First, additional functional P2X7 promoter polymorphisms affecting expression levels (in addition to the promoter −762 locus) may also affect tuberculosis susceptibility (Li et al., 2002). Second, it is possible that the marker allele is in linkage disequilibrium with the true disease-causing variant (Fuller et al., 2009). Third, the differences observed between the respective studies may also be due to the effects of other genes, which may modulate P2X7 function, for example, the major histocompatibility complex class II loci, which is at least 50% linked to disease
risk (Rodríguez et al., 2002). Fourth, associations may be influenced by the ethnic (genetic) makeup of the individuals included in the association studies described. We also explored check details potential sources of heterogeneity. First, the uniformity of the control population (such as the study size, mean age and the latent tuberculosis-infected states) may be used
as characteristics for the assessment of heterogeneity. For example, the study size varies from 100 to 384 of −762 loci in the control population, and the mean age of controls varies from 5.9 to 46.1 years, with one study including children as research participants (Xiao et al., 2009); as for control population, this metaanalysis included a latent tuberculosis population in one study (Fernando et al., 2007), and thus these factors may be associated with the heterogeneity of −762 studies. Second, the discrepancy in the allele frequencies, which vary markedly between different ethnicity groups, may be a possible source of heterogeneity. For example, the 1513AC polymorphism described Silmitasertib concentration in the Gambian population (Li et al., 2002) was
observed to have a lower frequency (7.6%) than that in the Australian-Caucasian population (17.2%) or in the Australian-Vietnamese population (25%) (Fernando et al., 2007), and the −762 C allele frequency was higher in the Russian-Caucasian population (69.3% vs. 68.2%, control vs. case) than that in the Gambian population (32.9% and 25.4%, control vs. case). An additional consideration in exploring the causes of heterogeneity with molecular association studies is the possibility of a gene–environment interaction (Thakkinstian et al., 2005). Cases and controls were not sex-matched, Carnitine palmitoyltransferase II with the exception of one study (Li et al., 2002). However, provided that the ethnic background was similar among patients and controls, the lack of such matching should not have introduced bias in the estimates. The metaanalysis presented in this report demonstrated that the P2X7 1513 C allele appeared to be associated with tuberculosis susceptibility. In contrast, the −762 C allele did not correlate significantly with protection against tuberculosis infection. This analysis further suggests that caution must be exercised when interpreting association studies using small sample sizes that have a low power to detect accurate allelic associations with disease susceptibility.