Aim : Whole exome sequencing (WES) is a recently developed method for discovering rare mutations associated with hereditary disorders. However, the feasibility and utilization of this method in ...identifying familial hypertriglyceridemia is not well known. The purpose of the study was to identify the genetic locus that causes hypertriglyceridemia and assess its prevalence in Taiwanese subjects with hypertriglyceridemia. Methods : We performed WES among two individuals with hypertriglyceridemia and one control subject in an index family (22 members). Based on the WES findings, we extended the study to genotype 65 unrelated adult index patients with a fasting serum triglyceride level of > 500 mg/dL and 125 normal controls using polymerase chain reaction. Results : Using WES alignment, variant calling and annotation, 15 presumptive causal variants were initially identified, including 13 cases by the autosomal dominant model and two cases by the autosomal recessive model. Only APOA5 c.553 G > T (rs2075291), resulting in the amino acid mutation Gly185Cys, co-segregated well with hypertriglyceridemia in terms of autosomal recessive inheritance (homozygote TT : mean triglyceride level : 1,071 mg/dL vs non TT (GT and GG) : mean triglyceride level : 118 mg/dL ; p < 0.001) in the index family. In the unrelated cohorts, the frequency of the TT genotype of rs2075291 was 12.3% in the hypertriglyceridemic group ; however, no TT genotype was found in the control group. Conclusions : Our results demonstrate that WES is feasible for identifying the genetic locus that causes hypertriglyceridemia. The TT genotype of APOA5 c.553G > T acts as an important indicator of hypertriglyceridemia in patients in Taiwan.
Aim: Familial hypercholesterolemia (FH) is underdiagnosed in most countries. The genetic heterogeneity of FH requires an algorithm to efficiently integrate genetic testing into clinical practice. We ...aimed to report the spectrum of genetic mutations from patients with clinically diagnosed FH in Taiwan. Methods: Patients with LDL-C>190 mg/dL or those with probable or definite FH according to the Taiwan Lipid Guidelines underwent genetic testing. Samples from 750 index patients from the Taiwan FH registry were screened using custom-made mass spectrometry, followed by targeted next generation sequencing (NGS) and/or multiplex ligation-dependent probe amplification (MLPA) if found negative. Results: The mean age of the patients was 52.4+-15.1 years and 40.9% were male. Mutations were detected in 445 patients (59.3%). The distribution of mutations was as follows: LDLR (n=395), APOB (n=58), PCSK9 (n=0), and ABCG5 (n=3). The most common mutations were APOB c.10579 C>T (p.R3527W) (12.6%), LDLR c.986 G>A (p.C329Y) (11.5%), and LDLR c.1747 C>T (p.H583Y) (10.8%). LDLR c.1187-10 G>A (IVS 8-10) and APOB c.10580 G >A (p.R3527Q) were detected using targeted NGS in Taiwan for the first time. Four novel mutations were identified, including LDLR c.1060 + 2T>C (IVS 7 + 2), LDLR c.1139 A>C (p.E380A), LDLR c.1322 T>C (p.A431T) + c.1867 A>G (p.I623V), and ABCG5 c.1337 G>A(p.R447Q). Conclusion: LDLR and APOB, but not PCSK9, mutations were the major genetic causes of FH. Four novel mutations in LDLR or ABCG5 were identified. This genetic screening method using mass spectrometry, targeted NGS, and MLPA analysis provided an efficient algorithm for genetic testing for clinically diagnosed FH in Taiwan.
Background Clinical observation and treatment of children with homozygous familial hypercholesterolemia (HoFH) has rarely been reported. We report clinical observations and treatment of 10 ethnic ...Chinese children with HoFH due to low-density lipoprotein receptor (LDLR) defect. Objectives In children with HoFH, we evaluated the response to conventional cholesterol-lowering drug therapy and performed LDLR gene analysis. Methods A retrospective review of lipid profile changes in pediatric patients diagnosed with HoFH seen in our pediatric endocrinology outpatient clinic was performed. HoFH was diagnosed by molecular study of these patients and their parents. Results One novel (c.64del G) and 12 known mutations were found in the LDLR gene. Mutation of p.C308Y was the most common and was found in 26% of the studied alleles.Seven patients had fair responses to conventional drug therapy (high-dose statin with ezetimibe) with a reduction of 50% or more of the total cholesterol levels. The low-density lipoprotein–cholesterol levels of three patients decreased to lower than 160 mg/dL. One who had a good response to conventional drug therapy developed significant atheromatous plaques (largest plaque: 7.4 × 2.7 cm) in the extracranial carotid arteries and myocardial ischemia changes at 11 years old. Conclusion The results suggest that despite aggressive therapy, many patients are not well controlled; atherosclerosis may progress, and novel therapies are required.
