Sjouke, B.

English

Familial hypercholesterolemia (FH) is an inherited disorder of cholesterol metabolism, resulting in increased LDL-cholesterol levels and, as a consequence, an increased risk for coronary heart disease. Recently, many causal FH mutations in different genes have been identified and advances in genetic diagnostics have provided more insight into the relation between different FH genotypes (e.g. type of mutation) and their phenotypic expression (e.g. LDL-C level, coronary heart disease), and vice versa. Part I (chapter 2 to 10) of this thesis describes recent studies on genotype-phenotype relations in familial forms of hypercholesterolemia. The author describes that the prevalence of FH is much higher as compared with the historical prevalence described in 1973 (~1:250 instead of 1:500 individuals). Moreover, the author shows that the phenotype of patients with FH mutations is very variable and, among others, overlaps with a lysosomal storage disease, called cholesteryl-ester storage disease. Part II (chapter 11 to 18) focuses on the management for patients with FH, and describes both current as well as future treatment perspectives for this patient population

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UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl)UvA-DARE (Digital Academic Repository)Extreme phenotypes in hypercholesterolemiaFrom genotype to therapySjouke, B.Publication date2017Document VersionOther versionLicenseOtherLink to publicationCitation for published version (APA):Sjouke, B. (2017). Extreme phenotypes in hypercholesterolemia: From genotype to therapy.[Thesis, fully internal, Universiteit van Amsterdam].General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s)and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an opencontent license (like Creative Commons).Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, pleaselet the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the materialinaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letterto: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. Youwill be contacted as soon as possible.Download date:09 Mar 2023Processed on: 28-12-2016507245-L-sub01-bw-SjoukeChapter 3Homozygous Autosomal Dominant Hypercholesterolemia in the Netherlands:  and Clinical OutcomeB. Sjouke, D.M. Kusters, I. Kindt, J. Besseling, J.C. Defesche, E.J. Sijbrands, J.E. Roeters van Lennep Stalenhoef, A. Wiegman, J. de Graaf, S.W. , J.J. Kastelein, and G.K. HovinghEuropean Heart Journal 2015 Mar 1; 36(9): 560-5.Processed on: 28-12-2016507245-L-sub01-bw-Sjouke28Chapter 33ABSTRACTBackgroundLDLR APOBPCSK9i.e. the Netherlands. Methods and ResultsLDLRAPOB PCSK9Conclusionphenotype is more variable than previously assumed. In light of the fact that novel therapies are, to be eligible for these novel agents. Processed on: 28-12-2016507245-L-sub01-bw-Sjouke29Homozygous Autosomal Dominant Hypercholesterolemia in the Netherlands3INTRODUCTIONLDLR APOBPCSK91,2in the 1990s.LDLR6-8 It is also criteria.9Scotland and Wales.10,11METHODSProcessed on: 28-12-2016507245-L-sub01-bw-Sjouke30Chapter 33LDLR, APOB, or PCSK9. Since the Hardy–Weinberg LDLR and an APOBCenter, Amsterdam, the Netherlands. 12  In case not all criteria Dunnen and Antonarakis.14 LDLR and APOBt-tests and Mann-Whitney U tests, PLDLR1 APOBLDLRp2, heterozygosity = 2pq, q2, and p qProcessed on: 28-12-2016507245-L-sub01-bw-Sjouke31Homozygous Autosomal Dominant Hypercholesterolemia in the Netherlands3RESULTSin either LDLR or APOBAPOB and LDLR Figure 1LDLR4 homozygotes for APOB Table 1APOB or bi-allelic PCSK9(nLDLRFigure 1.Processed on: 28-12-2016507245-L-sub01-bw-Sjouke32Chapter 33Table 1.Homozygotes Compound Heterozygotes LDLRLDLR APOB20 4 CHD    LDL-C 7.8  LDL-C Drug therapy‡  inhibitor – LDL-apheresisLDLRfor APOB LDLRhomozygous LDLR LDLR APOBLDLRLDLR APOB LDLR LDLR APOBLDLR LDLRAPOB LDLR APOB LDLR.Prevalencep2 pq = 1–p pqProcessed on: 28-12-2016507245-L-sub01-bw-Sjouke33Homozygous Autosomal Dominant Hypercholesterolemia in the Netherlands3PhenotypesFigure 2n/L, n 2520151050Prior to LLT A�er LLTLDL-C levels (mmo/L)Figure 2. ■program. Psuch they did not meet the clinical criteria for hoADH.99allelic LDLRProcessed on: 28-12-2016507245-L-sub01-bw-Sjouke34Chapter 33age of 69 years. Table 1or more,16Supplementary Material, Tables S1 and S2. DISCUSSION6previously addressed in a cohort size like ours.17967,8,18,191818,19 Processed on: 28-12-2016507245-L-sub01-bw-Sjouke35Homozygous Autosomal Dominant Hypercholesterolemia in the Netherlands32011.6,20prevalence of heterozygous ADH in the Netherlands2122prevalence of hoADH. As a consequence, these data could probably be extrapolated to other 1,9 It is 94study, sequencing of LDLR and APOB24Processed on: 28-12-2016507245-L-sub01-bw-Sjouke36Chapter 33screening strategies.2627 Moreover, the 28in the LDLR have been described to cause ADH.29LDLRAPOB, , or PCSK9 or to lifestyle factors.Processed on: 28-12-2016507245-L-sub01-bw-Sjouke37Homozygous Autosomal Dominant Hypercholesterolemia in the Netherlands3APOB Processed on: 28-12-2016507245-L-sub01-bw-Sjouke38Chapter 33REFERENCES1. Hypercholesterolemia. In: Scriver C, Beaudet A, 2. Kolansky DM, Cuchel M, Clark BJ, et al. zygous familial hypercholesterolemia. American hypercholesterolemia: a long term cohort study. 