Geng Liu

Patients with monogenic familial hypercholesterolemia (FH) have high risk for coronary artery disease (CAD). A recent FH Expert Panel suggested that FH was underdiagnosed and undertreated which needs early diagnosis. Moreover, the proportion of DNA-confirmed FH patients hospitalized with very early-onset (≤ 35 years) CAD remains uncertain. One hundred and five patients with age ≤ 35 years and LDL-C ≥ 3.4 mmol/L were tested for 9 genes (LDLR, APOB, PCSK9, APOE, STAP1, LIPA, LDLRAP1, ABCG5/8). Dutch Lipid Clinic Network (DLCN) and Simon Broome (SB) criteria for FH were also performed. The prevalence of genetically confirmed FH was 38.1% (n = 40) in 105 patients. DLCN categorized 26.7% patients to probable and definite FH while SB identified 17.1% of patients with possible to definite FH. Twenty-five (62.5%) and seventeen (42.5%) patients with pathogenic mutations were undiagnosed according to SB and DLCN criteria. FH variant carriers, especially homozygotes, had significantly higher plasma LDL-C levels. The best LDL-C threshold for genetically confirmed FH was 4.56 mmol/L in the present study. FH is really a common cause for very young CAD patients (≤ 35 years) with a 38.1% of causative mutations in China and best LDL-C threshold for predicting mutations was 4.56 mmol/L. The underdiagnostic rate of clinical criteria was around 42.5–62.5%, suggesting that the expanded genetic testing could indeed promote the diagnosis of FH.

Achievement of low-density lipoprotein cholesterol (LDL-C) goal is the most important for the patients with atherosclerotic cardiovascular diseases (ASCVD) who received lipid-lowering therapy. It is unclear that whether combination of ezetimibe with statin is superior to double-dose of statin regarding both of the lipid-lowering efficacy and improvement of inflammation in Chinese patients with ASCVD. Therefore, this study was performed to compare the effects of these two regimes on lipid profiles and inflammation markers. In this randomized control study, ninety eight patients with ASCVD, who were naïve to statins or other lipid-lowering agents, were enrolled into the study, and randomly assigned into two groups, A40 group (atorvastatin 40 mg/d, n = 50), A20E10 group (atorvastatin 20 mg/d combined with ezetimibe 10 mg/d, n = 48).The patients were followed up at week 4 and week 12 after treatment. The lipid profiles and oxidative low-density lipoprotein cholesterol (ox-LDL) were measured at the end of study. There were no differences in clinical characteristics including lipid, ox-LDL and hypersensitive C reactive protein (Hs-CRP) among groups at baseline. However, the average level of LDL-C was lower in group A20E10 than that in group A40 significantly (1.59 ± 0.44 mmol/L vs 1.99 ± 0.56 mmol/L, p = 0.001) during follow-up at week 12 after treatment. Importantly, the higher rate of achievement of LDL-C goal was attained at group of combination statin with ezetimibe (79.2% in group A20E10 vs 50.0% in group A40, p = 0.016). The difference of the level of ox-LDL between both the groups after 12 weeks treatment had not statistical significance (3.63 ± 1.13 U/L in group A20E10 vs 4.14 ± 1.32 U/L in group A40, p = 0.077).Similarly, the level of Hs-CRP between both the groups after treatment was not significantly different (p > 0.05). In this randomized study, the data showed that a combination of moderate statin and ezetimibe achieved more reduction of LDL-C compared to the double-dose statin but similar impact on inflammation markers.

Although there have been many reports in the genetics of familial hypercholesterolemia (FH) worldwide, studies in regard of Chinese population are lacking. In this multi-center study, we aim to characterize the genetic spectrum of FH in Chinese population, and examine the genotype-phenotype correlations in detail. A total of 285 unrelated index cases from China with clinical FH were consecutively recruited. Next-generation sequencing and bioinformatics tools were used for mutation detection of LDLR, APOB and PCSK9 genes and genetic analysis. Overall, the detection rate is 51.9% (148/285) in the unrelated index cases with a total of 119 risk variants identified including 84 in the LDLR gene, 31 in APOB and 4 in PCSK9 gene. Twenty-eight variants were found in more than one individual and LDLR c.1448G > A (p. W483X) was most frequent one detected in 9 patients. Besides, we found 8 (7 LDLR and 1 APOB) novel variants referred as “pathogenic (or likely pathogenic) variants” according to in silico analysis. In the phenotype analysis, patients with LDLR null mutation had significantly higher LDL cholesterol level than LDLR defective and APOB/PCSK9 mutation carriers and those with no mutations (p < 0.001). Furthermore, 13 double heterozygotes, 16 compound heterozygotes and 5 true LDLR homozygotes were identified and the true LDLR homozygotes had the most severe phenotypes. The present study confirmed the heterogeneity of FH genetics in the largest Chinese cohort, which could replenish the knowledge of mutation spectrum and contribute to early screening and disease management.