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CMAJ
CMAJ - November 3, 1998JAMC - le 3 novembre 1998

Lifestyle and genetic susceptibility

CMAJ 1998;159:1085

Dr. Michael M. Burgess and colleagues, in their article "Bioethics for clinicians: 14. Ethics and genetics in medicine" (CMAJ 1998;158[10]:1309-13 [full text / résumé]) correctly conclude that counselling patients at high risk for genetic diseases is complicated and may be associated with unexpected reactions. For example, from the caregiver's viewpoint it might seem obvious that a person with relatively high genetic susceptibility to a disease would be willing to modify some of his or her risk factors. However, patients may not reach this conclusion on their own.

As an example, we studied a family in which several members had early-onset coronary artery disease and virtually no high-density lipoproteins (HDL), the result of homozygosity for a truncated variant of apoliprotein (apo) AI.1 Although homozygosity for the apo AI mutation was clearly associated with increased risk of coronary artery disease, some elderly homozygous family members were unaffected. We found that risk factors such as smoking and hypertension modulated the onset and severity of the condition in homozygous people.2 When we informed these family members about their genetic susceptibility, some of them incorrectly inferred that the development of the condition was genetically predestined and that its future expression was outside their control. Therefore, they felt justified in continuing such high-risk behaviours as smoking. However, their attitude changed when we explained to them that (1) the relative hazard from genetic factors for a complex disease such as coronary artery disease was much smaller than that for a monogenic disease, such as cystic fibrosis,3,4 and (2) modifiable nongenetic factors contributed at least as much as genetic factors to the risk of coronary artery disease.3,4

Coronary artery disease results from the interaction of genetic and environmental factors, of which the latter are largely within an individual's control.4 The influence of a particular genetic factor in an individual at risk for this condition is usually the aggregate of many small effects.3 However, even in a family with a major gene affecting high-density lipoprotein metabolism, the expression of coronary artery disease can be delayed by modification of risk factors.2 For almost all complex diseases, the inherited factors create a background of susceptibility but are not the ultimate cause of the disease. With the potential for increased application of genomic diagnostic methods, health care providers must anticipate the full spectrum of patients' responses and allow sufficient time to properly explain test results.

Robert A. Hegele, MD
Blackburn Cardiovascular Genetics Laboratory
Robarts Research Institute
London, Ont.

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References

  1. Ng DS, Leiter LA, Vezina C, Connelly PW, Hegele RA. Apolipoprotein A-I Q[-2]X causing isolated apolipoprotein A-I deficiency in a family with analphalipoproteinemia. J Clin Invest 1994;93:223-9.
  2. Ng DS, Vezina C, Wolever TS, Kuksis A, Hegele RA, Connelly PW. Apolipoprotein A-I deficiency. Biochemical and metabolic characteristics. Arterioscler Thromb Vasc Biol 1995;15:2157-64.
  3. Hegele RA. The genetic basis of atherosclerosis. Int J Clin Lab Res 1997;27:2-13.
  4. 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.