LDLR and ApoB are Major Genetic Causes of Autosomal Dominant Hypercholesterolemia in a Taiwanese Population

Yang, Kai‐Chien; Su, Yi‐Ning; Shew, Jin‐Yuh; Yang, Kaiying; Tseng, Wei‐Kung; Wu, Chau‐Chung; Lee, Yuan‐Teh

doi:10.1016/s0929-6646(08)60044-3

Cited by 31 publications

(25 citation statements)

References 33 publications

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“…38 In the present study, we used the Dutch Lipid Clinic Network criteria with a comparatively comprehensive information included to identify patients with FH phenotype, and we, for the first time, performed the analysis from the patients in our division of dyslipidemia, which is the only national center of dyslipidemia in China with subjects from across the country. The observed elevated prevalence of APOB mutations (particularly the 34 specific mutations), in accordance with the report from Yang et al 34 showing that 18 out of 30 families were identified by harboring LDLR or APOB mutations with frequencies of 77.8% (14/18) and 22.2% (4/18), respectively, might indicate an important gene effect of APOB mutations on Chinese FH. Moreover, investigators from Taiwan and other ethnicities have suggested recently that the number of APOB mutations is increasing, 16,36 most notably in Taiwan.…”

Section: Discussionsupporting

confidence: 91%

“…Moreover, investigators from Taiwan and other ethnicities have suggested recently that the number of APOB mutations is increasing, 16,36 most notably in Taiwan. 34,38 The elevated prevalence of APOB mutations among Chinese patients might be possible, as pointed out by Andersen et al 38 Additionally, most currently available genetic testing in APOB is focused on exon 26 and p.Arg3500Trp rather than on the entire coding region. 39 Of note, there are case studies reporting mutations in the non-hot spot of APOB.…”

Section: Discussionmentioning

confidence: 99%

“…33 To date, an FH registry was complied only in Taiwan, and 2 small cohort studies with genetic diagnosis had been reported. 34,35 The limited data in China, however, might reflect an urgent need for national screenings for FH in this population. In the present study, we first used target exon sequencing in FH cohort of mainland China and showed the spectrum of FH gene mutations.…”

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confidence: 99%

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Familial Hypercholesterolemia Phenotype in Chinese Patients Undergoing Coronary Angiography

Zhu

et al. 2017

ATVB

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Large-scale clinical studies of FH have been reported from many countries, 2,7-16 but the features of FH in China are largely unknown. 17 Furthermore, the actual prevalence of FH is likely to be underestimated in the past, and the FH trait is masked by the CAD phenotype or more common risk factors without the genetically elevated cholesterol levels.3 Hence, the aim of present study was to investigate patients with FH phenotype and further provide molecular data on mutations for patients with FH in the Division of Dyslipidemia of Fu Wai Hospital, the only national center of dyslipidemia in China.© 2016 American Heart Association, Inc. Objective-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. Approach and Results-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 lowdensity 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%. Conclusions-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. Materials and MethodsMaterials and Methods are available in the online-only Data Supplement. Results Prevalence of FHBasic characteristics of the study population are summarized in Table 1. The mean (±SD) age of the participants was 57.2±10.5 years, of whom 68.7% were men and 83.8% were with CAD and 37.8% with pCAD (<55 years for men and <60 years for women). The mean total cholesterol and LDL-C were 165.25±50.58 and 101.54±43.63 mg/dL, respectively. In the sample, there were 1.0% def...

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Familial Hypercholesterolemia Phenotype in Chinese Patients Undergoing Coronary Angiography

Zhu

et al. 2017

ATVB

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“…Subsequent studies have confi rmed that the R3500Q allele(s) is a major cause of moderate to severe hypercholesterolemia in people of European descent ( Table 6 ) and that it confers increased risk of premature atherosclerotic disease ( 226,227,235,238,(287)(288)(289)(290)(291)(292). In Asian populations, the recurrent R3500W mutation ( 293,294 ) is reported to be the principle cause of ADH-2.…”

Section: Apob Mutations Defective Ldlr Binding and Adh-2mentioning

confidence: 99%

“…In a control analysis, all other SNP associations (n = 65) with LDL-C concentrations disappeared when APOB R3500Q was considered as a covariate. Nonetheless, because many of the associating SNPs are in high LD (i.e., many carriers of the R3500Q mutation share a common extended haplotype potentially originating from a Celtic ancestor some 6,000-7,000 years ago ( 296 )), it would have been nearly impossible without independent genetic ( 227,293,294 ) and supporting functional ( 280,283 ) data to conclude that the R3500Q mutation (rather than a mutation(s) in LD) is the cause of moderate hypercholesterolemia in the Old Order Amish and other populations.…”

Section: Apob Mutations Defective Ldlr Binding and Adh-2mentioning

confidence: 99%

Mechanisms and genetic determinants regulating sterol absorption, circulating LDL levels, and sterol elimination: implications for classification and disease risk

