Download Eric Sijbrands

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
additional factors
death
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.
50% 70
 100% 30

SMR (95%CI)
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
1
8
4
0
1
8
7
0
1
9
0
0
1
9
3
0
1
9
6
0
1
9
9
0
C
a
l
e
n
d
a
r
p
e
r
i
o
d
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
p.y.
11091
10796
6317
2973
688
184
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)
190
32048
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
A
g
e
(
y
e
a
r
s
)
9
0
Other risk factors
outpatient lipid clinic
premature CVD SMR 95% CI
– (51 families)
+ (62 families)
1.10
1.62
0.86-1.34
1.32-1.93
RR+ versus –
1.46
1.09-1.94
Type of LDLR mutation
outpatient lipid clinic
characteristic mRNA +
(n=24)
mRNA (n=14)
p
male, %
age
BMI
xanthomas, %
LDL-C
HDL-C
43
47
25.1
93
10.21
1.04
0.4
0.4
1.0
0.001
0.04
0.05
58
50
25.1
42
8.86
1.20
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