The distribution and characteristics of LDL receptor mutations in China: A systematic review

Jiang, Long; Sun, Li‐Zhong; Dai, Yong; Yang, Shiwei; Zhang, Feng; Wang, Luya

doi:10.1038/srep17272

Cited by 48 publications

(41 citation statements)

References 39 publications

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“…Likewise, mutations in the APOB gene were seen in 6% of our patients with FH with three double heterozygous patients harboring both APOB and LDLR mutations. In contrast to Caucasian populations, NM_000384.2( APOB ): c.10579 C>T was the most frequent APOB mutation in our study, and this variant was also the main APOB gene mutation among FH subjects in Taiwan and in China (Chiou & Charng, ; Jiang et al., ). We have sequenced all the coding regions of the PCSK9 gene and did not find any gain‐of‐function mutations in our cohort.…”

Section: Discussioncontrasting

confidence: 66%

“…Majority of the Chinese population in Hong Kong originated from southern China, and the three most common mutations in the LDLR gene were the NM_000527.4(LDLR): c.1241 T>G (10%), NM_000527.4(LDLR): c.1474G>A (6%), and NM_000527.4(LDLR): c. 682G>A (4%). The distribution of the common mutations in Hong Kong seems to differ from those reported in China and Taiwan (Chiou & Charng, 2012;Jiang et al, 2015). The common mutations reported in Chinese populations from the North of China (NM_000527.4(LDLR): c.1879G>A and NM_000527.4(LDLR): c.313+1G>A) and from Taiwan (NM_000527.4(LDLR): c.986G>A and NM_000527.4(LDLR): c.1747 C>T) were also present in our population but at a lower frequency.…”

Section: Discussionmentioning

confidence: 79%

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Genetic variations in familial hypercholesterolemia and cascade screening in East Asians

Chan

Cheung

Lee

et al. 2018

Molec Gen & Gen Med

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Background Familial hypercholesterolemia ( FH ) is a monogenic disorder of lipoprotein metabolism leading to an increased risk of premature cardiovascular disease. Genetic testing for FH is not commonly used in Asian countries. We aimed to define the genetic spectrum of FH in Hong Kong and to test the feasibility of cascade genetic screening. Methods Ninety‐six Chinese subjects with a clinical diagnosis of FH were recruited, and family‐based cascade screening incorporating genetic testing results was performed. Results Forty‐two distinct mutations were identified in 67% of the index FH cases. The majority of causative mutations were in the LDLR gene. The three commonest mutations in the LDLR gene were NM _000527.4( LDLR ): c.1241 T>G, NM _000527.4( LDLR ): c.1474G>A, and NM _000527.4( LDLR ): c. 682G>A, and nine novel variants were identified. The NM _000384.2( APOB ): c.10579 C>T variant of the APOB gene was found in 5% of the index subjects. The presence of causative mutation significantly increased the odds of successful family recruitment for screening with an OR of 3.7 (95% CI : 1.53–9.11, p = 0.004). Conclusion Approximately two‐third of the subjects in this clinically ascertained sample of patients with FH had a discrete genetic basis. Genetic identification improves the response rate and efficiency of family screening.

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Section: Discussioncontrasting

confidence: 66%

Section: Discussionmentioning

confidence: 79%

Genetic variations in familial hypercholesterolemia and cascade screening in East Asians

Chan

Cheung

Lee

et al. 2018

Molec Gen & Gen Med

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“…Arterial cells (macrophages, pericytes, and smooth muscle cells) take up these particles in an unregulated manner bypassing the specialized LDL receptor [3][4][5]. The mechanism of interaction of native (unmodified) LDL with a specific cell receptor is currently well known [5][6][7][8]. This interaction does not lead to excessive deposition of intracellular lipids since the lipid components of LDL are utilized by cells, and the excess is removed.…”

Section: Introductionmentioning

confidence: 99%

Signaling Pathways Potentially Responsible for Foam Cell Formation: Cholesterol Accumulation or Inflammatory Response—What is First?

Orekhov

Sukhorukov

Nikiforov

et al. 2020

IJMS

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Accumulation of lipid-laden (foam) cells in the arterial wall is known to be the earliest step in the pathogenesis of atherosclerosis. There is almost no doubt that atherogenic modified low-density lipoproteins (LDL) are the main sources of accumulating lipids in foam cells. Atherogenic modified LDL are taken up by arterial cells, such as macrophages, pericytes, and smooth muscle cells in an unregulated manner bypassing the LDL receptor. The present study was conducted to reveal possible common mechanisms in the interaction of macrophages with associates of modified LDL and non-lipid latex particles of a similar size. To determine regulatory pathways that are potentially responsible for cholesterol accumulation in human macrophages after the exposure to naturally occurring atherogenic or artificially modified LDL, we used transcriptome analysis. Previous studies of our Int.Int. J. Mol. Sci. 2020, 21, 2716 2 of 17 group demonstrated that any type of LDL modification facilitates the self-association of lipoprotein particles. The size of such self-associates hinders their interaction with a specific LDL receptor. As a result, self-associates are taken up by nonspecific phagocytosis bypassing the LDL receptor. That is why we used latex beads as a stimulator of macrophage phagocytotic activity. We revealed at least 12 signaling pathways that were regulated by the interaction of macrophages with the multiple-modified atherogenic naturally occurring LDL and with latex beads in a similar manner. Therefore, modified LDL was shown to stimulate phagocytosis through the upregulation of certain genes. We have identified at least three genes (F2RL1, EIF2AK3, and IL15) encoding inflammatory molecules and associated with signaling pathways that were upregulated in response to the interaction of modified LDL with macrophages. Knockdown of two of these genes, EIF2AK3 and IL15, completely suppressed cholesterol accumulation in macrophages. Correspondingly, the upregulation of EIF2AK3 and IL15 promoted cholesterol accumulation. These data confirmed our hypothesis of the following chain of events in atherosclerosis: LDL particles undergo atherogenic modification; this is accompanied by the formation of self-associates; large LDL associates stimulate phagocytosis; as a result of phagocytosis stimulation, pro-inflammatory molecules are secreted; these molecules cause or at least contribute to the accumulation of intracellular cholesterol. This chain of events may explain the relationship between cholesterol accumulation and inflammation. The primary sequence of events in this chain is related to inflammatory response rather than cholesterol accumulation.

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“…In China, there are few studies analyzing FH patients using genetic analysis, and novel genetic variants identified remain scarce . The rate of timely diagnosis and treatment of FH is far from satisfaction.…”

Section: Introductionmentioning

confidence: 99%

“…8 In China, there are few studies analyzing FH patients using genetic analysis, and novel genetic variants identified remain scarce. 9 The rate of timely diagnosis and treatment of FH is far from satisfaction. As PMI represents a critical clinical manifestation of patients with FH, the aim of this study was to investigate the prevalence of FH using genetic testing in a cohort of Chinese patients with PMI, and to evaluate different diagnostic criteria.…”

Section: Introductionmentioning

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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The distribution and characteristics of LDL receptor mutations in China: A systematic review

Cited by 48 publications

References 39 publications

Genetic variations in familial hypercholesterolemia and cascade screening in East Asians

Genetic variations in familial hypercholesterolemia and cascade screening in East Asians

Signaling Pathways Potentially Responsible for Foam Cell Formation: Cholesterol Accumulation or Inflammatory Response—What is First?

Prevalence of familial hypercholesterolemia in patients with premature myocardial infarction

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