Post on 19-May-2020
Cardiovascular riskGenetic risk and life style
Jean-Luc Vandenbossche MD, PhD
Cardiology CHU Saint-Pierre
Bruxelles
Genetic risk in cardiology: new insight from
genomic analysis
Genetic risk and C-V diseases
Are CV diseases genetically determined?
If Yes, Is there still a place for prevention?
CV diseases are “preventable”(?)
• InterHeart study Lancet 2004: 90% preventable
• “Family history”: a correcting factor of the SCORE
• Did Human genome project provide new useful information?
Interheart
PAR: population attributable risk / % de risqueattribuable au facteur de risque.
Muller C. Xanthomata, hypercholesterolemia, angina pectoris.Acta Med Scand 1938; 89: 75-84.
Gertler MM, Garn SM, White PD. Young candidates for coronary heart disease.J Am Med Assoc 1951; 147: 621-5.
Slack J, Evans KA. The increased risk of death from ischaemic heart disease infirst degree relatives of 121 men and 96 women with ischaemic heart disease.J Med Genet 1966; 3: 239-57.
Marenberg ME, Risch N, Berkman LF, Floderus B, de Faire U. Genetic susceptibility to death from coronary heart disease in a study of twins.N Engl J Med 1994; 330: 1041-6.
Lloyd-Jones DM, Nam BH, D’Agostino RB Sr, et al. Parental cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults: a prospective study of parents and offspring. JAMA 2004; 291: 2204-11.
FAMILY HISTORY: any significant CV event within 1° or 2° relatives, <55 years for Men and >65 Years for Women
Clinical case
• A 50y old woman asks for her personal CV risk, her 48 y old brother having presented an AMI.
-Her brother, smokes 2P/d since age of 18 y; is obese , unemployed
OR
- Her brother is a sportsman, never smoked, is vegetarian, and has a university degree
Our study also found that subjective, self-reported family history
of CHD and objectively measured genetic risk are not redundant.
Both can contribute to a better assessment of a patient’s CHD
risk because a GRS-based genetic risk measure is associated with
CHD independent of self-reported family history of CHD, as well
as established risk factors, that is, self-reported family history is
not a substitute for genetic risk assessment. Since family history
reflects both genetic and non-genetic factors, and since the
accuracy of patient reported family history is low, this non-
redundancy of self-reported family history and genetic
assessment is not surprising.
No obvious risk factors but…
• The 48 y o brother had a LDL chol of 250mg% and tendinous xanthoma
OR
• The 48 y o brother had a LDL chol of 145 mg%
- Her brother is a sportsman, never smoked, is vegetarian, and has a university degree
Genetics has to play a role
• In the first case, suspicion of a Monogenic disease ( Familial Hypercholesterolemia-heterozygote): CV risk X4 (prevalence 1/250-500; 25000 cases in Belgium- only 4 % identified!)
• In the second case, this premature cardiac event without obvious cause carries most probably a non monogenic but polygenic risk
NATURE REVIEWS | GENETICS published on line 13 march 2017
200
Nucléotide
SNP: single nucleotide polymorphism
Toutes les 300 paires de base, la base peut varier dans la population (héritage ancestral). Le plus souvent deux possibilités ( deuxallèles). Il faut qu’ un allèle soitreprésenté au moins dans >1% de la population pour le considérercomme un SNP.
Every other 300 base pairs, the base may vary in the general population ( heritage from ancestral mutations). Most of the time only 2 options ( 2 alleles). To consider as a SNP, each allele has to be present at least in> 1% of the population.
Segment invariant
SNPs (10 M) explains >90% of the inter-individual variability.
As all our SNPs are transmitted to our children, it explains the great similarity between parents and offspring ( each parent giving one allele, if you possess both unfavorable alleles, the genetic risk will increase)
Explains huge interindividualvariability
intron
Exon
SNPs are located in “loci”: these loci can be outside of a gene and without any effect; Loci close to genes( in regulatory sequences) can modulate the activity of the gene. Most of the loci identified for an association with CV disease are within this region.
Disease causal pathways
Genotype score: sum of numbers of unfavorable alleles for 9 SNPs ( 0-18)
Disease causal pathways
Population characteristics
Take Home messages
• 20% of the general population has a 2 X ( polygenic ) risk, identifiable very early in life , more predictably than by the ongoing “ family history”.
• Optimal life style can reduce this risk by 50%.
• Higher risk patients have a greater clinical response to statins than others.
• More studies should confirm that early treatment with statins or other new treatments could further eliminate their residual increased risk, in adjunction with life style measures.
• 0.2% of the general population has a 4 X risk (FH)!