Interaction of the glutathione S-transferase genes and cigarette smoking on risk of lower extremity arterial disease: the Atherosclerosis Risk in Communities (ARIC) study

Atherosclerosis. 2001 Feb 15;154(3):729-38. doi: 10.1016/s0021-9150(00)00582-7.


Glutathione S-transferases M1 or T1 (GSTM1/GSTT1) affect the body's ability either to detoxify or to activate chemicals in cigarette smoke. Cigarette smoking increases the risk of lower extremity arterial disease (LEAD). We conducted a cross-sectional study to evaluate a hypothesized interaction of the genetic polymorphisms of GSTM1 and T1 with cigarette smoking in the risk of LEAD in the ARIC study. A stratified-random sample, including 212 LEAD cases (ankle-brachial index <0.9 in men or <0.85 in women) and 1277 non-cases, was selected from the ARIC cohort of 12041 middle-aged participants free of CHD, transient ischemic attack and stroke at baseline (1987-1989). Overall, the differences in the frequencies of GSTM1-0 and GSTT1-0 (the homozygous deletion genotype) were not statistically significant between cases and non-cases (44 vs. 41% and 28 vs. 18%). However, smoking was more prevalent among LEAD cases than non-cases. The results suggest that the non-deletion genotype GSTM1-1 interacts with smoking to increase the risk of LEAD, but this interaction was not statistically significant. The functional genotype GSTT1-1 was significantly associated with increased risk of LEAD given smoking after adjustment for other risk factors. In individuals with GSTT1-1, the odds ratios (ORs) (95% confidence intervals) of LEAD were 3.6 (1.4, 9.0) for current smoking and 5.0 (1.9, 13.0) for 20+ pack-years. However, in those with GSTT1-0, the ORs were 0.8 (0.2, 2.8) for current smoking and 0.6 (0.1, 2.1) for 20+ pack-years. The interaction was significant (P<0.05) on the additive scale for current smoking and on both the additive and multiplicative scales for 20+ pack-years. Among non-smokers, GSTT1-1 was not associated with LEAD. The results suggest that the GSTT1-1 polymorphism may be a susceptibility factor modifying the risk of LEAD associated with cigarette smoking.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Arteriosclerosis / etiology*
  • Arteriosclerosis / genetics*
  • Cross-Sectional Studies
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease*
  • Genotype
  • Glutathione Transferase / genetics*
  • Humans
  • Leg / blood supply*
  • Male
  • Middle Aged
  • Odds Ratio
  • Risk Factors
  • Smoking / adverse effects*


  • glutathione S-transferase T1
  • Glutathione Transferase
  • glutathione S-transferase M1