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Review New technologies for delineating and characterizing the lipid exome: prospects for understanding familial combined hyperlipidemia. 2009
Horswell SD, Ringham HE, Shoulders CC. · Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, Du Cane Rd., London, W12 0NN United Kingdom. · J Lipid Res. · Pubmed #19023136 No free full text.
Abstract: This review summarizes the progress made in cutting through the biological and genetic complexity of the Gordian knot that is familial combined hyperlipidemia. We particularly focus on how the application of new genomic technologies, especially massively parallel sequencing and high-throughput genotyping platforms, promise to accelerate the gene discovery process in this common, highly atherogenic disorder, with important diagnostic and therapeutic implications.
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Article Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response. free! 2005
Naoumova RP, Tosi I, Patel D, Neuwirth C, Horswell SD, Marais AD, van Heyningen C, Soutar AK. · MRC Clinical Sciences Centre, Hammersmith Hospital, London W12 0NN, UK. · Arterioscler Thromb Vasc Biol. · Pubmed #16224054 links to free full text
Abstract: OBJECTIVE: Analysis of long-term (30 years) clinical history and response to treatment of 13 patients with the D374Y mutation of PCSK9 (PCSK9 patients) from 4 unrelated white British families compared with 36 white British patients with heterozygous familial hypercholesterolemia attributable to 3 specific mutations in the low-density lipoprotein (LDL) receptor gene (LDLR) known to cause severe phenotype. METHODS AND RESULTS: The PCSK9 patients, when compared with the LDLR patients, were younger at presentation (20.8+/-14.7 versus 30.2+/-15.7 years; P=0.003), had higher pretreatment serum cholesterol levels (13.6+/-2.9 versus 9.6+/-1.6 mmol/L; P=0.004) that remained higher during treatment with simvastatin (10.1+/-3.0 versus 6.5+/-0.9 mmol/L; P=0.006), atorvastatin (9.6+/-2.9 versus 6.4+/-1.0 mmol/L; P=0.006), or current lipid-lowering therapy, including LDL apheresis and partial ileal bypass in 2 PCSK9 patients (7.0+/-1.6 versus 5.4+/-1.0 mmol/L; P=0.001), and were affected >10 years earlier by premature coronary artery disease (35.2+/-4.8 versus 46.8+/-8.9 years; P=0.002). LDL from PCSK9 patients competed significantly less well for binding to fibroblast LDL receptors than LDL from either controls or LDLR patients. CONCLUSIONS: These British PCSK9 patients with the D374Y mutation have an unpredictably severe clinical phenotype, which may be a unique feature for this cohort, and requires early and aggressive lipid-lowering management to prevent cardiovascular complications.
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