Mortality from familial hypercholesterolemia (FH)

1. Mortality from familial hypercholesterolemia (FH)

2. Eric Sijbrands resume Eric Sijbrands is consultant in internal medicine and head of the lipid clinic of the Erasmus University Medical Center Rotterdam. After he obtained his qualification as medical doctor in 1990, he was given the opportunity to receive his training in internal medicine and to work in scientific research at the Universities of Leiden and Amsterdam. He made a Ph.D. thesis on gene-gene and gene-environment interaction in patients with genetic hyperlipidemia. His present research is focussed on genetic epidemiology of cardiovascular disease (hyperlipidemia, diabetes mellitus, and pharmacogenetics of hypertension).

3. Learning objectives • selection on outcome • standardization • burden of monogenetic disorder • genetic heterogeneity • gene-environment interaction

4. Performance objectives understand the clinical consequences of monogenetic disorders

5. FH - characteristics introduction • autosomal dominant • heterozygosity 1:500 • mutations in the LDL receptor gene on chromosome 19 • total cholesterol > 8 mmol/L • tendon xanthomas

6. FH - what is already known introduction • cardiovascular disease at young age • excess mortality • population data are lacking

7. Burden of untreated FH introduction • analyses of mortality in: • a large pedigree ‘free from selection on CVD’ • 113 small pedigrees referred to a lipid clinic

8. cause disease death Monogenetic disorder introduction

9. cause disease death additional factors Monogenetic disorder introduction

10. Natural history introduction

11. Large pedigree: FH-V408M introduction Sijbrands EJG, et al. BMJ 2001;322:1019-23.

12. Standardization introduction SMR = observed / expected deaths strata per gender strata per age category strata per calendar period

13. SMR large pedigree • V408M death p.y. SMR (95%CI) • 50% 70 6950 1.32 (1.03-1.67) • 100% 30 3186 1.59 (1.07-2.26)

14. SMR large pedigree

15. Kaplan-Meier large pedigree

16. Conclusion 1 large pedigree gene-environment interaction

17. 113 small pedigrees outpatient lipid clinic number cardiologist 39 GP 51 insurance 4 other 19 total 113 Sijbrands EJG, et al. Atherosclerosis 1998;136:247-54.

18. 113 FH patients outpatient lipid clinic characteristic n=113 male / female 55/58 age 48 (20 to 69) xanthomas 66 cholesterol 11.04 mmol/L

19. SMR outpatient lipid clinic age deaths p.y. SMR (95%CI) 1- 19 6 11091 0.45 (0.17-0.98) 20- 39 12 10796 1.01 (0.52-1.76) 40- 54 43 6317 1.88 (1.36-2.53) 55- 69 69 2973 1.76 (1.36-2.22) 70- 79 38 688 1.22 (0.87-1.68) 80-103 22 184 0.96 (0.60-1.46) 1-103 190 32048 1.34 (1.16-1.55)

20. SMR outpatient lipid clinic

21. Other risk factors outpatient lipid clinic premature CVD SMR 95% CI – (51 families) 1.10 0.86-1.34 + (62 families) 1.62 1.32-1.93 RR+ versus –1.46 1.09-1.94

22. Type of LDLR mutation outpatient lipid clinic characteristic mRNA + mRNA - p (n=24) (n=14) male, % 58 43 0.4 age 50 47 0.4 BMI 25.1 25.1 1.0 xanthomas, % 42 93 0.001 LDL-C 8.86 10.21 0.04 HDL-C 1.20 1.04 0.05

23. Type of LDLR mutation outpatient lipid clinic

24. Conclusion 2 outpatient lipid clinic • other risk factors for CVD • type of mutation is not relevant

25. FH - what these studies add • many untreated patients (40%) reach a normal life span • burden of FH depends on time • variation in mortality suggests an interaction between genetic and environmental CVD risk factors

26. Future ... • individual risk • molecular diagnosis • additional genes • environmental factors • exact indication for tailored intervention