University of Copenhagen & Copenhagen University Hospital LDL polygenic risk scores in practice Anne Tybjærg-Hansen MD DMSc Professor, Chief Physician Copenhagen University Hospital and Faculty of Health and Medical Sciences, University of Copenhagen, Denmark FH Global Summit, Atlanta 211019 Outline • Introduction to polygenic risk score • Polygenic risk scores for LDL cholesterol and FH • Polygenic risk scores for CAD and FH – polygenic versus omnigenic scores • Take home message Introduction to polygenic risk score Genome-wide association study of LDL cholesterol (from GLGC) P<10-8 Willer CJ et al. Nat Genet 2013 Creating a polygenic score GWAS SNPs Individually: tiny effects ComBined: larger effect Effect of gene score on trait level 1.0 1.2 Odds ratio Genome-wide association study of LDL cholesterol Polygenic risk score P<10-8 Willer CJ et al. Nat Genet 2013 Genome-wide association studies (GWAS’) for lipids In sufficiently large samples, many ~ 100,000 previously non-significant loci would European ancestry become nominally significant, 95 loci although effect sizes are close to zero. ~ 600,000 ~85,000 non-Europeans ~200,000 >118 novel loci 7,898 non-Europeans (~268 known loci) 62 novel loci 30.4 mill SNPs Klarin et al. 2010 2013 2018 Polygenic risk scores for LDL cholesterol and Familial Hypercholesterolemia Rigshospitalet The Centre of Diagnostic Investigations Diagnostic criteria for FH 1/220 individuals • Definite FH: > 8 points • Probable FH: 6-8 points • Possible FH: 3-5 points • Unlikely FH: 0-2 points Mette Christoffersen 9 Rigshospitalet The Centre of Diagnostic Investigations Clinical vs. mutation diagnosis Polygenic cause? 20-40% High Lp(a)? 60-80 % Polygenic cause? Modified from Eur Heart J. 2013, 34:3478-3490 EAS Consensus Mette Christoffersen 10 Rigshospitalet The Centre of Diagnostic Investigations Previous work on polygenic risk scores in FH Lancet, 2013 LDL-C weighted gene score Mette Christoffersen 11 Rigshospitalet The Centre of Diagnostic Investigations •Genomewide polygeniC risk score on LDL •2 million SNPs (MAF>0.01) •MonoGeniC causes: LDLR, APOB, PCSK9, ABCG5/8 and LDLRAP1 Natarajan P et al. Nat Commun 2018;9(1):3493 Mette Christoffersen 12 Rigshospitalet The Centre of Diagnostic Investigations LDL-C >5% percentile 2% vs. 23% 0.8 mmol/L Natarajan P et al. Nat Commun 2018;9(1):3493 Mette Christoffersen 13 Polygenic risk scores for CAD and FH – polygenic versus omnigenic scores Extreme polygenic risk for CAD comparable to FH Odds ratio versus remainder 6.6 mill SNPs >400.000 individuals of population from UK BioBank 8% with ≥3-fold risk 2% with ≥4-fold risk 0.5% ≥5-fold risk FH-mutations (LDLR, APOB, PCSK9) Prevalence: 0.5% ~3-fold CAD-risk Fig. 2a Khera et al. Nat Genet 2018 Comparison with previous risk scores 1st percentile of score 1st percentile of score 1st percentile of score Prevalence for CAD: 5.9% Prevalence for CAD: 7.2% Prevalence for CAD: 11.1% 50 variants 49,310 variants 6,630,150 variants (%) prevalence CAD CAD Percentile of polygenic risk score Khera et al. Nat Genet 2018 Take home message • The risk of LDL cholesterol >5th percentile is similar in monogenic carriers of FH mutations and in individuals with a high polygenic score (top 5th percentile) • But the number of individuals with a high polygenic score for LDL cholesterol is app. 10-fold higher than for monogenic mutations • App. 8% of the population have a polygenic risk of CAD which corresponds to the risk of monogenic mutations for FH (≥3 fold) • But the number of individuals with a high polygenic risk of CAD is almost 20-fold higher • Omnigenic risk scores are (probably) superior to polygenic scores at predicting CAD risk That’s all folks! Clinical utility and unresolved issues Potential clinical implications and implentation • Scores are established at birth and can be used early in life • Practical considerations regarding type of technology used • Risk reporting: absolute score, its percentile compared to the general population, risk evaluation • Who would report and interpret the results? Unresolved issues • Which score model should be used? • Prospective replication • Standards for clinical validation • Ethnic based scores? • Sex specific scores? • Or one size fits all? • How will the score be integrated into an overall risk assessment? JACC October 2018 Conventional risk factors + genetic risk score Conventional risk factors Genetic risk score CAD prediction • >1.7 mill SNPs • 22,242 CAD cases • 460,387 controls from UKBiobank Khera et al. NEJM 2016 UK BioBank • N=500,000 • Recruited from 2006-2010 • 40-69 years old • 98% White • EXtensively phenotyped • Baseline questionnaire • Clinical endpoints from electronic health records • Biochemistry • DNA (GWAS n=500,000. Exome sequencing due in 2020) • Imaging (n=100,000) All data open for all researchers • 9 mill. invited, participation rate ~5% Modifiers of the penetrance of familial hypercholesterolemia mutations on coronary artery disease risk Sekar Kathiresan, M.D. CEO, Verve Therapeutics Cardiology Division, Massachusetts General Hospital Institute Member, Broad Institute, onleave Professor of Medicine, Harvard Medical School,on leave October 21, 2019 Disclosures Grants Equity Consulting Bayer Verve Therapeutics MedGenome, Color Novartis Maze Therapeutics Genomics, Novo Nordisk, Merck, Eli Lilly, Alnylam, Regeneron, Acceleron, Corvidia, Illumina 911 call: 42yo male with dizziness, profuse sweating 42yo male with fatal myocardial infarction (MI) MI risk factors Lipid To t a l cholesterol 241 mg/dl LDL cholesterol 167 mg/dl HDL cholesterol 40 mg/dl Triglycerides 170 mg/dl Non-lipid Blood pressure 120/80 mm/Hg Body mass index 26 kg/m2 Non-smoker No type 2 diabetes Two scientific questions Beyond LDLR, What might modify the APOB, PCv SK9, are there other genes penetrance of that cause FH? FH mutations on CAD risk? ABCG5 or ABCG8: sterol transporters, pump plant sterols back into intestine Eric Lee,slideshare ABCG5 or ABCG8 homozygous deficiency: sitosterolemia, high LDL, premature CAD Homozygous null Eric Lee,slideshare Berge, Science (2000) Does heterozygous ABCG5 or ABCG58 deficiency impact LDL or CAD risk? Heterozygous ABCG5 deficiency raises plasma sitosterol, LDL and CAD risk LDL Cholesterol 25 mg/dl higher ABCG5 loss of function mutations: Atherosclerosis roughly 1 in 1000 are carriers 2-fold increased risk Can now add ABCG5 to list of genes where coding mutations confer large effect on MI risk Gene Carrier Blood Clinical frequency biomarker Effect Low-density LDL 3-10 fold lipoprotein receptor 1 in 250 (LDLR) ATP-binding cassette transporter G5 1 in 1000 LDL 2-fold (ABCG5) Lipoprotein lipase 1 in 500 2-fold (LPL) TRL Apolipoprotein A5 1 in 3000 4-fold (APOA5) Apolipoprotein(a) 1 in 100 (LPA) Lp(a) 3-fold Do*, Stitziel* et al., Nature (2015) Khera*, Won* et al., JAMA (2017) Clarke et al., N Engl J Med (2009) 42yo male with fatal myocardial infarction family carried ABCG5 p.Arg446Ter Lipid To t a l cholesterol 241 mg/dl LDL cholesterol 167 mg/dl HDL cholesterol 40 mg/dl Triglycerides 170 mg/dl Non-lipid Blood pressure 120/80 mm/Hg Body mass index 26 kg/m2 Non-smoker No type 2 diabetes Two scientific questions What might modify the v penetrance of FH mutations on CAD risk? What might modify penetrance of an FH mutation on risk for CAD? FH Mutation LDL Cholesterol Atherosclerosis What might modify penetrance of an FH mutation on risk for CAD? Inherited Inherited Specific mutation Polygenic CAD score Polygenic LDL score FH Mutation LDL Cholesterol Atherosclerosis What might modify penetrance of an FH mutation on risk for CAD? Inherited Inherited Specific mutation Polygenic CAD score Polygenic LDL score FH Mutation LDL Cholesterol Atherosclerosis Non-genetic Non-genetic Lifestyle Lifestyle LDL-lowering therapy Traditional risk factors Therapy What might modify penetrance of an FH mutation on risk for CAD? Inherited Inherited Specific mutation Polygenic CAD score Polygenic LDL score FH Mutation LDL Cholesterol Atherosclerosis Non-genetic Non-genetic Lifestyle Lifestyle LDL-lowering therapy Traditional risk factors Therapy Two genetic paths to MI risk Polygenic Monogenic MI at age < 50 age-of-onset MI Polygenic model: capture risk through 6.6M common variants, distill genomic risk into a single # Gaussian distribution in population 0.4 0.3 0.2 Density Cases Controls 0.1 N=60K N=120K 0.0 −4 −2 0 2 4 Polygenic Score Khera*,Chaffin*,Nature Genetics (2018) Klarin et al., Nature Genetics (2017) Nikpay et al., Nature Genetics (2015) WTCC, Nature (2007) Deloukas et al., Nature Genetics (2013) McPherson et al., Science (2007) Samani et al., Nature Genetics (2011) Helgadottir et al., Science (2007) Kathiresan et al.,Nature Genetics (2009) High polygenic CAD score identified in 17% of early MI patients 100 patients à Risk with early myocardial infarction Monogenic 3.8-fold High polygenic 3.7-fold Do*, Stitziel*,Won*, Nature(2015) Khera*, Chaffin*,Circulation (2019) Does polygenic CAD score modify penetrance of FH mutations? UK Biobank: sequence for FH genes + calculate polygenic CAD score Dataset 1 Dataset 2 Akl Fahed CAD cases Controls Population-based N = 6.5K N = 6.5K N = 50K Amit Khera Fahed,Wang, Khera,unpublished Without considering polygenic background, FH mutation increases CAD risk 5.6 fold FH mutation carrier: average risk is OR 5.6 Fahed,Wang, Khera,unpublished Based on polygenic background, CAD risk for FH mutation can be refined: from OR ~1.0 to ~20.0 FH mutation carrier: Polygenic background average risk is OR 5.6 important Fahed,Wang, Khera,unpublished For an