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The Molecular and Clinical Heterogeneity of
FH
G.Kees Hovingh MD PhDAMC, Amsterdam, the Netherlands
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Disclaimer
Dr. Kees Hovingh is consultant and speaker for biotechas 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.
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FH, the traditional picture...
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The same genotype may lead to extremely different phenotypes
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8
And people might look alike while not sharing the genotype..
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FH diagnosis
Clin
ical
dia
gnos
is
Mol
ecul
ar
diag
nosi
s
clinical +, mutation -
clinical -, mutation +
Simon BroomeDutch Lipid Criteria
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FH; “one disease?”
Clin
ical
dia
gnos
is
Mol
ecul
ar d
iagn
osis
clinical +, mutation -
clinical -, mutation +
EAS-consensus
patient: treat LDL-Cfamily: “monitor LDL-C”
patient: treat LDL-Cfamily: mutation test consider to treat LDLC
patient: monitor LDL-Cfamily: monitor LDL-C
Intervention is based on LDL-C, not on genetic result
clinical +, mutation +
Nordestgaard B et al Eur H J 2013;34:3478
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Range of LDL-C in heFH?
Besseling, Hovingh, work in progress
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HoADH in the Netherlands
2 null alleles+1 null allele, 1 defective
2 defective alleles
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HoADH in the Netherlands
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Clinical Heterogeneity in daily life, outpatient clinic setting august 2015....
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Clinical Heterogeneity in daily life, outpatient clinic setting august 2015....
referal letter:
“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)”
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LDL-C 9mmol/LAMI age 51
LDL-C 3 mmol/L
LDL-C 6.5 mmol/L
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LDL-C 9mmol/LAMI age 51
LDL-C 3 mmol/L
LDL-C 6.5 mmol/L
APOB truncation??
Genetic analysis would help in this family
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LDL-C 9mmol/LAMI age 51
LDL-C 6 mmol/L
LDL-C 3 mmol/L
FH; a matter of selection bias?
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Is the FH phenotype (LDL-C and CVD) attenuated with increasing distance-to-
index?
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Data - collection• FH screening program in the Netherlands (‘94 - ‘14)
• Genetic cascade approach
• Questionnaire and blood sample (lipids since ‘04)
Index Subject for FH
1) Medical information 2) DNA Analysis
NO mutation: cascade stops in this branch
Mutation +approach 1st
degree relatives
1) Medical information 2) DNA Analysis
Mutation +approach 1st
degree relatives
1) Medical information 2) DNA Analysis
etc
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Study population
Degrees of distance-to-index
1 2 3 4 5 6
No. (%) 7,512 (41.9%) 3,887 (21.7%) 1,493 (8.3%) 456 (2.5%) 38 (0.2%) 3 (0%)
Men * 3,568 (47.5%) 1,866 (48%) 735 (49.2%) 232 (50.9%) 22 (57.9%) 1 (33.3%)
Age in age † 40.9 (20.5) 33.1 (21.6) 26 (17.1) 17 (13,0) 16.7 (9.7) 8.9 (2.6)
Year of screening
§ 2006
[2003 - 2009]2006
[2003 - 2009]2007
[2004 - 2010]2009
[2006 - 2011]2008
[2005 - 2011]2001
[2001 - 2007]
Body mass index in kg/m2 †
23.8 (5) 22.6 (5.3) 21.8 (5.2) 19.6 (4.8) 20.1 (5.4) 18.7 (5.7)
Smokers 1,969 (26.2%) 920 (23.7%) 306 (20.5%) 56 (12.3%) 9 (23.7%) 0 (0%)
Alcohol use 3,388 (45.1%) 1,633 (42%) 566 (37.9%) 100 (21.9%) 17 (44.7%) 0 (0%)
CVD in medical history *‡
759 (10.1%) 285 (7.3%) 36 (2.4%) 1 (0.2%) 0 (0%) 0 (0%)
Hypertension * 812 (10.8%) 304 (7.8%) 54 (3.6%) 8 (1.8%) 0 (0%) 0 (0%)
* no. (%); † mean (SE); ‡ Defined as MI, CABG, PTCA, CVA or angina; § median [IQR]
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* no. (%); † mean (SE); § median [IQR]LLT: lipid lowering therapy
Description heterozygous FH
Degrees of distance-to-index
1 2 3 4 5 6
Diabetes * 223 (3%) 84 (2.2%) 21 (1.4%) 1 (0.2%) 0 (0%) 0 (0%)
Statin user * 2,997 (39.9%)
1,050 (27%) 265 (17.7%) 31 (6.8%) 0 (0%) 0 (0%)
User of other LLT *
802 (10.7%) 240 (6.2%) 57 (3.8%) 9 (2%) 0 (0%) 0 (0%)
Lipid profiles (mg/dL)
LDL-C † 211 (80) 199 (75) 189 (72) 177 (65) 190 (77) 168 (152)
HDL-C † 46 (14) 46 (14) 46 (38,67) 53 (0.32) 46 (14) 41 (16)
Triglycerides § 99 [67- 148]
95[66 - 142]
92 [63 - 133]
88 [59 - 133]
90[58 - 123]
134[104 - 190]
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heFH; clinical diverse
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CVD incidence in heterozygous FH
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Does genetics matter?
Huijgen, Eur H J 2012 3(18):2325-30
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Does genetics matter?
No !!!
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Mol
ecul
ar
diag
nosi
s
clinical +, mutation -
clinical -, mutation +
The new PCSK9??
if we do not sequence; we will
not get to this!
Clin
ical
dia
gnos
is
Another benefit of genetic analysis in FH
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“with every success it gets harder to find the next one”
LDLR APOB
PCSK9
???
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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!
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