The Molecular and Clinical Heterogeneity of

FH

G.Kees Hovingh MD PhDAMC, Amsterdam, the Netherlands

g.k.hovingh@amc.uva.nl

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.

FH, the traditional picture...

The same genotype may lead to extremely different phenotypes

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And people might look alike while not sharing the genotype..

FH diagnosis

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clinical +, mutation -

clinical -, mutation +

Simon BroomeDutch Lipid Criteria

FH; “one disease?”

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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

Range of LDL-C in heFH?

Besseling, Hovingh, work in progress

HoADH in the Netherlands

2 null alleles+1 null allele, 1 defective

2 defective alleles

HoADH in the Netherlands

Clinical Heterogeneity in daily life, outpatient clinic setting august 2015....

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)”

LDL-C 9mmol/LAMI age 51

LDL-C 3 mmol/L

LDL-C 6.5 mmol/L

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

LDL-C 9mmol/LAMI age 51

LDL-C 6 mmol/L

LDL-C 3 mmol/L

FH; a matter of selection bias?

Is the FH phenotype (LDL-C and CVD) attenuated with increasing distance-to-

index?

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

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]

* 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]

heFH; clinical diverse

CVD incidence in heterozygous FH

Does genetics matter?

Huijgen, Eur H J 2012 3(18):2325-30

Does genetics matter?

No !!!

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The new PCSK9??

if we do not sequence; we will

not get to this!

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Another benefit of genetic analysis in FH

“with every success it gets harder to find the next one”

LDLR APOB

PCSK9

???

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!