A rare variant at 11p13 is associated with tuberculosis susceptibility in the Han Chinese population.

According to the WHO 2014 global tuberculosis (TB) report1, China has the second largest number of incident TB cases, which accounts for 11% of the global burden. Moreover, the recent TB infection survey conducted in China indicated that one-fifth of the population had been latently infected by Mycobacterium. tuberculosis (M. tb)2. Although a majority of the M. tb-infected population will not progress to clinical TB because of host resistance to the pathogen, it was estimated that approximately 10% of infected individuals will develop TB disease during their lifetime3. The large reservoir of infected people is a crucial threat to China’s TB control program for achieving the END TB goal in 20354. Whether a person who is latently infected with M. tb would become a clinical case may largely depend on the host defense against M. tb. The vast difference between M. tb infection rate and population TB incidence suggests that the human host plays an important role in preventing TB development after infection. Evidence from studies of twins also support the assumption that host genetics contribute to the susceptibility of TB5. In recent years, TB candidate genes, such as the vitamin D receptor gene6, cytokine genes7, and toll-like receptors genes8, have been studied to explain host genetic susceptibility to TB in various ethnic backgrounds. However, due to limited sample sizes and/or the diversity of ethnicity, evidence of the association between hot spot loci of candidate genes and TB susceptibility is still rare. Genome-wide association studies (GWASs) have provided a large amount of information regarding the genetic contribution of hundreds of thousands of genomic variants to TB susceptibility9,10,11, and some of the variants were highly associated with TB susceptibility. However, no GWAS of TB predisposition has been conducted in China yet. Common variants of the genome usually have little effect on common disease risk, usually conferring small odds ratios on disease risk effect. Recently, Rivas et al. proposed that rare variants would have a larger effect and higher penetrance in disease occurrence12. In this study, we selected SNPs with allele frequencies of less than 5% in the Han Chinese population and that were found to be significantly associated with TB by previous GWASs. Thus, the single nucleotide polymorphism (SNP) rs2057178 at 11p13 and the SNP rs4331426 at 18q11.2, which were identified in previous GWASs, were selected to verify their association with TB predisposition10,11. More importantly, the suggestion of Wilkinson13 was adopted to test the latent TB infection status of the control group to control for the exposure factor of M. tb infection in this study. Meanwhile, the Gene Expression Omnibus Database was used to explore the relationship between the selected SNPs and whole genome mRNA expression levels14,15. Lymphoblastoid cell lines, which carry the complete set of germline genetic material, have been instrumental, in general, as a source of biomolecules and as a system to carry out various immunological and epidemiological studies16. Dissemination of M. tb in infected persons may be connected with the initiation of adaptive immune responses, which are under strict host genetic control17. The transcriptome level among the lymphoblastoid cell lines may be closely associated with disease-associated genetic variants. Thus, we consider that specific gene expression levels in lymphoblastoid cell lines may be closely regulated by host genomic variants. RNAs extracted from lymphoblastoid cell lines of the 45 unrelated CHB of the HapMap Project were quantified to explore the relationship between selected SNPs and the expression levels of potential TB susceptibility genes.