Familial coronary artery disease Paul Brennan Clinical Director Northern Genetics Service Newcastle Hospitals NHS Foundation Trust North East and North Cumbria Genomic Medicine Centre Familial coronary artery disease Family history of CAD associated with ~1.5-2X increase in risk* MZ twins 44% concordant c.f. DZ 14% 40-60% of susceptibility is inherited * M>F What do we know so far? Gene: blue car Polymorphic variants: allowable variation at level of DNA code or protein sequence: Gene: blue car Polymorphic variants: allowable variation at level of DNA code or protein sequence: Single nucleotide polymorphisms (SNPs) Gene: blue car Mutation: Frequency in general population CAD risk Familial coronary artery disease Frequency in general population CAD risk 1/500 FH LDLR FH APOB PCSK9 FH LDLRAP1 Familial coronary artery disease AR AD Frequency in general population CAD risk 1/500 FH LDLR FH APOB PCSK9 FH LDLRAP1 Familial coronary artery disease AR AD INHERITED FAMILIAL / SPORADIC single gene polygenic + environment modifiers Frequency in general population 1/4 1/2 Familial coronary artery disease 9p21 het 9p21 hom CAD RR Frequency in general population 1/4 1/2 Familial coronary artery disease frequency 3VD 2VD 1VD 0VD CAD RR p21 het 9p21 hom Frequency in general population CAD RR 1/100 1/4 1/2 3/4 Familial coronary artery disease DIFFERENT SNPs (cross-sectional GWAS) Familial coronary artery disease 50 DIFFERENT SNPs These account for ~15-20% of the heritability (inherited susceptibility) BUT 40-60% of susceptibility is inherited, isnt it? missing heritability phenomenon maybe the stats are wrong maybe there are many more common variants maybe they dont have a simple additive effect maybe there are many more rare variants (samples too small to detect) Familial coronary artery disease 50 DIFFERENT SNPs Can we use them to refine clinical CAD risk? NOPE, NOT YET Familial coronary artery disease 50 DIFFERENT SNPs Can we use them to prevent or treat CAD? NOPE, NOT REALLY, YET Familial coronary artery disease 50 DIFFERENT SNPs NumberMechanismRelevance 15 conventional risk factors Lipid metabolism Blood pressure regulation PCSK9 inhibitors 35 unconventional Cell proliferation Endothelial function Thrombosis Unknown Potential targets for novel therapies Familial coronary artery disease KEY MESSAGES 1.Start by identifying Mendelian hypercholesterolaemia families 2.Wait for the impact of genetic studies on personalised medicine: Risk prediction Tailored therapies / chemoprophylaxis