(Hi)story of Lp(a) into the CV arena Florian Kronenberg Medical - - PDF document

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Apr 25, 2023 101 likes •296 views

(Hi)story of Lp(a) into the CV arena Florian Kronenberg Medical University of Innsbruck, Division of Genetic Epidemiology Disclosures Speaker honoraria: Kaneka, Fresenius, Miltenyi Biotec Advisory activities: Kaneka, Amgen No support

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(Hi)story of Lp(a) into the CV arena

Florian Kronenberg

Medical University of Innsbruck, Division of Genetic Epidemiology

Disclosures

■ Speaker honoraria: Kaneka, Fresenius, Miltenyi Biotec ■ Advisory activities: Kaneka, Amgen ■ No support for research activities from companies

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2 Overview or how to set the stage

1. The long bumpy ride into the CV arena 2. The black hole of LPA 3. Therapy: the future has already started

I apologize that not every milestone can be mentioned

First indications that Lp(a) might make it into the CV arena

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3 First time mentioning of a 30 and 50 mg/dL threshold ? The discovery of the apo(a) size polymorphism F B B S1 S1 S1/S2 S1 S2 S3 S4

Utermann et al.: J. Clin. Invest. 80: 458-65, 1987

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KIV2 KIV1 KV P

n = 1 to >40 KIV2 copies

KIV3 KIV4 KIV5 KIV6 KIV7 KIV8 KIV9 KIV10

3‘ 5‘

20 KIV2 repeats (=29 KIV repeats)

Apolipoprotein(a)

(Mr ≈ 300‐800 kDa)

10 to >50 KIV copies Fibre‐FISH

Association of apo(a) isoforms and Lp(a) concentrations

53 47 48 10 7 13 9 7 4 0.6 10 20 30 40 50 60 11-16 17-19 20-22 23-25 26-28 29-31 32-34 35-37 >37 Null

Number of K-IV repeats Median Lp(a) mg/dL Molecular weight

low (LMW) = small high (HMW) = large

J. Int. Med. 273: 6-30, 2013 (updated)

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5 The hard start in prospective studies Editorial Lp(a) and risk for myocardial infarction

Results from the Copenhagen City Heart Study

Kamstrup et al.: JAMA 301:2331-9, 2009

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6 Oxidized phospolipids arrive in the arena

Tsimikas et al.: J.Am.Coll.Cardiol. 47:2219-28, 2006

Results from the Bruneck Study

Oxidized phospolipids arrive in the arena

Kiechl et al.: Arterioscler.Thromb.Vasc.Biol. 27:1788-95, 2007

HR = 2.4 (1.3-4.3) HR = 2.8 (1.6-5.0)

Results from the Bruneck Study

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Mendelian Randomization studies: the strong support for causality

Small apo(a) isoforms

strong association (explains about 50%) association?  causality?

High Lp(a) CHD

association

Lp(a) and CHD: Mendelian randomization Do carriers of small apo(a) isoforms more often have CHD?

"reverse causation" determined at the time of conception

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10 20 30 40 50 60 Tyrolean Welsh German Israeli Chinese Indian

Controls CHD

Apo(a) isoforms and risk for CHD

Combined OR = 1.78 p<0.001 % % of controls / patients with small apo(a) isoforms Populations

Sandholzer et al.: Arterioscler Thromb 12: 1214-26, 1992

Lp(a) concentrations, apo(a) isoforms and CVD

Small apo(a) isoforms

strong association (explains about 50%)

High Lp(a)

strong association

Kronenberg & Utermann:

J. Int. Med. 273: 6-30, 2013

25-35% of the population

CVD

association

causal association

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9 SNPs as risk factor for CHD: revitalization for the field

%

Clarke et al.: NEJM 361: 2518-28, 2009

rs10455872 as risk factor for CHD

Clarke et al.: NEJM 361: 2518-28, 2009

■ This SNP is associated with higher Lp(a) levels ■ Claimed that this SNP tags small apo(a) isoforms

Compared to 2.08 for small apo(a) isoforms

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Large 76% Small 24%

Apo(a) phenotypes Non‐Carrier 97% 3% Carrier Non‐Carrier 51% 49% Carrier rs10455872

r rs3798220

rs10455872

r rs3798220

Carrier-status of the 2 SNPs as marker for small isoforms?

