifying family members of probands, as has a reverse screening of family members of children with FH in China. FH registries are gaining momentum across the region, with registries now established in almost half of the countries and regions evaluated. This review concludes with a Call to Action on FH for Asia Pacific to engage healthcare professionals, improve public awareness, and form national FH alliances, comprising all relevant healthcare professional organizations, as a platform to expedite national quality improvement programs in the management of FH.

Abstract 13636: Evolocumab Shows No Significant Cost-effectiveness for Myocardial Infarction in China

Introduction: The proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab has been demonstrated to reduce the incidence of cardiovascular events. This study sought to evaluate the value of evolocumab in the healthcare perspective by conducting a long-term cost-effectiveness analysis in Chinese patients with myocardial infarction (MI). Hypothesis: We assessed the hypothesis that evolocumab was inefficient for the secondary prevention of MI. Methods: A Markov cohort state-transition model was developed in decision analysis software. The model subjects could have non-fatal MI and/or stroke events, as well as die from cardiovascular disease or other causes. We integrated Chinese population specific demographics and event rates with the risk reduction of evolocumab based on large trials and meta-analysis. Age-related change, event costs and utilities were included from published sources. The model had 1-year cycle and the time horizon was 25 years. The primary outcome was the incremental cost-effectiveness ratio (ICER), defined as cost per quality-adjusted life-year (QALY) saved. Results: At its current list price (33,748 CNY annually per person), the ICER was 927,713 CNY per QALY gained. In one-way deterministic sensitivity analyses, the ICER was closely associated with the utility of cardiovascular disease event free and the cost of cardiovascular death. Probabilistic sensitivity analyses demonstrated that the probability of the cost-effectiveness of evolocumab was 1.96% at the present willingness-to-pay threshold of 212,676 CNY per QALY gained. To achieve the cost-effectiveness threshold, a net value-based price of 10,255 CNY annually would be required, which is 70% lower than the present price. Alternative scenarios analyses of treatment benefit showed in MI patients with poorly controlled familial hypercholesterolemia (FH), the ICER for evolocumab was 187,736 CNY per QALY gained, which achieved the accepted cost-effectiveness threshold. Conclusions: In conclusion, the cost-effectiveness ratio of evolocumab is less favorable in MI; However, it showed good cost-effectiveness in MI patients with poorly controlled FH in China.

Current status of familial hypercholesterolemia in Chinese populations.

Heterozygous familial hypercholesterolemia often went unrecognized in China when population cholesterol levels were low, but rapid economic development has changed the situation. This review will discuss the current position of awareness, diagnosis, and management of familial hypercholesterolemia in Chinese populations. The phenotype of familial hypercholesterolemia in China and other Chinese populations has become similar to that in Western countries, although it may still be somewhat less severe. The prevalence in Chinese populations is also similar to that in other countries and it has been found in up to 7% of Chinese patients with premature coronary heart disease. Most of the mutations are in the low-density lipoprotein receptor gene but the pattern of mutations differs from that in Whites. Chinese patients may be more responsive to statins than Whites but patients with familial hypercholesterolemia are often undertreated. Increasing population cholesterol levels have changed the phenotype of familial hypercholesterolemia in China and Chinese patients now resemble those in Western countries. International initiatives are facilitating increased awareness and identification of cases and more effective management of the condition.

Familial hypercholesterolemia in China half a century: A review of published literature

AimsTo investigate the status of familial hypercholesterolemia (FH) research and the characteristics of patients with FH in China. MethodsPublished papers in Chinese or English language from PubMed, SinoMed and CNKI databases from 1971 to March 2018 were searched using ‘Familial hypercholesterolemia’, ‘Chinese’ and ‘Han’ as keywords. A systematic review of studies on familial hypercholesterolemia was then conducted. ResultsA total of 391 articles were found, in which 22% were in English and 78% were in Chinese; approximately 43% are case reports and 34% are genetic reports according to the study type; 52% discussed the status of the disease and 11% investigated the subclinical status according to the study content. Furthermore, 96% of the articles were published by tertiary hospitals and 46% were conducted by cardiologists. The first expert consensus was issued in February 2018. Of the 163 case reports published before 2018, 48.7% used the Chinese FH clinical diagnostic criteria and 34.4% did not clearly indicate the diagnostic criteria. The incidence rates of low-density lipoprotein receptor (LDLR) and apolipoprotein B (APOB) mutations were 82% and 9%, and proprotein convertase subtilisin/kexin type 9 (PCSK9) mutations were rare in Chinese patients with FH. However, the data on lipid-lowering treatment rates, compliance rates and cardiovascular events in FH remain insufficient. ConclusionsLarge-scale epidemiological investigation of FH has not been demonstrated, the recognition of FH remains rudimentary, and the guidelines are incomplete in China. The diagnosis and management of Chinese FH needs to be improved.

