The Molecular and Clinical Heterogeneity of FH

1. The Molecular and Clinical Heterogeneity of FH • G.Kees Hovingh MD PhD • AMC, Amsterdam, the Netherlands • g.k.hovingh@amc.uva.nl

2. Disclaimer Dr. Kees Hovingh is consultant and speaker for biotech as well as pharmaceutical companies that develop molecules that influence lipoprotein metabolism, including Regeneron, Pfizer, MSD, Sanofi, Amgen, Roche and Genzyme Kees Hovingh is head of the Clinical Trial Unit of the department of Vascular Medicine at the AMC, Amsterdam, and PI for clinical trials in dyslipidemia conducted with i.e. Amgen, Sanofi, Lilly, Novartis, Kowa, Genzyme, Cerenis, Pfizer, Astra. The department receives the honoraria and investigator fees.

3. FH, the traditional picture...

4. The same genotype may lead to extremely different phenotypes

5. And people might look alike while not sharing the genotype.. 8

6. FH diagnosis clinical +, mutation - Simon Broome Dutch Lipid Criteria Clinical diagnosis Molecular diagnosis clinical -, mutation +

7. Molecular diagnosis FH; “one disease?” patient: treat LDL-C family: “monitor LDL-C” clinical +, mutation - patient: treat LDL-C family: mutation test consider to treat LDLC Clinical diagnosis clinical +, mutation + EAS-consensus patient: monitor LDL-C family: monitor LDL-C clinical -, mutation + Intervention is based on LDL-C, not on genetic result Nordestgaard B et al Eur H J 2013;34:3478

8. Range of LDL-C in heFH? Besseling, Hovingh, work in progress

9. HoADH in the Netherlands + 2 null alleles 1 null allele, 1 defective 2 defective alleles

10. HoADH in the Netherlands

11. Clinical Heterogeneity in daily life, outpatient clinic setting august 2015....

12. “DC, please analyze CVD risk in mother of 9 year old boy with FH seen @ my outpatient clinic, best Bert Wiegman (BTW; I ordered lab for her, she’ll bring it)” Clinical Heterogeneity in daily life, outpatient clinic setting august 2015.... referal letter:

13. LDL-C 9mmol/L AMI age 51 LDL-C 3 mmol/L LDL-C 6.5 mmol/L

14. LDL-C 9mmol/L AMI age 51 APOB truncation?? LDL-C 3 mmol/L Genetic analysis would help in this family LDL-C 6.5 mmol/L

15. FH; a matter of selection bias? LDL-C 9mmol/L AMI age 51 LDL-C 6 mmol/L LDL-C 3 mmol/L

16. Is the FH phenotype (LDL-C and CVD) attenuated with increasing distance-to-index?

17. Index Subject for FH 1) Medical information 2) DNA Analysis 1) Medical information 2) DNA Analysis Mutation + approach 1st degree relatives 1) Medical information 2) DNA Analysis etc NO mutation: cascade stops in this branch Mutation + approach 1st degree relatives Data - collection • FH screening program in the Netherlands (‘94 - ‘14) • Genetic cascade approach • Questionnaire and blood sample (lipids since ‘04)

19. Study population

20. Description heterozygous FH

21. heFH; clinical diverse

22. CVD incidence in heterozygous FH

23. Does genetics matter? Huijgen, Eur H J 2012 3(18):2325-30

24. Does genetics matter? No !!!

25. Clinical diagnosis Another benefit of genetic analysis in FH The new PCSK9?? if we do not sequence; we will not get to this! clinical +, mutation - Molecular diagnosis clinical -, mutation +

26. ??? PCSK9 APOB LDLR “with every success it gets harder to find the next one”

27. Conclusion 1) FH; a diverse disease: LDL-C is the driver, not genetics 2) No “devaluation” of phenotype in families: CVD risk and LDL-C 3) Genetics do help! 4) without molecular biology: no novel insights!