Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database.

Familial hypercholesterolemia (FH) (OMIM 143890) is most commonly caused by variations in the LDLR gene which encodes the receptor for Low Density Lipoprotein (LDL) cholesterol particles. We have updated the University College London (UCL) LDLR FH database (http://www.ucl.ac.uk/ldlr) by adding variants reported in the literature since 2001, converting existing entries to standard nomenclature, and transferring the database to the Leiden Open Source Variation Database (LOVD) platform. As of July 2007 the database listed 1066 unique LDLR gene events. Sixty five percent (n = 689) of the variants are DNA substitutions, 24% (n = 260) small DNA rearrangements (<100bp) and 11% (n = 117) large DNA rearrangements (>100bp), proportions which are similar to those reported in the 2001 database (n = 683, 62%, 24% and 14% respectively). The DNA substitutions and small rearrangements occur along the length of the gene, with 24 in the promoter region, 86 in intronic sequences and 839 in the exons (93 nonsense variants, 499 missense variants and 247 small rearrangements). These occur in all exons, with the highest proportion (20%) in exon 4 (186/949); this exon is the largest and codes for the critical ligand binding region, where any missense variant is likely to be pathogenic. Using the PolyPhen and SIFT prediction computer programmes 87% of the missense variants are predicted to have a deleterious effect on LDLR activity, and it is probable that at least 48% of the remainder are also pathogenic, but their role in FH causation requires confirmation by in vitro or family studies.

Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk.

AIMS: To determine the relative frequency of mutations in three different genes (low-density lipoprotein receptor (LDLR), APOB, PCSK9), and to examine their effect in development of coronary heart disease (CHD) in patients with clinically defined definite familial hypercholesterolaemia in UK. PATIENTS AND METHODS: 409 patients with familial hypercholesterolaemia patients (158 with CHD) were studied. The LDLR was partially screened by single-strand conformational polymorphism (SSCP) (exons 3, 4, 6-10 and 14) and by using a commercial kit for gross deletions or rearrangements. APOB (p.R3500Q) and PCSK9 (p.D374Y) were detected by specific assays. Coding exons of PCSK9 were screened by SSCP. RESULTS: Mutations were detected in 253 (61.9%) PATIENTS: 236 (57.7%) carried LDLR, 10 (2.4%) carried APOB p.Q3500 and 7 (1.7%) PCSK9 p.Y374. No additional mutations were identified in PCSK9. After adjusting for age, sex, smoking and systolic blood pressure, compared to those with no detectable mutation, the odds ratio of having CHD in those with an LDLR mutation was 1.84 (95% CI 1.10 to 3.06), for APOB 3.40 (0.71 to 16.36), and for PCSK9 19.96 (1.88 to 211.5; p = 0.001 overall). The high risk in patients carrying LDLR and PCSK9 p.Y374 was partly explained by their higher pretreatment cholesterol levels (LDLR, PCSK9 and no mutation, 10.29 (1.85), 13.12 and 9.85 (1.90) mmol/l, respectively, p = 0.001). The post-statin treatment lipid profile in PCSK9 p.Y374 carriers was worse than in patients with no identified mutation (LDL-C, 6.77 (1.82) mmol/l v 4.19 (1.26) mmol/l, p = 0.001, HDL-C 1.09 (0.27) mmol/l v 1.36 (0.36) mmol/l, p = 0.03). CONCLUSIONS: The higher CHD risk in patients carrying PCSK9 p.Y347 or a detected LDLR mutation supports the usefulness of DNA testing in the diagnosis and management of patients with familial hypercholesterolaemia. Mutations in PCSK9 appear uncommon in patients with familial hypercholesterolaemia in UK.