Genetically confirmed familial hypercholesterolemia in outpatients with hypercholesterolemia.

BackgroundFamilial hypercholesterolemia (FH) is an autosomal dominant disorder of lipoprotein metabolism which can lead to premature coronary heart disease (pCHD). There are about 3.8 million potential FH patients in China, whereas the clinical and genetic data of FH are limited.MethodsDutch Lipid Clinic Network (DLCN) criteria was used to diagnose FH in outpatients with hypercholesterolemia. Resequencing chip analysis combined with Sanger sequencing validation were used to identify mutations in the definite FH patients according to DLCN criteria. In silico analysis was conducted in mutations with previously unknown pathogenicity. Then, the novel mutant receptors were transfected into human embryo kidney 293 (HEK-293) cells. The binding and the internalization activities of the mutant receptors were analyzed by flow cytometry.ResultsThe prevalence of definite FH in outpatients with hypercholesterolemia in this study is 3.2%. Using genetic testing, one homozygous FH (HoFH), one heterozygous FH (HeFH) and three compound heterozygous FH patients were confirmed. Eight mutations in low-density lipoprotein receptor (LDLR) gene were identified, in which c.357delG was a novel mutation and co-segregated with the FH phenotype. Bioinformatic analysis confirmed that c.357delG was a pathogenic mutation. Furthermore, when compared with the wild-type LDLRs by flow cytometry analysis, the binding and internalization activities of c.357delG mutant LDLRs were reduced by 35% and 49%, respectively.ConclusionsThis study identified eight LDLR gene mutations in five patients with definite FH, in which c.357delG is a novel pathogenic mutation. These findings increase our understanding of the genetic spectrum of FH in China.

Familial Hypercholesterolemia Phenotype in Chinese Patients Undergoing Coronary Angiography

Familial hypercholesterolemia (FH) is characterized by an elevated low-density lipoprotein cholesterol and increased risk of premature coronary artery disease. However, the general picture and mutational spectrum of FH in China are far from recognized, representing a missed opportunity for the investigation. A total of 8050 patients undergoing coronary angiography were enrolled. The diagnosis of clinical FH was made using Dutch Lipid Clinic Network criteria, and the information of relatives was obtained by inquiring for the probands or from their own medical records of certain clinics/hospitals. Molecular analysis of FH was performed using target exome sequencing in LDLR (low-density lipoprotein cholesterol receptor gene), APOB (apolipoprotein B gene), and PCSK9 (proprotein convertase subtilisin/kexin type 9 gene). As a result, 3.5% of the patients with definite/probable FH phenotype (definite 1.0% and probable 2.5%) were identified. Women FH had fewer premature coronary artery disease (women <60, or men <55 years of age) when compared with men FH (70.6% versus 82.7%; P<0.001), whereas angiographic extension of coronary artery disease was significantly increased with FH diagnosis in both men and women (P<0.001). Patterns of medication use in definite/probable FH were as follows: nontreated, 20.6%; low intensity, 6.0%; moderate intensity, 68.3%; and high intensity, 5.0%. However, none of them had achieved the low-density lipoprotein cholesterol <100 mg/dL. Additionally, mutational analysis was performed in 245 definite/probable FH cases, and risk variants were identified in 115 patients, giving a detection rate of 46.9%. We showed firsthand a common identification but poor treatment of patients with FH phenotype in Chinese coronary angiography patients. Genetic data in our FH cases might contribute to update the frequency and spectrum of Chinese FH scenarios.

