Discussion
Hayashi S et al. In 1992 (Supplemental Table 1) first reported an
association on the CYP1A1 T3801C and A2455G polymorphisms and
with CRC risk. So far, a lot of studies have performed the above two
issues. However, the results are still inconsistent. Moreover, seven
previously published meta-analyses [16– 22] have arrived at
significant disagreement results, especially in different races, as list
in supplemental Tables 6 and 7. Moreover, As far as we know that this is
the first meta-analysis to investigate the significant results by BFDP
test to avoid confounding factors.
The CYP1A1 T3801C polymorphism was associated with rectal cancer
risk in overall races and CRC risk in females; the CYP1A1 A2455G
polymorphism was associated with an increased CRC risk in overall
analysis, Caucasians, Europe countries populations, and males. Five
genetic model and several subgroup analyses was conducted, this analysis
came at the cost of multiple comparisons, in this instance, the pooled
OR with their 95% CI must be adjusted to avoid the false positive
results [32]. Wakefield et al. [31] provided a precise Bayesian
measure of false discovery to adjust the positive results. The method
especially suited for SNP and disease susceptibility study. Therefore,
we applied BFDP value to evaluate the positive results in this study.
After we further performed a sensitivity analysis and BFDP test, BFDP
> 0.8 were found in all analyses.
Therefore, these positive associations might most likely result from
false-positive results, rather than from true associations or biological
factors. The reason may be because some small sample and low-quality
studies were easier to accept if there was a positive report. They tend
to yield false-positive results because they may be not rigorous and are
often of low-quality. In addition, controls of HWD may be genotype
errors and selection bias in molecular epidemiological studies.
Therefore, we performed a sensitivity analysis restricted to studies
that only included high-quality articles and controls of HWE.
Supplemental Tables 6– 7 list the results of seven previously
published meta-analyses [16-22] on the CYP1A1 T3801C and
A2455G polymorphisms with CRC risk, respectively. The largest sample
size study [19] was performed in 2014 involving 18 studies (7,171
cases and 8,957 controls) for the CYP1A1 T3801C polymorphism; on
the CYP1A1 A2455G polymorphism, The largest sample size study
[16] was reported in 2016 including 20 studies (8665 cases and 8853
controls). Several studies should be excluded in the above two studies
[16, 29]. The present study included 27 studies (9,672 cases and
12,689 controls) on the CYP1A1 T3801C polymorphism and 24 studies
(8,933 cases and 11,692 controls) on the CYP1A1 A2455G
polymorphism with CRC risk. In addition, four previous meta-analyses
[16, 18, 19, 21] reported the association on the CYP1A1T3801C polymorphism with CRC risk, only a meta-analysis [18]
observed a significant decreased CRC risk in Chinese population; another
three meta-analyses found that the CYP1A1 T3801C polymorphism was
not significantly associated with CRC risk; five published meta-analyses
[16, 17, 20– 22] have been performed to investigate the
association on the CYP1A1 A2455G polymorphism with CRC risk. Of
these, four studies [16, 20– 22] reported a significantly
increased CRC risk in Asians and Caucasians and one study [17]
observed a significantly increased CRC risk in Asia and Europe, but not
in America. These results of previously published studies were not
consistent, especially in ethnicity. An obvious inconsistency was found
in classification of ethnic groups among these published meta-analyses,
cells with red color in supplemental Table 1. Moreover, we still found a
significant difference on the HWE of controls in these published studies
(cells with blue color in supplemental Table 1). In addition, previously
published meta-analyses involved incomplete studies and some repeat
studies. All studies did not adjusted significant results for multiple
comparisons. Therefore, their meta-analyses are still incredible.
Though all our efforts were made to improve our research, the current
study still exist several limitations. First, only published articles
were included while positive results are known to be published more
readily than negative ones. Second, several subgroup analyses only
included small sample size, such as in smoking subgroups (Table 2 and
Table 3), the results should be interpreted with caution and it is
necessary that a well-designed large sample study to explore the true
association. Third, we did not collect the adjusted data because the
original study provided little information. Hence, a more precise
analysis should be performed when enough data was available in future.
In summary, this study suggests that these positive findings may most
likely result from false-positive results, rather than from true
associations or biological factors.