Browsing by Author "Humphries, S.E."
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- Applicability of the low-density lipoprotein cholesterol gene score in a south European populationPublication . Mariano, C.; Futema, M.; Humphries, S.E.; Bourbon, M.Aim: The correct identification of the dyslipidaemia is of great importance in order to implement specific interventions, especially for cardiovascular disease (CVD) prevention. The Global Lipids Genetics Consortium (GLGC) reported 158 loci associated with lipid traits, by genome-wide association studies (GWAS), although practical value of GWAS approach is still a subject of debate, half of these loci are previously known to influence serum lipid concentrations. Previous studies (Talmud et al., 2013; Futema et al., 2015) have demonstrated that the co-inheritance of low-density lipoprotein (LDLC)-raising alleles from 6 of these SNPs is associated with the Familial Hypercholesterolaemia (FH) phenotype. Here we investigated the applicability of the LDL-C genetic risk score in the Portuguese FH population.
- FH Phenotype: monogenic, polygenic and other causesPublication . Mariano, C.; Alves, A.C.; Medeiros, A.M.; Chora, J.R.; Futema, M.; Humphries, S.E.; Bourbon, M.Familial Hypercholesterolaemia (FH) is a monogenic lipid disorder caused by mutations in LDLR, APOB, and PCSK9 genes. However, 50% of individuals with clinical diagnosis of FH do not have a mutation in one of these three genes, so other causes for their phenotype must exist. The FH phenotype has been associated recently to other monogenic disorders as lysosomal acid lipase deficiency (LALD) and sitosterolaemia or can have a polygenic origin. The aim of this work was to characterize the origin of the FH phenotype in a cohort of patients with clinical diagnosis of FH.
- Recommendations for LDLR variant interpretation by the ClinGen’s Familial Hypercholesterolemia Expert PanelPublication . Chora, J.R.; Iacocca, M.; Tichy, L.; Wand, H.; Kurtz, L.C.; Zimmermann, H.; Meredith, A.L.; Williams, M.; Humphries, S.E.; Hooper, A.J.; Brunham, L.; Pereira, A.C.; Chen, M.; Wang, J.; Trinder, M.; Jannes, C.E.; Chonis, J.; Kim, S.; Pesaran, T.; Johnston, T.; Carrie, A.; Leigh, S.; Hegele, R.A.; Sijbrands, E.; Freiberger, T.; Knowles, J.W.; Bourbon, M.Familial Hypercholesterolemia (FH): - Lipid metabolism autosomal dominant condition; - Elevated low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) values since childhood → increased risk of atherosclerotic cardiovascular disease; - High heterozygote prevalence (1/250-1/500); Homozygous rare (1/ 300 000- 1/ 1 000 000); - Caused by pathogenic variants in LDLR (>90%), APOB (5- 10%) and PCSK9 (1-3%) genes; -Marked increase in FH variants submitted to ClinVar; -45% of variants were classified with more than one method and 466 variants submitted with potential clinical significance had conflicting or no classifications.
- Specification of ACMG/AMP guidelines for standardized variant interpretation in familial hypercholesterolemia: On behalf of the ClinGen FH Variant Curation Expert PanelPublication . Iacocca, M.A.; Chora, J.R.; Freiberger, T.; Carrie, A.; Sijbrands, E.J.; Wand, H.; Williams, M.; Kurtz, C.L.; Tichy, L.; Alves, A.C.; Zimmermann, H.; Meredith, A.; Wang, J.; Cuchel, M.; Hooper, A.J.; Humphries, S.E.; Defesche, J.C.; Santos, R.D.; Kullo, I.J.; Brunham, L.R.; Hegele, R.A.; Knowles, J.W.; Bourbon, M.Familial Hypercholesterolemia (FH): Lipid metabolism autosomal dominant condition; Patients present elevated low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) values since childhood → increased risk of atherosclerotic cardiovascular disease; High heterozygote prevalence (1/250); Homozygous rare (1/1 000 000); Caused by pathogenic variants in LDLR (>90%), APOB (5-10%) and PCSK9 (1-3%) genes.
- The applicability of the low-density lipoprotein cholesterol gene score in the Portuguese populationPublication . Mariano, C.; Futema, M.; Humphries, S.E.; Bourbon, M.Aim: The correct identification of the dyslipidaemia is of great importance in order to implement specific interventions, especially for cardiovascular disease (CVD) prevention. The Global Lipids Genetics Consortium (GLGC) reported 158 loci associated with lipid traits, by genome-wide association studies (GWAS), although practical value of GWAS approach is still a subject of debate, half of these loci are previously known to influence serum lipid concentrations. Previous studies (Talmud et al., 2013; Futema et al., 2015) have demonstrated that the co-inheritance of low-density lipoprotein (LDL-C)-raising alleles from 6 of these SNPs is associated with the Familial Hypercholesterolaemia (FH) phenotype. Here we investigated the applicability of the LDL-C genetic risk score in the Portuguese FH population.
