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)!