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atherosclerosis - risk factors and molecular genetics

Risk Factors:

major risk factors:

hypercholesterolaemia & hypertriglyceridaemia:

  • risk of IHD doubles when average popn cholesterol increases from 5.5mM to 6.5mM
  • an increase in 1% in LDL levels in medium term follow up is associated with a 2% increased risk of IHD, whilst in the longer term, there is a 3-4% increased IHD risk
  • strength of total cholesterol as a risk factor for IHD falls with increasing age b/n 40-60yrs. after which it remains stable
  • HDL-C levels are strongly & inversely correlated with IHD risk in both men & women:
    • 1% descrease is assoc. with 3-5% increase in IHD risk
    • levels < 0.9mM predict increased IHD risk at all TG levels
      • these levels are fequently observed in those with premature IHD with normal total chol.
      • predict future IHD in those with normal total chol. & previous IHD
  • ratio of total chol:HDL chol. is the single most powerful predictor of IHD risk
  • TG levels are more strongly correlated with IHD risk in women than in men
  • apo A-I & apo B may be more powerful predictors of IHD risk than either HDL or LDL alone
  • apo E4 allele may be a risk for IHD & for re-stenosis after coronary angioplasty
  • Lp(a) may be a risk for IHD
  • diet and its affect upon the gut microbiome may have a significant role in hyperlipidaemia, hypertension, diabetes and the development of atherosclerosis1)


  • continuous, linear association between systolic & diastolic BP and AMI
  • overall, HT is associated with 2-3x increase in IHD mortality rates
  • LVH:
    • associated with increased risk for AMI and for sudden death
    • NB. echocardiography assessment for LVH shows 7x prevalence than does ECG criteria

cigarette smoking:

  • 1 packet/day ⇒ 2x risk of IHD
  • long term smoking correlates with severity of atherosclerosis
  • also lowers HDL-cholesterol


  • synergistic as well as independent risk factor for IHD, atherosclerosis

minor risk factors:

family history:

  • parental death from IHD has similar strength of association to IHD risk as does BP, cholesterol & smoking

physical inactivity:

  • BUT strenuous physical activity may trigger plaque rupture!
  • regular exercise reduces IHD risk & reduces rate of recurrent AMI

male gender:

  • male:female relative IHD mortality rates/100,000 pop. in Australia in 1995:
    • < 50yrs: 5.1:1; 60yrs: 3:1; 70yrs: 2:1; 80yrs: 1.5:1;


  • for each 5yr increase in age, IHD death rates almost double for both men & women:
  • male IHD mortality rates/100,000 pop. in Australia in 1995:
    • 60-64yrs: ~400; 70-74yrs: ~1200; 75-79yrs: 2000; 80-84yrs: ~3100; >84yrs: 5000;


  • presumably via coronary spasm &/or haemodynamic changes may trigger plaque rupture


high carbohydrate intake


clotting factors:

  • fibrinogen
  • plasminogen activator inhibitor I
  • vWf


  • dietary vitamin E, flavenoids (eg. red wine) act as anti-oxidants and may be protective for IHD
  • dietary omega-3 fatty acids (eg. fish) > 2meals per week reduced IHD by 50% & reduced reinfarction & mortality post-AMI by 30%
  • saturated fats and trans-fatty acids increase total cholesterol
  • moderate alcohol consumption appears to reduce IHD risk by 20%
  • one additional serving of red meat per day increases mortality risk by ~13%
  • dietary carnitine (red meat, energy drinks) is converted to TMAO by TMAO-producing bacteria in the gut (vegans do not generally have these bacteria), and TMAO in the blood appears to increase rate of atherosclerosis development


  • 2.3kg weight gain (1 body mass index unit) reduces HDL-cholesterol by 5% as well as increasing levels of LDL & VLDL
  • women aged 30-55yrs with BMI >30 had 6.3x risk of HT than BMI < 20
  • women who gained 25kg weight since they were 18yrs had 5.2x risk of HT
    • Ref: Ann Int Med 1998 Jan 15; 128: 81-8;
  • much of risk is due to associated hyperlipidaemia. hypertension, diabetes, but:
    • abdominal obesity has an independent effect, increasing cardiovascular & all-cause mortality in men
    • in a US Cancer prevention study with 12yr follow up of people excluding: smokers, PH heart disease, stroke, cancer, recent unintentional weight loss, in poor health, died in 1st yr of F/U, or non-white, 62,116 men & 262,019 women were followed up:
      • for each increase of 1 in BMI, CVD mortality over the 12yrs increased by:
        • males: 10% for 30-44yrs old; 3% for 65-74yrs old;
        • females: 8% for 30-44yrs old; 2% for 65-74yrs old;
        • ref: NEJM 1998 Jan 1; 338:1-7.


  • Australian aboriginals & NZ maoris have IHD rates 2.7x national average - for young & middle aged: 10-20x greater
    • due to HT, smoking, diabetes, obesity, excessive alcohol consumption
  • Maltese in Australia

socio-economic groups:

molecular genetics:

genes associated with ischaemic heart disease (IHD) with well-defined phenotypes:

  • familial hypercholesterolaemia (FH):
    • HZ prevalence 1:500
    • underlies only a small % of IHD
    • > 150 mutant alleles identified (chromosome 19p13.3)
      • ⇒ impaired function of LDL receptor
  • familial defective ApoB (FDB):
    • defective binding of apoB to the LDL receptor (chromosome 2q24-p23)
      • ⇒ abnormal clearance of LDL particles
    • not all have high levels of LDL cholesterol & expression of IHD is variable
  • type III hyperlipoproteinaemia:
    • apoE2/E2 phenotype (chromosome 19q13) + other abn. (eg. hypothyroidism/diabetes)
      • ⇒ impaired clearance of TG-rich remnant particles via hepatic apoE receptor
        • ⇒ raised cholesterol & TG levels, tendon & palmar xanthomata, peripheral & coronary atherosclerosis (although accounts for small % of IHD)
  • familial combined hyperlipidaemia (FCH):
    • probably due to HZ expression of several well-characterised recessive disorders (eg. liporotein lipase defic.)
      • ⇒ small dense LDL particles (“pattern B” LDL), raised apoB, low HDL-C, raised chol. & TG
  • homocysteinaemia - 10% of pts with “unexplained” IHD

genes associated with IHD, phenotype not fully defined:

  • ACE gene:
    • ? significance of DD allele
  • ApoAI/CIII/AIV cluster:
    • ? significance of these genes - a polymorphism defined by 4 restriction enzymes explained 80% of the excess risk assoc. with FH of IHD in a Scottish study

other candidate genes for atherosclerosis:

  • all biologic processes implicated in pathogenesis of atherosclerosis are likely to have genetic determinants
    • BP control
    • response of endothelium to shear stress
    • cellular cholesterol homeostasis
    • interactions with the arterial wall
    • lipoprotein oxidation
    • immune responses
    • angiogenesis
atherosclerosis_riskfactors.txt · Last modified: 2020/06/18 19:01 by gary1