- The familial hypercholesterolaemia phenotype: monogenic familial hypercholesterolaemia, polygenic hypercholesterolaemia and other causesPublication . Mariano, C.; Alves, A.C.; Medeiros, A.; Chora, J.R.; Antunes, M.; Futema, M.; Humphries, S.E.; Bourbon, M.Familial Hypercholesterolaemia (FH) is a monogenic disorder characterised by high LDL-C concentrations and increased cardiovascular risk. However, in clinically defined FH cohorts worldwide, an FH-causing variant is only found in 40-50% of the cases. The aim of this work was to characterise the genetic cause of the FH phenotype in Portuguese clinical FH patients. Methods and Results Between 1999 and 2017, 731 index patients (311 children and 420 adults) who met the Simon Broome diagnostic criteria had been referred to our laboratory. LDLR, APOB, PCSK9, APOE, LIPA, LDLRAP1, ABCG5/8 genes were analysed by PCR amplification and Sanger sequencing. The 6-SNP LDL-C genetic risk score (GRS) for polygenic hypercholesterolaemia was validated in the Portuguese population and cases with a GRS over the 25th percentile were considered to have a high likelihood of polygenic hypercholesterolaemia. An FH-causing mutation was found in 39% of patients (94% in LDLR, 5% APOB and 1% PCSK9), while at least 29% have polygenic hypercholesterolaemia and 1% have other lipid disorders. A genetic cause for the FH phenotype was found in 503 patients (69%). All known causes of the FH phenotype should be investigated in FH cohorts to ensure accurate diagnosis and appropriate management.
- The FH phenotype: monogenic familial hypercholesterolaemia, polygenic dyslipidaemia and other causesPublication . Mariano, C.; Medeiros, A.M.; Alves, A.C.; Chora, J.R.; Futema, M.; Humphries, S.E.; Antunes, M.; Bourbon, M.Introduction: (i) Cardiovascular disease (CVD), particularly coronary heart disease (CHD) and stroke, are the leading cause of morbidity and mortality worldwide; (ii) Dyslipidaemia is an important but modifiable cardiovascular risk factor. For instance, Familial Hypercholesterolaemia (FH) is a monogenic autosomal condition where patients present very high LDL-C values and an increase cardiovascular risk; (iii) FH is caused by mutations in 3 genes: LDLR, APOB and PCSK9. However in only about 40%-50% of the cases an FH causing mutation is found.
- The FH phenotype: monogenic familial hypercholesterolaemia, polygenic dyslipidaemia and other causesPublication . Mariano, C.; Antunes, M.; Medeiros, A.M.; Alves, A.C.; Futema, M.; Humphries, S.E.; Bourbon, MafaldaFamilial hypercholesterolaemia (FH) is a monogenic autosomal condition where patients present very high LDL-C values and an increase cardiovascular risk. FH is caused by mutations in 3 genes: LDLR, APOB and PCSK9. However in only about 40%-50% of the cases an FH causing mutation is found. The FH phenotype has been associated recently to other monogenic disorders as lysosomal acid lipase deficiency or can have a polygenic origin. The aim of this work was to characterize the origin of FH phenotype in a cohort of patients with a clinical diagnosis of FH.
- To Correct or not to Correct (for treatment): Estimating Pre-treatment LDL-C Concentrations in Genetically Characterized Patients with Familial Hypercholesterolaemia on Lipid-lowering MedicationPublication . Stevens, C.A.T.; Elshorbagy, A.; Vallejo-Vaz, A.J.; Dharmayat, K.; Lyons, A.; Bourbon, M.; Chora, J.; Humphries, S.E.; Catapano, A.L.; Hovingh, G.; Mata, P.; Santos, R.; Soran, H.; Watts, G.F.; Raal, F.; Freiberger, T.; Ray, K.K.; on behalf of all the EAS FHSC CollaboratorsBackground and Aims: Pretreatment LDL-C measurements aid familial hypercholesterolaemia (FH) diagnosis, and are crucial in epidemiologic studies investigating FH, but are often unavailable because individuals are already on lipid-lowering medication (LLM). Several formulae have been reported to estimate pre-treatment LDL-C in people on LLM by ‘correcting’ their LDL-C concentrations for LLM type and dosage, based on observational or trial evidence of drug efficacy. We compared 4 published correction factors in estimating pre-treatment LDL-C in patients with FH. Methods: Cross-sectional analysis of adults with pathogenic/likely-pathogenic FH variants in the EAS-FH Studies Collaboration (FHSC) Registry. At the time of LDL-C measurement, N=3012 participants were not on LLM (Untreated group), and N=3226 were on LLM monotherapy, with information on LLM type and dosage allowing estimation of pre-treatment LDL-C (Corrected group) based on correction factors by Ruel 2018, Ellis 2016, Haralambos 2015 and Besseling 2014. We compared the groups for clinical characteristics and LDL-C by gene and variant. Results: The Corrected group was older than the Untreated group (median[IQR]: 50[39,63] vs. 38[28,50]y), with similar proportion of women (54.5% vs. 56.8%;p=0.14) but more comorbidities (all p<0.001). In the Corrected group, 3120 were on statins, 106 on ezetimibe, none on PCSK9-inhibitors. The Corrected group had higher LDL-C vs. Untreated group, with the difference greater at upper percentiles, regardless of correction factor. LDL-C was highest in those with LDLR>APOB>PCSK9 gene variants, but Corrected was still higher than Untreated LDL-C within each gene group. The difference in Corrected vs. Untreated LDL-C varied by variant, from +0.6 to +3.5mmol/L (20 commonest variants). The LDL-C differences persisted after adjusting for age, sex and comorbidities. Conclusions: Application of current LDL-C correction factors appears to overestimate pre-treatment LDL-C in epidemiologic settings, or the Untreated and Corrected groups might have inherently different LDL-C profiles. The accuracy of using LDL-C correction factors in FH therefore warrants further investigation.