Spectrum of mutations in index patients with familial hypercholesterolemia in Singapore: Single center study.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disease characterized by the presence of high plasma low density lipoproteins cholesterol (LDL-c). Patients with FH, with mutation detected, are at increased risk of premature cardiovascular disease compared to those without mutations. The aim of the study was to assess the type of mutations in patients, clinically diagnosed with FH in Singapore. METHODS: Patients (probands) with untreated/highest on-treatment LDL-c>4.9 mmol/l were recruited (June 2015 to April 2017). Anthropometric, biochemical indices, blood and family history were collected. DNA was extracted and Next Generation Sequencing (NGS) was performed in 26 lipid-related genes, including LDLR, APOB and PCSK9, and validated using Sanger. Multiplex-ligation probe analyses for LDLR were performed to identify large mutation derangements. Based on HGVS nomenclature, LDLR mutations were classified as "Null"(nonsense, frameshift, large rearrangements) and "Defective"(point mutations which are pathogenic). RESULTS: Ninety-six probands were recruited: mean age: (33.5 ±â€¯13.6) years. 52.1% (n = 50) of patients had LDLR mutations, with 15 novel mutations, and 4.2% (n = 4) had APOB mutations. Total cholesterol (TC) and LDL-c were significantly higher in those with LDLR mutations compared to APOB and no mutations [(8.53 ±â€¯1.52) vs. (6.93 ±â€¯0.47) vs. (7.80 ±â€¯1.32)] mmol/l, p = 0.012 and [(6.74 ±â€¯0.35) vs. (5.29 ±â€¯0.76) vs. (5.98 ±â€¯1.23)] mmol/l, p=0.005, respectively. Patients with "null LDLR" mutations (n = 13) had higher TC and LDL-c than "defective LDLR" mutations (n = 35): [(9.21 ±â€¯1.60) vs. (8.33 ±â€¯1.41)]mmol/l, p = 0.034 and [(7.43 ±â€¯1.47) vs. (6.53 ±â€¯1.21)]mmol/l, p=0.017, respectively. CONCLUSIONS: To our knowledge, this is the first report of mutation detection in patients with clinically suspected FH by NGS in Singapore. While percentage of mutations is similar to other countries, the spectrum locally differs.

Apolipoprotein B100 is a better treatment target than calculated LDL and non-HDL cholesterol in statin-treated patients.

INTRODUCTION: Clinical trials have shown that apolipoprotein B100 (apoB) is better than calculated low-density lipoprotein cholesterol (c-LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C) as a target for statin treatment. However, there are no published reports of how well these targets are reached in patients with more severe hyperlipidaemias than represented in trials, as seen in lipid clinics. METHODS: We audited 195 patients attending a tertiary centre lipid clinic, who had been treated with a statin for more than one year. We measured total cholesterol, HDL-cholesterol (HDL-C) and triglyceride and from these calculated LDL-cholesterol (LDL-C) and non-HDL-C. We determined the average measured apoB values, at critical target values of LDL-C and non-HDL-C, by linear regression and compared them with values of apoB considered equivalent to these cholesterol indexes by expert groups. We also assessed the number of patients, both before and after treatment, in whom c-LDL-C and non-HDL-C could not be calculated due to hypertriglyceridaemia. RESULTS: At the LDL-C target of 2.6 mmol L(-1) and the non-HDL-C target of 3.4 mmol L(-1), the measured apoB values were significantly higher than consensus apoB target values. The difference was most marked for c-LDL-C in hypertriglyceridaemic subjects and for non-HDL-C in patients without hypertriglyceridaemia. A similar pattern was seen using centile-derived consensus values but the differences were accentuated because this approach generates lower equivalent consensus apoB values. CONCLUSION: ApoB offers a more consistent treatment target independent of hypertriglyceridaemia and would obviate technical problems related to high triglycerides.