Familial hypercholesterolemia in China: Prevalence and evidence of underdetection and undertreatment in a community population

Familial hypercholesterolemia (FH) is the most common and serious monogenic disorder of lipid metabolism that causes premature coronary and heart disease [ [1] Watts G.F. Gidding S. Wierzbicki A.S. et al. Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation. Int J Cardiol. 2014; 171: 309-325 Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar ]. FH is often undetected and undertreated [ [1] Watts G.F. Gidding S. Wierzbicki A.S. et al. Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation. Int J Cardiol. 2014; 171: 309-325 Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar ]. The prevalence of FH is at least one in 500 in the general population, depending on diagnostic criteria [ [2] Benn M. Watts G.F. Tybjaerg-Hansen A. Nordestgaard B.G. Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication. J Clin Endocrinol Metab. 2012; 97: 3956-3964 Crossref PubMed Scopus (468) Google Scholar ]. Currently there is no consensus on the diagnosis of FH although the Dutch Lipid Clinic Network (DLCN) criteria have been widely used [ [1] Watts G.F. Gidding S. Wierzbicki A.S. et al. Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation. Int J Cardiol. 2014; 171: 309-325 Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar ]. In Asia, diagnostic criteria has been proposed by Harada-Shiba et al. [ [3] Harada-Shiba M. Arai H. Oikawa S. et al. Guidelines for the management of familial hypercholesterolemia. J Atheroscler Thromb. 2012; 19: 1043-1060 Crossref PubMed Scopus (144) Google Scholar ], but as with the Simon-Broome criteria from the UK [ [4] Scientific Steering Committee Simon Broome Register Group Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group. BMJ. 1991; 303: 893-896 Crossref PubMed Google Scholar ], may have low sensitivity for detecting FH, since it does not use a numerical score and relies on the detection of tendon xanthomata, an infrequent sign in young subjects.

Functional analysis of low-density lipoprotein receptor in homozygous familial hypercholesterolemia patients with novel 1439 C→T mutation of low-density lipoprotein receptor gene

Familial hypercholesterolemia (FH), caused by low density lipoprotein (LDL) receptor (LDL-R) gene mutations, is associated with increased risk of premature coronary heart disease. Until now, limited molecular data concerning FH are available in China. The present study described the clinical profiles and cell biological defects of a Chinese FH kindred with novel LDL-R gene mutation. The patient's LDL-R gene coding region was sequenced. The patient's lymphocytes were isolated and the LDL-R expression, binding and up-take functions were observed by immunohistochemistry staining and flow cytometry detection. The patient's heart and the major large vessels were detected by vessel ultrasound examination and myocardial perfusion imaging (MPI). The patient's LDL-R expression, LDL binding and up-take functions were significantly lower than normal control (39%, 63% and 76% respectively). A novel homozygous 1439 C-->T mutation of the LDL-R gene was detected in the patient and his family. ECG showed atypical angina pectoris. Echocardiogram showed stenosis of the coronary artery and calcification of the aortic valve and its root. Blood vessel ultrasound examination showed the thickness of large vessel intima, and the vessel lumen was narrowed by 71%. MPI showed ischemic changes. The LDL-R synthesis dysfunction of FH patients leads to arterial stenosis and calcification, which are the major phenotype of the clinical disorder. The mutation of the LDL-R gene is determined. These data increase the mutational spectrum of FH in China.

Two novel mutations of the LDL receptor gene associated with familial hypercholesterolemia in a Chinese family

Familial hypercholesterolemia (FH) is a type of dominant autosomal disease that causes high levels of plasma low-density lipoprotein cholesterol (LDL-C). In the past years, molecular data related to FH were limited in China. Now, to gain more information about FH, we analyzed one proband with a severe FH phenotype as well as his relatives. After the entire coding sequence and the intron-exon junctions of the low-density lipoprotein receptor (LDLR) gene were amplified using PCR, we sequenced the LDLR gene of a Chinese FH family. RT-PCR was used to detect changes in the mRNA. Two novel mutations were identified in the LDLR gene of this family. One, W165X, was a G > A substitution at the third nucleotide of codon 165. The other, IVS5-1G > A, was also a G > A substitution at the acceptor splice site of intron 5. The most striking discovery is that the proband was heterozygous for W165X but homozygous for IVS5-1G > A. The cDNA sequencing showed that the IVS5-1G > A mutation caused the insertion of 10 nucleotides, namely GCTCTCACAA, between exon 5 and exon 6. The two nucleotide variations are thought to be the FH-causing mutations because the co-segregation of the mutant allele with the phenotype of FH has been shown in this Chinese family. These data show an increase in the mutational spectrum of FH in China and verify a scarce mutational form in the LDLR gene.