4. EAS Guidelines for the management of management of dyslipidaemias of the European 6. EL, Motulsky AG. Hyperlipidemia in coronary disorder, combined hyperlipidemia. Journal of 7. of hypercholesterolemic homozygotes in South 8. Moorjani S, Roy M, Gagne C, et al. Homozygous Canadians in Quebec Province. Arteriosclerosis 9. 10. 11. 12. van der Graaf A, Avis HJ, Kusters DM, et al. Molecular basis of autosomal dominant hyper-cholesterolemia: assessment in a large cohort receptor and apolipoprotein B in individuals 14. nl-nl/menu/cijfers/default.htm.16. Wierzbicki AS, Humphries SE, Minhas R. 17. familial hypercholesterolemia. Atherosclerosis 18. familial hypercholesterolemia in Lebanon: a 19. hypercholesterolemia in the Hokuriku district of 20. StOEH. StOEH Annual Report 2011, 2012.21. hypercholesterolemia than expected in adult 22. coronary artery disease, and cholesterol-Processed on: 28-12-2016507245-L-sub01-bw-Sjouke39Homozygous Autosomal Dominant Hypercholesterolemia in the Netherlands39.24. density lipoprotein receptor or apolipoprotein Nordestgaard BG, Chapman MJ, Humphries SE, diagnosed and undertreated in the general coronary heart disease: Consensus Statement of the European Atherosclerosis Society. European 26. analysis of cascade screening for familial hyper-27. the American Society for Apheresis. Journal of 28. autosomal dominant hypercholesterolemia 29. Humphries SE. Update and analysis of the receptor familial hypercholesterolemia database. of pathogenic autosomal dominant hyper-Determinants of lipid levels among children Processed on: 28-12-2016507245-L-sub01-bw-Sjouke40Chapter 33SUPPLEMENTARY MATERIALSupplementary Table 1.Common  nomenclaturecDNA/proteinGeneAge SexCurrent treatmentFirst event (age)TC  untreatedLDL-C  untreated TC treated LDL-C treated  LDLR24MNone17.816.911.19.0LDLR6None 21.920.8LDLR40LDL-apheresis 20.2NA 6.7–2.1*4.9–1.0*LDLR LDL-apheresis22.4G186G splice defectLDLRMNone12.010.46.9G186G splice defectLDLR2914.86.6LDLR67MNone8.6LDLRNA8.0NALDLRMNone14.212.110.7LDLR11None21.620.17.4–2.9*6.2–2.0* LDLRNANA6.74.4NANALDLR72M9.0NA6.24.8Processed on: 28-12-2016507245-L-sub01-bw-Sjouke41Homozygous Autosomal Dominant Hypercholesterolemia in the Netherlands3Common  nomenclaturecDNA/proteinGeneAge SexCurrent treatmentFirst event (age)TC  untreatedLDL-C  untreated TC treated LDL-C treated LDLRMNALDLRNoneNALDLR24None6.94.2LDLR48M 12.0NANANALDLRNone7.6LDLR28MNone11.810.67.1LDLR26None18.27.0LDLR14None 9.78.47.26.0APOB62NANoneNANANAAPOBNone9.67.8APOB77MAbdominal aneurysm 10.1NANA4.2APOBNANANANA9.2Processed on: 28-12-2016507245-L-sub01-bw-Sjouke42Chapter 33Supplementary Table 2.Common nomenclaturecDNA/proteinAgeSexTreatmentFirst  event  (age)TC untreatedLDL-C untreated TC  treated LDL-C treated  exon 7-84.4 kb 9-12 in intron 12 21Mlaropiprant 2000/40 None20.118.911.0 exon 7-84.4 kb 9-12 in intron 12 18colesevelam acid/laropiprant 1000/20 None18.917.712.0 exon 7-8 2000 None8.04.1promoter and  exon 1LDL-apheresis None19.8NA10/14–4.0*promoter and  exon 1M, None 17.8NA12.7 exon 12-1824Mcolesevelam None16.07.86.81480del121bp M18.0NA6.6Processed on: 28-12-2016507245-L-sub01-bw-Sjouke43Homozygous Autosomal Dominant Hypercholesterolemia in the Netherlands3Common nomenclaturecDNA/proteinAgeSexTreatmentFirst  event  (age)TC untreatedLDL-C untreated TC  treated LDL-C treated 2No16.614.212.6cx2401del]/ M10.88.42417insGc.2416dup/9MNone20.12417insG c.2416dup/ 27laropiprant 1000/20 19.918.812.610.82417insG c.2416dup/ 16MNone18.917.29.98.4p.Cys222* 49MNANANANANAp.Asp266Glu2401del]/ None10.1p.Asp266Glu2401del]/ 29 None10.0 M8.7 6.92.8Processed on: 28-12-2016507245-L-sub01-bw-Sjouke44Chapter 33Common nomenclaturecDNA/proteinAgeSexTreatmentFirst  event  (age)TC untreatedLDL-C untreated TC  treated LDL-C treated D461NN407K p.Asp482Asn p.Asn428LysM40 mg/day, None9.0NA4.7D461NN407K p.Asp482Asnp.Asn428Lys61M2.9G186GSplice defect None12.09.7G186GSplice defect McolesevelamNANA6.8 46None10.02.6 17MNone11.29.44.8 NANANA NANANA 29MNoneNANA None4.9

Extreme phenotypes in hypercholesterolemia:From genotype to therapy

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Extreme phenotypes in hypercholesterolemia:From genotype to therapy

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