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Mortality from familial hypercholesterolemia (FH). Eric Sijbrands. resume.

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eric sijbrands
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
Learning objectives
  • selection on outcome
  • standardization
  • burden of monogenetic disorder
  • genetic heterogeneity
  • gene-environment interaction
performance objectives
Performance objectives

understand the clinical consequences of monogenetic disorders

fh characteristics
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
FH - what is already known

introduction

  • cardiovascular disease

at young age

  • excess mortality
  • population data are lacking
burden of untreated fh
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 disorder9

cause disease death

additional factors

Monogenetic disorder

introduction

natural history
Natural history

introduction

large pedigree fh v408m
Large pedigree: FH-V408M

introduction

Sijbrands EJG, et al. BMJ 2001;322:1019-23.

standardization
Standardization

introduction

SMR = observed / expected deaths

strata per gender

strata per age category

strata per calendar period

slide13
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)
slide14
SMR

large pedigree

kaplan meier
Kaplan-Meier

large pedigree

conclusion 1
Conclusion 1

large pedigree

gene-environment

interaction

113 small pedigrees
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.

113 fh patients
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

slide19
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)

slide20
SMR

outpatient lipid clinic

other risk factors
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

type of ldlr mutation
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

type of ldlr mutation23
Type of LDLR mutation

outpatient lipid clinic

conclusion 2
Conclusion 2

outpatient lipid clinic

  • other risk factors for CVD
  • type of mutation is not relevant
fh what these studies add
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
Future ...
  • individual risk
    • molecular diagnosis
    • additional genes
    • environmental factors
  • exact indication for

tailored intervention