Vitamin D receptor gene associations with pulmonary tuberculosis in a Tibetan Chinese population

Our comprehensive analysis of SNPs in VDR suggests that VDR genotypes and haplotypes associate with PTB risk. We found two PTB risk associated SNPs, rs11574143 and rs11168287, and one PTB protective SNP, rs11574079, in VDR. The other two VDR SNPs, rs7975232 and rs3819545, had did not associate with PTB susceptibility.

In previously published studies, there is no research reported that the association between VDR gene and PTB susceptibility. We for the first time studied the correlations between three SNPs (rs11574143, rs11168287 and rs11574079) in VDR gene and PTB susceptibility in a Tibetan Chinese population, rs3819545 showed no correlations with PTB susceptibility, and we got some valuable results. Further studies should involve some others regions and ethnic groups.

A few studies have analyzed the association between the VDR ApaI (rs7975232) polymorphism and TB susceptibility. A study conducted by Selvaraj et.al. in the Indian population shows that the ‘A/A’ genotype is associated with resistance to pulmonary TB in males, but not in females [21]. In a study carried out in pulmonary TB patients of south India, the Bb genotype of VDR BsmI was associated with susceptibility to TB, whereas A/A genotype of ApaI and B/B genotype of BsmI were associated with resistance to pulmonary TB [22, 23]. Our results are inconsistent with the results of some previously published studies, a possible explanation could be their ethnic differences.

Comparisons with other researches showed that population or various ethnicities give different results. Many studies have suggested associations between VDR SNPs and PTB in variety populations [22, 24, 25]. The different results shown by Central Indian and South Indian populations may be due to the diversity of these two Indian populations and their difference in origins [26]. A latest study was in accordance with those obtained by other authors for West African populations, but in total discrepancy with the results for Indian, Iranian and Chinese populations [27]. Several case-control studies, performed in populations with high TB incidence, had studied the correlation between the VDR gene polymorphisms and genetic susceptibility to PTB, but the results were inconclusive, presumably because the populations were ethnically and geographically different and genetically diverse [25, 28, 29]. Wei et al. reported no association was found between VDR polymorphisms (either allele or genotype) and susceptibility to pediatric PTB in the Chinese Han population [30]. Also, a study in Cambodia [31] and Tanzania [32] found no associations between VDR gene and PTB. These differing results could be caused by gene-environment interaction, gene-gene interaction, and gene-agent interactions. These reports suggest that the differing association results between VDR genotypes in different ethnic populations may result from gene-environment [33] and gene-gene interactions [34, 35].

There are other factors that may influence the results. It is known that before vitamin D enters the macrophage, inactive vitamin D in serum could be bound to vitamin D binding protein or in a free state. A recent study showed that VDR variant (rs7968585) can predict risk for hip fracture, cancer, myocardial infarction, and mortality among older Caucasian individuals with a low vitamin D status [36]. This association was only apparent in individuals with a low vitamin D status, highlighting the importance of taking into account gene-environment interactions. Vitamin D status appears to be involved in the activation of macrophages and restricts the intracellular development of mycobacteria [37]. This effect of vitamin D may be influenced by polymorphisms in the VDR gene. However, although the relationship between the internal environment and the host gene is unknown, it may explain the heterogeneity observed in the association studies and it should be addressed as an influencing factor. The polymorphic variants of VDR gene along with other gene and environmental factors may be responsible for an altered cell-mediated immunity against M. tuberculosis in a susceptible or resistant host. Although several investigators reported and suggested that the VDR polymorphism may be of immune-regulatory significance for PTB but it is not clear that the polymorphisms determine susceptibility to the development of clinical disease or susceptibility to infection. Further studies are required to determine how VDR polymorphisms influence susceptibility to infection or to clinical disease development. In order to understand the pathogenesis of pulmonary TB that is useful for prophylaxis and therapy. Ethnic-specific genetic association with TB susceptibility may guide TB therapy and prophylaxis in an ethnic-specific manner. A post hoc power analysis was conducted and the power analysis showed that except rs11168287, other SNPs failed to reach minimum level (80 %) for this case-control study. In this case, we could not conclude that the difference was not statistically significant, but need to increase sample size to verify. Future research should pay attention to this point.

Because we limited ethnicity of our subjects to Tibetan Chinese, and limited the locations of our subjects to Xi’an City and its surrounding area, there were no substantial population admixtures in our study populations. However, some limitations should be considered when interpreting our results. Our sample size was small and only included 217 PTB cases. Also, gene-environment and gene-gene interactions may effect VDR expression and activity. And the assessment of the environmental factors such as tobacco, diet and alcohol consumption and the possibility of inaccurate exposure should be considered. The susceptibility and resistance to PTB are the result of the interactions between environment, socioeconomic status and host genes, therefore, further studies are required to elucidate the complex associations between the VDR gene variants and the immune response against PTB. These data will lead to a better understanding of the immunological and genetic pathways in tuberculosis, and will provide new ideas for potential treatments and prophylaxes to reduce the prevalence and incidence of PTB caused by M. tuberculosis infections.