Calandra

Tarugi

Speedy

et al. 2011

Journal of Lipid Research

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This review covers the dietary and biochemical origins and fates of key classes of sterol molecules in humans, namely, cholesterol and the relatively under-recognized and often unappreciated noncholesterol sterols and stanols; the intra-and intercellular systems that govern their transport; and the contribution of innate genetic programs to the biochemically observed levels of plasma LDL-cholesterol (LDL-C). The reasons for these foci are both biological and medical. The former is the burgeoning knowledge of the normal physiological roles that cholesterol performs within cell membranes in supporting receptor-mediated signaling activities ( 1-4 ), the movement of diverse molecules through different membranebound compartments (5)(6)(7)(8), and multiple other cell functions (9)(10)(11), including myelination ( 12 ). The latter, Abstract This review integrates historical biochemical and modern genetic fi ndings that underpin our understanding of the low-density lipoprotein (LDL) dyslipidemias that bear on human disease. These range from life-threatening conditions of infancy through severe coronary heart disease of young adulthood, to indolent disorders of middle-and oldage. We particularly focus on the biological aspects of those gene mutations and variants that impact on sterol absorption and hepatobiliary excretion via specifi c membrane transporter systems ( NPC1L1 , ABCG5/8 ); the incorporation of dietary sterols ( MTP ) and of de novo synthesized lipids ( HMGCR, TRIB1 ) into apoB-containing lipoproteins ( APOB ) and their release into the circulation ( ANGPTL3, SARA2, SORT1 ); and receptor-mediated uptake of LDL and of intestinal and hepatic-derived lipoprotein remnants ( LDLR, APOB, APOE, LDLRAP1, PCSK9, IDOL ).The insights gained from integrating the wealth of genetic data with biological processes have important implications for the classifi cation of clinical and presymptomatic diagnoses of traditional LDL dyslipidemias, sitosterolemia, and newly emerging phenotypes, as well as their management through both nutritional and pharmaceutical means. -Calandra, S., P. Tarugi Abbreviations: ABCG5, ATP-binding cassette, subfamily G, member 5; ABCG8, ATP-binding cassette, subfamily G, member 8; ABL, abetalipoproteinemia; ADH, autosomal dominant hypercholesterolemia; ANGPTL3, angiopoietin-like 3; ARH, autosomal recessive hypercholesterolemia; BMI, body mass index; CAC, coronary artery calcifi cation; CAD, coronary artery disease; CHD, coronary heart disease; CMRD, chylomicron retention disease; CYP7A1 , cholesterol 7 ␣ -hydroxylase; EGF, epidermal growth factor; ER, endoplasmic reticulum; FCHL, familial combined hyperlipidemia; FDB, familial defective apoB; FH, familial hypercholesterolemia; FHBL, familial hypobetalipoproteinemia; GWAS, genome-wide association study; HMGCR, HMGCoA reductase; IDOL, inducible degrader of LDLR; LD, linkage disequilibrium; LDL-C, LDL-cholesterol; LDLR, LDL receptor; LRP1, LDLRAP1, LDLR-associated protein 1; LDLR-related protein 1; LXR, liver X receptor; MI, myocardial infarction; MTP, m...

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A novel mutation of the LDL receptor gene leading to familial hypercholesterolemia

Wang

Lin

et al. 2009

Euro J Lipid Sci & Tech

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In China, about 1 million people are expected to suffer from familial hypercholesterolemia (FH), with a similar prevalence of FH to that in Caucasian populations. The mutations underlying FH in China are largely unknown because only a few studies have been conducted. In the present study, DNA sequencing analysis was used to scan the low-density lipoprotein receptor (LDLR) and ApoB100 genes in a Chinese family with clinically diagnosed FH. The results showed that the proband had abnormal patterns at nucleotide 517 of exon 4 due to a C/T heterozygosity, and at 1757 of exon 12 due to an A/C heterozygosity in the LDLR gene. Two mutations, C152R and S565X, were identified in the LDLR protein of the proband. DNA analysis of other family members showed that the two mutations should be located in different alleles of the proband. By flow cytometry analysis, the p.S565X mutant receptor displays reduced binding and internalization activity (16 and 19%, respectively) compared with the wild-type receptor. The proband is a compound heterozygote due to the C152R and S565X mutations, which are the possible molecular mechanisms of the etiology of FH in this family.

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LDLR and ApoB are Major Genetic Causes of Autosomal Dominant Hypercholesterolemia in a Taiwanese Population

Abstract: The results of our study reveal a characteristic mutation pattern of ADH in Taiwan, mainly in the LDLR and APOB genes. However, PCSK9 gene mutation may not be a major cause of ADH in our study population.

Cited by 31 publications

References 33 publications

Familial Hypercholesterolemia Phenotype in Chinese Patients Undergoing Coronary Angiography

Familial Hypercholesterolemia Phenotype in Chinese Patients Undergoing Coronary Angiography

Mechanisms and genetic determinants regulating sterol absorption, circulating LDL levels, and sterol elimination: implications for classification and disease risk

A novel mutation of the LDL receptor gene leading to familial hypercholesterolemia

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