Mortality from familial hypercholesterolemia (FH)
Eric Sijbrands
Erasmus University Medical Center Rotterdam
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).
Learning objectives
selection on outcome standardization burden of monogenetic disorder genetic heterogeneity gene-environment interaction
Performance objectives
understand the clinical consequences of monogenetic disorders
FH - characteristics
introduction
autosomal dominant heterozygosity 1:500 mutations in the LDL receptor gene on chromosome 19 total cholesterol > 8 mmol/L tendon xanthomas
FH - what is already known
introduction
cardiovascular disease at young age excess mortality population data are lacking
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
Monogenetic disorder
introduction cause disease death
Monogenetic disorder
introduction cause disease death
additional factors
Natural history
introduction
Large pedigree: FH-V408M
introduction
Sijbrands EJG, et al. BMJ 2001;322:1019-23.
Standardization
introduction
SMR = observed / expected deaths strata per gender strata per age category strata per calendar period
SMR
large pedigree
V408M
death p.y.
SMR (95%CI)
50% 70 100% 30
6950 1.32 (1.03-1.67) 3186 1.59 (1.07-2.26)
SMR
large pedigree
3 . 0 2 . 0
SMR
1 . 0
0 . 5 F e m a l e s M a l e s 111111 889999 470369 000000 Ce ap ldo er ni ad r
Kaplan-Meier
large pedigree
Conclusion 1
large pedigree
gene-environment interaction
113 small pedigrees
outpatient lipid clinic
number cardiologist GP insurance other total 39 51 4 19 113
Sijbrands EJG, et al. Atherosclerosis 1998;136:247-54.
113 FH patients
outpatient lipid clinic
characteristic n=113 male / female age xanthomas cholesterol 55/58 48 (20 to 69) 66 11.04 mmol/L
SMR
outpatient lipid clinic age 1- 19 20- 39 40- 54 55- 69 70- 79 80-103 1-103 deaths 6 12 43 69 38 22 190 p.y. 11091 10796 6317 2973 688 184 32048 SMR 0.45 1.01 1.88 1.76 1.22 0.96 (95%CI) (0.17-0.98) (0.52-1.76) (1.36-2.53) (1.36-2.22) (0.87-1.68) (0.60-1.46)
1.34 (1.16-1.55)
SMR
outpatient lipid clinic
3 . 0 2 . 0
SMR
1 . 0
0 . 5 F e m a l e s M a l e s 3 0 5 0 7 0 9 0
As g ) e ( y e a r
Other risk factors
outpatient lipid clinic
premature CVD SMR 95% CI – (51 families) + (62 families) RR+ versus – 1.10 1.62 1.46 0.86-1.34 1.32-1.93 1.09-1.94
Type of LDLR mutation
outpatient lipid clinic characteristic mRNA + (n=24)
male, % age BMI xanthomas, % LDL-C HDL-C 58 50 25.1 42 8.86 1.20
mRNA (n=14)
43 47 25.1 93 10.21 1.04
p
0.4 0.4 1.0 0.001 0.04 0.05
Type of LDLR mutation
outpatient lipid clinic
Conclusion 2
outpatient lipid clinic
other risk factors for CVD type of mutation is not relevant
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
Future ...
individual risk – molecular diagnosis – additional genes – environmental factors exact indication for tailored intervention