Aim: Familial hypercholesterolemia (FH) is underdiagnosed in most countries. The genetic heterogeneity of FH requires an algorithm to efficiently integrate genetic testing into clinical practice. We ...aimed to report the spectrum of genetic mutations from patients with clinically diagnosed FH in Taiwan. Methods: Patients with LDL-C＞190 mg/dL or those with probable or definite FH according to the Taiwan Lipid Guidelines underwent genetic testing. Samples from 750 index patients from the Taiwan FH registry were screened using custom-made mass spectrometry, followed by targeted next generation sequencing (NGS) and/or multiplex ligation-dependent probe amplification (MLPA) if found negative. Results: The mean age of the patients was 52.4±15.1 years and 40.9% were male. Mutations were detected in 445 patients (59.3%). The distribution of mutations was as follows: LDLR (n=395), APOB (n=58), PCSK9 (n=0), and ABCG5 (n=3). The most common mutations were APOB c.10579 C＞T (p.R3527W) (12.6%), LDLR c.986 G＞A (p.C329Y) (11.5%), and LDLR c.1747 C＞T (p.H583Y) (10.8%). LDLR c.1187-10 G＞A (IVS 8-10) and APOB c.10580 G＞A (p.R3527Q) were detected using targeted NGS in Taiwan for the first time. Four novel mutations were identified, including LDLR c.1060＋2 T＞C (IVS 7＋2), LDLR c.1139 A＞C (p.E380A), LDLR c.1322 T＞C (p.A431T)＋c.1867 A＞G (p.I623V), and ABCG5 c.1337 G＞A (p.R447Q). Conclusion: LDLR and APOB, but not PCSK9, mutations were the major genetic causes of FH. Four novel mutations in LDLR or ABCG5 were identified. This genetic screening method using mass spectrometry, targeted NGS, and MLPA analysis provided an efficient algorithm for genetic testing for clinically diagnosed FH in Taiwan.
Background: Asymmetrical dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide synthase and has been associated with systemic atherosclerosis; however, the role of ADMA in ...patients with coronary artery disease (CAD) has not been investigated.
Hypothesis: The present study was designed to determine whether the plasma ADMA level predicts the presence of CAD independently, and whether the plasma ADMA level correlates with the extent and severity of coronary atherosclerosis.
Methods: In all, 97 consecutive patients with angina and positive exercise stress test were enrolled prospectively for coronary angiography. According to the result of angiography, the subjects were divided into two groups: Group 1 (n = 46): patients with normal coronary artery or mild CAD (< 50% stenosis of major coronary arteries); group 2 (n = 51): patients with significant cad (≥ 50% stenosis of major coronary arteries). plasma levels of adma and l‐arginine were determined by high‐performance liquid chromatography. in addition, we used coronary atherosclerotic score to assess the extent and severity of cad.
Results: The plasma levels of ADMA in Group 2 patients were significantly higher than those in Group 1 patients (0.66 ± 0.17 μM vs. 0.44 ± 0.09 μM, p < 0.001); these were accompanied by significantly lower plasma l‐arginine/adma ratio in patients with significant cad (group 1 vs. 2: 194.0 ± 55.3 vs. 136.7 ± 50.3, p < 0.001). in a multivariate stepwise logistic regression analysis, both plasma adma level and plasma l‐arginine/adma ratio were identified as independent predictors for cad. moreover, there were significant positive and negative correlations between coronary atherosclerotic score and plasma adma level as well as plasma l‐arginine/adma ratio, respectively (plasma adma level: r = 0.518, p < 0.001; l‐arginine/adma ratio: r = 2 0.430, p < 0.001).
Conclusions: Both plasma ADMA level and plasma L‐arginine/ADMA ratio were useful in predicting the presence of significant CAD and correlated significantly with the extent and severity of coronary atherosclerosis. Our findings suggest that plasma ADMA level may be a novel marker of CAD.
The aim of this study was to investigate the potential relationships between the carotid intima media thickness (carotid IMT), high sensitive C-reactive protein (hsCRP), and cholesterol burden in ...heterozygous familial hypercholesterolemia (FH) subjects. Thirty-two genetically-verified heterozygous patients with FH and 34 healthy controls were recruited into our study in Taiwan. We measured conventional risk factors, hsCRP, and carotid IMT of study subjects. The cholesterol-year score was used to estimate the lifetime cholesterol burden. Subjects with heterozygous FH had significantly elevated total cholesterol, elevated low-density lipoprotein cholesterol, and increased carotid IMT compared with control subjects. Carotid IMT correlated well with the cholesterol-year score. In patients with FH, univariate analysis showed that hsCRP was highly correlated with carotid IMT. Multiple linear regression analysis indicated that hsCRP was the only independent predictor of carotid IMT in patients with FH. In conclusion, patients with heterozygous FH had significantly higher carotid IMT and the level of hsCRP was independently associated with atherosclerotic progression. (R: 0.639, R2 : 0.408, p <0.001).
The extent of coronary artery calcium (CAC) is correlated with coronary artery disease prognosis. However, the relation of CAC to endothelial function and high-sensitivity C-reactive protein (hs-CRP) ...in patients with asymptomatic heterozygous familial hypercholesterolemia (FH) requires clarification. The study aim was to investigate the relations among CAC, endothelial function, and hs-CRP in patients with asymptomatic heterozygous FH. Thirty-two patients with asymptomatic heterozygous FH (mean age 42 years) and 34 healthy control subjects (mean age 36 years) were enrolled. We measured CAC by electron-beam computed tomography and endothelial function by flow-mediated dilation of the brachial artery. A higher percentage of patients with FH had a positive CAC score compared with the control group. Comparing the FH group with detectable CAC (CAC score >0) and undetectable CAC (CAC score of 0), we found higher hs-CRP levels (0.29 ± 0.23 vs 0.07 ± 0.08 mg/dl, p = 0.001) and reduced flow-mediated dilation (0.04 ± 0.03 vs 0.08 ± 0.03, p = 0.005) in the detectable CAC group. Multivariate analysis showed an independent correlation of hs-CRP with detectable CAC (relative risk 5.034, 95% confidence interval 1.525 to 16.613, p = 0.04). In conclusion, FH subjects with positive CAC scores have decreased flow-mediated dilation and increased hs-CRP levels. Furthermore, hs-CRP level is the only independent predictor of the presence of CAC.
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