Cases and controls were matched on age, gender and smoking status and did not differ significantly with regard to other selected demographic characteristics (). On average, the study population was 62 years of age at baseline. As expected, never smokers comprised only a small percentage (~8%) of lung cancer cases.
Baseline characteristics of lung cancer cases and controls, Washington County, MD (1989–2005)
Among the controls, the frequencies observed for GSTM1
wild-type, hemizygous deletion, and homozygous deletion genotypes were 9%, 40%, and 50% respectively (). For GSTT1
, the distribution was 24%, 51%, and 20% for wild-type, hemizygous deletion, and homozygous deletion genotypes, respectively. These frequencies of GSTM1
homozygous deletion genotype seen in the controls were similar to those previously observed for Caucasians (8
). The tests for HWE showed no deviation (for GSTM1
: p-value = 0.80 and for GSTT1
Genotype distributions of GSTM1 and GSTT1 for selected characteristics separated by cases and controls
Compared to those with the GSTM1 wild-type genotype, the risks of lung cancer were 1.49 (95% CI =0.66–3.40) and 1.80 (95% CI = 0.81–4.02) for those with the hemizygous deletion and homozygous deletion genotypes, respectively (p- trend = 0.13, ). For GSTT1, compared to the wild-type genotype, the risks of lung cancer were 1.17 (95% CI = 0.71–1.92) and 1.06 (95% CI= 0.58–1.95) for those with the hemizygous and homozygous deletion genotypes, respectively (p-= 0.83). None of these associations were statistically significant.
The relative odds of developing lung cancer according to GSTM1 and GSTT1 genotypes, total and stratified by cigarette smoking characteristics, Washington County, MD (1989–2005)
When stratified by smoking status, the odds ratios for lung cancer among those with the hemizygous and homozygous deletion GSTM1 genotypes ranged between 1.40 and 1.99 in both former and current smokers (). Among those who smoked <=20 cigarettes per day equals to 1 pack or less per day, compared to the wild-type genotype the odds ratios were 3.06 (95% CI= 0.83–11.28; p-value= 0.09) for the hemizygous deletion genotype and 3.35 (95% CI= 0.94–11.86; p-value= 0.06) for the homozygous deletion genotype (p-trend= 0.12) (). In contrast, the odds ratios were slightly in the protective direction for smokers who smoked > 1pack per day. The p-value for the test for interaction by smoking intensity was 0.07.
The smoking-stratified results for GSTT1 were opposite those seen for GSTM1. Specifically, no associations were seen in ever smokers who smoked ≤1 pack per day, whereas among heavier smokers the associations for the hemizygous deletion and homozygous deletion GSTT1 genotypes were in the direction of increased risk.
To illustrate the potential value of the refined classification of GST genotypes that explicitly accounts for hemizygotes, we reanalyzed our data using the traditional null-versus-present comparison in which the referent group included the hemizygous deletion GSTM1 genotype. When the data were re-classified to conform to the traditional null-versus-present genotype, the risks associated with the GSTM1 genotype were always attenuated toward the null compared to the more refined classifications we presented in our primary analyses (Null vs present comparison, ). This was particularly true among lighter smokers among whom the odds ratios diminished from 3.35 to 1.31 for the GSTM1 homozygous deletion variant.