A Chinese homozygote of familial hypercholesterolemia: identification of a novel C263R mutation in the LDL receptor gene

Familial hypercholesterolemia (FH) is an autosomal dominant disorder caused by mutations in the low-density lipoprotein receptor (LDLR) gene; it is characterized by a high concentration of LDL, which frequently gives rise to tendon xanthomas and premature coronary artery disease (CAD). Individuals with heterozygous FH in China often exhibit a milder phenotype than those in other countries. The diagnosis of heterozygous FH relies on the clinical phenotype and this does not always permit unequivocal diagnosis of the disease. In the course of investigation of FH in a Chinese population sample, we found a family whose proband showed a markedly raised concentration of LDL cholesterol in plasma, and the presence of skin and tendon xanthomata. We used single-strand conformation polymorphism (SSCP) analysis to screen all the 18 exons and the exon-intron boundaries of the LDLR gene. One novel homozygous mutation, replacing T by C at nucleotide 850 in exon 6 was identified. This change substituted cysteine for arginine at codon 263 (C263R) of the LDLR. By means of mutant allele-specific amplification, we unequivocally diagnosed six heterozygotes with this novel mutation in the proband's family. forms of heterozygous FH are characterized by high serum LDL cholesterol levels, which are usually associated with premature coronary heart disease (CHD) and tendon xanthomas in early middle age, while homozygous FH individuals frequently suffer fatal CHD by their third decade (Goldstein et al. 1995). To date, more than 200 different mutations of the LDLR gene have been characterized worldwide (Hobbs et al. 1990; Hobbs et al. 1992; Varret et al. 1997). Chinese individuals with heterozygous FH are often recognized by virtue of their being parents of offspring with mutations in both alleles of the LDLR gene (Mak et al. 1998). Unlike their heterozygous parents, the Chinese homozygous FH patients are as severely affected, as are those elsewhere (Sun et al. 1994). In this article, we present an investigation of a Chinese family whose proband, with severe hypercholesterolemia, carried a novel mutation of the LDLR gene in a homozygous form, while the other six patients in the family, who carried this mutation in a heterozygous form, have a milder phenotype of FH. The main objective of our analysis was to delineate the full spectrum of mutations that underline FH in the Chinese population; our work represents a first step towards the implementation of nationwide DNA testing for this disease.

Familial hypercholesterolemia in China. Identification of mutations in the LDL-receptor gene that result in a receptor-negative phenotype.

Familial hypercholesterolemia (FH), caused by many different mutations in the low-density lipoprotein (LDL)-receptor gene, invariably leads to severe premature coronary heart disease (CHD) in homozygous individuals. Heterozygous FH patients are less severely affected but are still at increased risk of CHD in most populations. Although FH homozygotes in China are affected similarly to those elsewhere, heterozygotes are not detected in the general population and obligate heterozygotes are often not hypercholesterolemic by Western standards. Mutations in the LDL-receptor genes of 10 homozygous FH patients from the Jiang-su province of China and their heterozygous parents were analyzed. These include one large and two minor deletions and eight point mutations: four are predicted to introduce a premature stop codon, five to result in a single amino acid substitution or deletion, and one to produce a protein with an abnormal cytoplasmic tail. Expression of the mutant LDL-receptor cDNAs in vitro confirmed that these mutations impaired LDL-receptor function and that several would cause a receptor-negative phenotype. Thus, the lack of clinical expression in obligate FH heterozygotes is not due to unusually "mild" mutations in the LDL-receptor gene, and other genetic or environmental factors must therefore be important in determining phenotypic expression.