J. Int. Med. 276: 243-7, 2014 (updated)

Do they get the wrong message? Results from the KORA Study in 5999 subjects

Effect of 49 independent Lp(a)-associated SNPs on CAD risk

CAD data retrieved from CARDIoGRAM consortium (GWAS on CAD risk; n =60,000 cases + 120,000 controls)

Risk increase proportional to Lp(a)-effect
7 SNPs even genome-wide significant

in LD with rs3798220 in LD with rs10455872

For each copy of the minor allele (MAF~1%):

Effect on Lp(a): ~65 mg/dL
CAD risk: OR= 1.73

Mack et al.: J. Lipid Res. 58:1834-44, 2017

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11 Overview or how to set the stage

1. The long bumpy ride into the CV arena 2. The black hole of LPA 3. Therapy: the future has already started

Apo(a) K-IV repeat polymorphism

Special characteristics:

95% are heterozygous at DNA level
50% express only 1 isoform in plasma
<1% express no isoform in plasma

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<15 15-30 30-45 45-60 >60

Large variance in Lp(a) levels in various apo(a) isoform classes

Lipoprotein(a) mg/dL

% <15 15-30 30-45 45-60 >60

11-18 19-22 33% with low concentrations Small isoforms

<15 15-30 30-45 45-60 >60 <15 15-30 30-45 45-60 >60 <15 15-30 30-45 45-60 >60

Large isoforms 8% with high concentrations

KORA F3+F4, n=6221

23-28 29-34 >34 K-IV Other genetic variants that modulate Lp(a) levels?

Structure of apolipoprotein(a) ■ Hard to resolve with Next Generation Sequencing ■ Mutations in this repetitive region?

Molecular weight of apo(a) 300-800 kD

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Coverage in the ExAC project browser (>60.000 exomes)

KIV-2 repeat region No (reliable) variation information

http://exac.broadinstitute.org/gene/ENSG00000198670

Variation in the LPA KIV-2 region is not easily accessible ■ Up to 70% of the protein are coded in the KIV-2 and are thus not accessible to common

mutation screening

■ A robust KIV-2 screening method is required for mutation screening in this white spot

Ultra‐deep “batch NGS sequencing”

■ All KIV-2 are amplified as a mixture using primer binding to all repeats (“batch sequencing”) ■ Developed a low level variant caller for the KIV-2 region: all reads are mapped to one KIV-2

repeat

■ Variants down to 0.5-1% mutational level can be called

Coassin et al.: Eur. Heart J. 38:1823-31, 2017 Coassin et al.: J. Lipid Res. 60:186-99, 2019

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14 KIV‐2 exon 1 KIV‐2 exon 2

15 30 45 60 75 90 105 120 135

Number of probands [n]

KIV2 region might be more variable than previously thought

Screening in 123 samples from GCKD and SAPHIR G4925A located at an exonic splice donor site

Coassin et al.: Eur. Heart J. 38:1823-31, 2017 Coassin et al.: J. Lipid Res. 60:186-99, 2019

G4925A frequency and effect on Lp(a) levels and CVD

■ Splice site variant ■ Competitive allele-specific TaqMan

PCR („castPCR“)

■ Genotyping in population-based

study (n=2892)

■ 22.1% Carrier frequency ■ Clusters in isoforms 19-25 ■ Reduces Lp(a) by 31 mg/dL ■ Explains 20.6% of Lp(a) variance in

LMW carriers

■ Associated with lower CVD risk

Coassin et al.: Eur. Heart J. 38:1823-31, 2017

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15 A bit more complicated due to a mutation in a white spot

Coassin et al.: Eur. Heart J. 38:1823-31, 2017

Overview or how to set the stage

1. The long bumpy ride into the CV arena 2. The black hole of LPA 3. Therapy: the future has already started

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16 Lp(a)-lowering by IONIS antisense to apo(a)

Viney et al.: Lancet 388:2239-53, 2016 Sam Tsimikas

How much should Lp(a) be decreased?

Burgess et al.: JAMA Cardiol 3:619-27, 2018

A change in Lp(a) levels of 101.5 mg/dL is required to have the same effect on CHD risk as a 38.67-mg/dL change in LDL-cholesterol

Brian Ference

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SADE.ALI.19.03.0722

■ HPS2-THRIVE 2018: 50-60 mg/dL can be deducted ■ Burgess et al. JAMA Cardiol 2018: 101.5 mg/dL (MR-approach) ■ Lamina & Kronenberg, JAMA Cardiol. 2019 : 65.7 mg/dL (MR-approach) ■ FOURIER trial 2019: patients with higher Lp(a) levels showed a tendency to a

stronger risk reduction

■ ODYSSEY trial 2019: lowering of Lp(a) and LDLC contribute independently to

MACE reduction

lowering of Lp(a) by 41 mg/dL lowers MACE by 22%

Summary of the estimates for required Lp(a)-lowering

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■ Lp(a) is one of the most important genetically determined risk factors for CVD ■ There were many ups and downs during the ride into the CV arena ■ Genetic Mendelian randomization studies strongly support causality ■ These studies also provide estimates by how much Lp(a) should be lowered